General Information

Among women in the United States, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2024, an estimated 313,510 new cases of breast cancer (including 2,790 cases in men) will be diagnosed, and 42,780 deaths (including 530 deaths in men) will occur.[1] The incidence of breast cancer, particularly for estrogen receptor (ER)–positive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003. This may be temporally related to a decrease in hormone replacement therapy (HRT) after early reports from the Women’s Health Initiative (WHI).[2] An estimated 19,680 new cases of ovarian cancer are expected in the United States in 2024, with an estimated 12,740 deaths. Ovarian cancer is the sixth most deadly cancer in women.[1] An estimated 67,880 new cases of endometrial cancer are expected in the United States in 2024, with an estimated 13,250 deaths.[1] (Refer to the PDQ summaries on Breast Cancer Treatment; Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment; and Endometrial Cancer Treatment for more information about breast, ovarian, and endometrial cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (refer to the Risk Factors for Breast Cancer, Risk Factors for Ovarian Cancer, and Risk Factors for Endometrial Cancer sections below for more information), and by the observation of some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many families. (Refer to the PDQ summary Cancer Genetics Overview for more information about linkage analysis.) Pathogenic variants in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

Risk Factors for Breast Cancer

This section discusses factors that can modify an individual's risk of developing breast cancer. These risk factors can affect women in the general population, women who have a family histories of breast cancer, and women who carry pathogenic variants in breast cancer risk genes. For more information on breast cancer risk factors in the general population, see Breast Cancer Prevention, and for more information on risks associated with BRCA1/2 pathogenic variants, see the Cancer Risks, Spectrum, and Characteristics section in BRCA1 and BRCA2: Cancer Risks and Management.

The following breast cancer risk factors are discussed in this section:

• Age.
• Family history of breast cancer.
• Benign breast disease, mammographic density, and background parenchymal enhancement.
• Parity, age at first birth, and breastfeeding.
• Contraceptives.
• Hormone replacement therapy (HRT).
• Radiation exposure.
• Alcohol and smoking.
• Physical activity.

These factors can increase or decrease breast cancer risk in all women. However, they may affect breast cancer risk differently in women with increased breast cancer susceptibility (i.e., women who have high-risk family histories and/or pathogenic variants in hereditary breast cancer genes). Factors that increase breast cancer risk in the general population may lower breast cancer risk, increase breast cancer risk more than expected, or have no effect on breast cancer risk in women with high breast cancer susceptibility. In some cases, these risk factors may affect high-risk women in the same way that they affect average-risk women. Furthermore, modifying risk factors has a greater effect on the absolute breast cancer risk in women with high breast cancer susceptibility than in women with low breast cancer susceptibility.[3] It is imperative that providers discuss breast cancer risk factors with high-susceptibility patients, since risk patterns deviate from those seen in women in the general population. Providers may also want to convey whether these risk factors increase, decrease, or do not affect breast cancer risk in women with high breast cancer susceptibility, based on available evidence. This information may change how providers approach breast cancer risk management in women with high breast cancer susceptibility.

Risk Factors for Ovarian Cancer

Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancers Prevention for information about risk factors for ovarian cancer in the general population.

Risk Factors for Endometrial Cancer

Refer to the PDQ summary on Endometrial Cancer Prevention for information about risk factors for endometrial cancer in the general population.

Autosomal Dominant Inheritance of Breast and Gynecologic Cancer Predisposition

Autosomal dominant inheritance of breast and gynecologic cancers is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

• Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
• Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition can still pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the syndromes associated with BRCA1 or BRCA2 pathogenic variants. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 pathogenic variants and of PTEN hamartoma tumor syndromes (including Cowden syndrome) due to PTEN pathogenic variants.[120] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ATM gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch syndrome, basal cell nevus (Gorlin) syndrome, and multiple endocrine neoplasia type 1.[120] Lynch syndrome is mainly associated with colorectal cancer and endometrial cancer, although several studies have demonstrated that patients with Lynch syndrome are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis; cancers of the stomach, small intestine, liver and biliary tract, brain, breast, prostate, and adrenal cortex; and sebaceous skin tumors (Muir-Torre syndrome).[121-127]

Germline pathogenic variants in the genes responsible for these autosomal dominant cancer syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

The family characteristics that suggest hereditary cancer predisposition include the following:

• Multiple cancers within a family.
• Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).
• Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast cancer and ovarian cancer in the same individual or endometrial and colon cancer in the same individual).
• Cases of male breast cancer. The inheritance risk for autosomal dominant genetic conditions is 50% for both males and females, but the differing penetrance of the genes may result in some unaffected individuals in the family.

Figure 1 and Figure 2 depict some of the classic inheritance features of a BRCA1 and BRCA2 pathogenic variant, respectively. Figure 3 depicts a classic family with Lynch syndrome. For more information about pedigree nomenclature, see the Family history section in Cancer Genetics Risk Assessment and Counseling.

Figure 1. BRCA1 pedigree. This pedigree shows some of the classic features of a family with a BRCA1 pathogenic variant across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. BRCA1 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA1 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.

Figure 2. BRCA2 pedigree. This pedigree shows some of the classic features of a family with a BRCA2 pathogenic variant across three generations, including affected family members with breast (including male breast cancer), ovarian, pancreatic, or prostate cancers and a relatively young age at onset. BRCA2 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA2 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.

Figure 3. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer, a young age at onset in some individuals, and incomplete penetrance. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure. Because the cancer risk is not 100%, individuals who have Lynch syndrome may not develop cancer, such as the mother of the female with colon cancer diagnosed at age 37 years in this pedigree (called incomplete penetrance).

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in carriers of BRCA1 or BRCA2 pathogenic variants from those occurring in noncarriers. Breast cancers occurring in carriers of BRCA1 pathogenic variants are more likely to be ER-negative, progesterone receptor (PR)–negative, human epidermal growth factor receptor two (HER2/neu)–negative (i.e., triple-negative breast cancers [TNBC]), and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the BRCA1/2-associated breast cancer pathology and Pathologies of BRCA1/2-associated ovarian, fallopian tube, and primary peritoneal cancers sections in BRCA1 and BRCA2: Cancer Risks and Management for more information.)

Some pathologic features distinguish carriers of Lynch syndrome–associated pathogenic variants from noncarriers. The hallmark feature of endometrial cancers occurring in Lynch syndrome is mismatch repair (MMR) deficiencies, including the presence of microsatellite instability (MSI), and the absence of specific MMR proteins. In addition to these molecular changes, there are also histologic changes including tumor-infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated tumor histology, lower uterine segment origin, and synchronous tumors.

Considerations in Risk Assessment and in Identifying a Family History of Breast and Ovarian Cancer Risk

The accuracy and completeness of family histories must be considered when they are used to assess risk. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than does breast or ovarian cancer on the maternal side, so information may be more difficult to obtain. When self-reported information is compared with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[128,129] Additional limitations of relying on family histories include adoption; families with a small number of women; limited access to family history information; and incidental removal of the uterus, ovaries, and/or fallopian tubes for noncancer indications. Family histories will evolve; therefore, it is important to update family histories from both parents over time. (Refer to the Accuracy of the family history section in Cancer Genetics Risk Assessment and Counseling for more information.)

Models for Prediction of Breast and Gynecologic Cancer Risk

Models to predict an individual’s lifetime risk of developing breast and/or gynecologic cancer are available.[130-133] In addition, models exist to predict an individual’s likelihood of having a pathogenic variant in BRCA1, BRCA2, or one of the MMR genes associated with Lynch syndrome. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 pathogenic variant section of this summary for more information about some of these models.) Not all models can be appropriately applied to all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to those of the study population on which the model was based. Different models may provide widely varying risk estimates for the same clinical scenario, and the validation of these estimates has not been performed for many models.[131,134,135]

Models for Predicting the Likelihood of a BRCA1/BRCA2 Pathogenic Variant

Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 pathogenic variants in individuals or families. These models include those using logistic regression,[140,168-173] genetic models using Bayesian analysis (BRCAPRO and BOADICEA),[140,142] and empiric observations.[174-179]

In addition to BOADICEA, BRCAPRO is commonly used for genetic counseling in the clinical setting. BRCAPRO and BOADICEA predict the probability of being a carrier and produce estimates of breast cancer risk (refer to Table 2). The discrimination and accuracy (factors used to evaluate the performance of prediction models) of these models are much higher for their ability to report on carrier status than for their ability to predict fixed or remaining lifetime risk.

BOADICEA is a polygenetic model that uses complex segregation analysis to examine both breast cancer risk and the probability of having a BRCA1 or BRCA2 pathogenic variant.[142] Even among experienced providers, the use of prediction models has been shown to increase the power to discriminate which patients are most likely to be carriers of BRCA1/BRCA2 pathogenic variants.[180,181] Most models do not include other cancers seen in the BRCA1 and BRCA2 spectrum, such as pancreatic cancer and prostate cancer. Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to predict BRCA1 and BRCA2 pathogenic variant status.[182] One study has shown that the prediction models for genetic risk are sensitive to the amount of family history data available and do not perform as well with limited family information.[183] BOADICEA is being expanded to incorporate additional risk variants (genome-wide association studies [GWAS] and SNVs) to better predict pathogenic variant status and to improve the accuracy of breast cancer and ovarian cancer risk estimates.[184]

The performance of the models can vary in specific ethnic groups. The BRCAPRO model appeared to best fit a series of French Canadian families.[185] There have been variable results in the performance of the BRCAPRO model among Hispanic individuals,[186,187] and both the BRCAPRO model and Myriad tables underestimated the proportion of carriers of pathogenic variants in an Asian American population.[188] BOADICEA was developed and validated in British women. Thus, the major models used for both overall risk (Table 1) and genetic risk (Table 2) have not been developed or validated in large populations of racially and ethnically diverse women. Of the commonly used clinical models for assessing genetic risk, only the Tyrer-Cuzick model contains nongenetic risk factors.

The power of several of the models has been compared in different studies.[189-192] Four breast cancer genetic-risk models, BOADICEA, BRCAPRO, IBIS, and eCLAUS, were evaluated for their diagnostic accuracy in predicting BRCA1/BRCA2 pathogenic variants in a cohort of 7,352 German families.[193] The family member with the highest likelihood of carrying a pathogenic variant from each family was screened for BRCA1/BRCA2 pathogenic variants. Carrier probabilities from each model were calculated and compared with the actual variants detected. BRCAPRO and BOADICEA had significantly higher diagnostic accuracy than IBIS or eCLAUS. Accuracy for the BOADICEA model was further improved when statuses of the tumor markers ER, PR, and HER2/neu were included in the model. The inclusion of these biomarkers has been shown to improve the performance of BRCAPRO.[194,195]

Genetic testing for BRCA1 and BRCA2 pathogenic variants has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This, in turn, gives providers better data to estimate an individual patient’s risk of carrying a pathogenic variant, but risk assessment continues to be an art. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or risk-reducing surgeries).

Considerations When Conducting Genetic Testing

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References

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BRCA1 and BRCA2

For more information about BRCA1 and BRCA2 pathogenic variants and BRCA-associated cancer risks, see BRCA1 and BRCA2: Cancer Risks and Management.

Lynch Syndrome

Lynch syndrome is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer.[1] The condition is caused by germline variants in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch variants.[2] The MLH1 and MSH2 genes are the most common susceptibility genes for Lynch syndrome, accounting for 80% to 90% of observed pathogenic variants,[3,4] followed by MSH6 and PMS2.[5-10] (Refer to the Lynch Syndrome section in Genetics of Colorectal Cancer for more information about this syndrome.)

After colorectal cancer, endometrial cancer is the second hallmark cancer of a family with Lynch syndrome. Even in the original Family G, described by Dr. Aldred Scott Warthin, numerous family members were noted to have extracolonic cancers including endometrial cancer. Although the first version of the Amsterdam criteria did not include endometrial cancer,[11] in 1999, the Amsterdam criteria were revised to include endometrial cancer as extracolonic tumors associated with Lynch syndrome to identify families at risk.[12] In addition, the Bethesda guidelines in 1997 (revised in 2004) did include endometrial and ovarian cancers as Lynch syndrome–related cancers to prompt tumor testing for Lynch syndrome.[13,14]

The lifetime risk of ovarian carcinoma in females with Lynch syndrome is estimated to be as high as 12%, and the reported relative risk (RR) of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected Lynch syndrome.[15-20] There may be differences in ovarian cancer risk depending on the Lynch syndrome–associated pathogenic variant. In PMS2-associated Lynch syndrome, one study of 284 families was unable to identify an increased risk of ovarian cancer.[21] Another prospective registry of 3,119 Lynch syndrome–pathogenic variant carriers described the cumulative risk of ovarian cancer to range from 10% to 17% in MLH1, MSH2, and MSH6 carriers. In contrast, 0 of 67 women with a pathogenic variant in PMS2 developed ovarian cancer in 303 follow-up years.[22] Overall, there are too few cases of PMS2 pathogenic variant carriers to make definitive recommendations for ovarian cancer management. Characteristics of Lynch syndrome–associated ovarian cancers may include overrepresentation of the International Federation of Gynecology and Obstetrics stages I and II at diagnosis (reported as 81.5%), underrepresentation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in carriers of BRCA pathogenic variants.[23,24]

Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[25-28] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[28] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [29] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[29] The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[30] A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 MLH1 carriers but not in carriers of other MMR variants.[31] Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.[32]

A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[33-36] although this has not been consistently observed.[37] Through a study of 325 Canadian families with Lynch syndrome, primarily encompassing MLH1 and MSH2 carriers, the lifetime cumulative risk for breast cancer among MSH2 carriers was reported to be 22%.[33] Similarly, breast cancer risks were elevated in a study of 423 women with Lynch syndrome, with substantially higher risks among those with MSH6 and PMS2 pathogenic variants, compared with MLH1 and MSH2 pathogenic variants.[34] In fact, breast cancer risk to age 60 years was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MLH1. These findings are consistent with another study of 528 patients with Lynch syndrome–associated pathogenic variants (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 variants were much more frequent among patients with only breast cancer, compared with those with only colorectal cancer (P = 2.3 x 10^-5).[35] Additional data to support an association of MSH6 with breast cancer were provided through a study of over 10,000 cancer patients across the United States who had genetic testing.[36] Findings indicated that MSH6 was associated with breast cancer with an odds ratio (OR) of 2.59 (95% CI, 1.35–5.44). Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.

Refer to the Lynch Syndrome section of the Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes section of this summary for information about clinical management of Lynch syndrome.

Li-Fraumeni Syndrome (LFS)

Breast cancer is also a component of the rare LFS, in which germline variants of the TP53 gene on chromosome 17p have been documented. Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death.[39] Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells.[40,41] Widely used clinical diagnostic criteria for LFS were originally developed by Chompret et al. in 2001 (called the Chompret Criteria) [42] and revised in 2009 based on additional emerging data.[43]

LFS is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[40,44,45]

Germline variants in TP53 are thought to account for fewer than 1% of breast cancer cases.[46] TP53-associated breast cancer is often human epidermal growth factor receptor two (HER2/neu)–positive, in addition to being estrogen receptor (ER)–positive, progesterone receptor (PR)–positive, or both.[47-49] Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy.

PTEN Hamartoma Tumor Syndromes (Including Cowden Syndrome)

PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. PTEN pathogenic variants are diverse and can present as nonsense, missense, frameshift, or splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif; several recurrent pathogenic variants have been observed at this location.[61] Pathogenic variants in the 5’ end of PTEN or within the phosphatase core of PTEN tend to affect more organ systems.[62]

Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[63,64] These include major, minor, and pathognomonic criteria that consist of certain mucocutaneous manifestations and adult-onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria based on a systematic literature review has been suggested [65] and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines.[66] Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. Increased genetic testing (especially multigene panels) has identified individuals with germline PTEN pathogenic variants who do not meet diagnostic criteria for PHTS. Diagnostic criteria will need to be reconciled with these recently discovered phenotypes. Hence, it is unclear whether PHTS diagnoses should be based on clinical features or a positive PTEN genetic test result. The American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with the following: 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome.[67] Detailed recommendations, including diagnostic criteria for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[66,67] Additionally, a predictive model that uses clinical criteria to estimate the probability of a PTEN pathogenic variant is available; a cost-effectiveness analysis suggests that germline PTEN testing is cost effective if the probability of a variant is greater than 10%.[68]

Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTEN testing in the United States, Europe, and Asia.[69] Most individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members carried a germline PTEN pathogenic variant. The authors concluded that melanoma, kidney cancer, and colorectal cancer should be added to the spectrum of cancers associated with PTEN germline pathogenic variants (in addition to breast cancer, thyroid cancer, and endometrial cancer). This conclusion was based on the high melanoma, kidney, and colorectal cancer lifetime risk estimates found in individuals with PTEN pathogenic variants. A second study of approximately 100 patients with a germline PTEN pathogenic variant confirmed these findings and suggested a cumulative cancer risk of 85% by age 70 years.

Although PTEN pathogenic variants, which are estimated to occur in 1 in 200,000 individuals,[63] account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology.[63,71] Lifetime breast cancer risk is estimated to be between 25% and 50% among women with Cowden syndrome.[72] Other studies have reported risks as high as 85%;[69,70,73,74] however, there are concerns regarding selection bias in these studies. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral.[75] Lifetime risk of endometrial cancer is estimated to be between 19% and 28%, depending on the cohort studied, with an increased risk of premenopausal onset.[69,70,76] Because of the low prevalence of PTEN pathogenic variants in the population, the proportion of endometrial cancer attributable to Cowden syndrome is small. There are no data that link PTEN pathogenic variants to an increased risk of ovarian cancer. Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. CNS manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum.[77,78] (Refer to the PDQ summaries on Genetics of Colorectal Cancer and Genetics of Skin Cancer for more information about PTEN hamartoma tumor syndromes [including Cowden syndrome].)

Hereditary Diffuse Gastric Cancer (HDGC)

For more information about HDGC, see the following:

• For general information about HDGC, see Hereditary Diffuse Gastric Cancer.
• For information about HDGC-associated lobular breast cancer, see the Breast Cancer Risk section in Hereditary Diffuse Gastric Cancer.
• For information about management of breast cancer risk in HDGC, see the Breast Cancer Risk Management section in Hereditary Diffuse Gastric Cancer.

Peutz-Jeghers Syndrome (PJS)

Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[91] In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors;[92] although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered.

PJS is caused by pathogenic variants in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[83,84] Unlike the adenomas seen in familial adenomatous polyposis, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (LOH) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[95,96] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency may be sufficient for initial tumor development in PJS.[97] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[98] indeed, compound mutant mice heterozygous for pathogenic variants in STK11 +/- and homozygous for pathogenic variants in TP53 -/- have accelerated development of both hamartomas and cancers.[99]

Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.[82,88]

Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein. No strong genotype-phenotype correlations have been identified.[88] Up to 30% of variants are large deletions involving one or more exons of STK11, underscoring the importance of deletion analysis in suspected cases of PJS.[82]

STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% pathogenic variant detection rate in STK11, studies adding techniques to detect large deletions have found pathogenic variants in up to 94% of individuals meeting clinical criteria for PJS.[82,90,100] Given the results of these studies, it is unlikely that other major genes cause PJS.

PALB2

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic pathogenic variants in PALB2 have also been shown to cause Fanconi anemia.[104]

PALB2 pathogenic variants have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations.[105-123] Pathogenic variant prevalence has ranged from 0.4% to 3.9%. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 pathogenic variants in families with hereditary breast cancer.[106] Among 559 cases with CBC and 565 matched controls with unilateral breast cancer, pathogenic (truncating) PALB2 pathogenic variants were identified in 0.9% of cases and in none of the controls (RR, 5.3; 95% CI, 1.8–13.2).[117]

Data based on 154 families with loss-of-function PALB2 variants suggest that this gene may be an important cause of hereditary breast cancer, with risks that overlap with BRCA2.[124] In this study, analysis of 362 family members from 154 families with PALB2 pathogenic variants indicated that the AR of female breast cancer by age 70 years ranged from 33% (95% CI, 24%–44%) for those with no family history of breast cancer to 58% (95% CI, 50%–66%) for those with two or more FDRs with early-onset breast cancer. Furthermore, among 63 breast cancer cases in which HER2 status was known, 30% had triple-negative breast cancer (TNBC). An earlier Finnish study reported on a PALB2 founder pathogenic variant (c.1592delT) that confers a 40% risk of breast cancer to age 70 years [107] and is associated with a high incidence (54%) of TNBC and lower survival.[108] Pathogenic variants have been observed in early-onset and familial breast cancer in many populations.[109,110] A large report of 1,824 patients with TNBC unselected for family history, recruited through 12 studies, identified 1.2% with a PALB2 pathogenic variant.[125] (Refer to the BRCA2-associated breast cancer pathology section in BRCA1 and BRCA2: Cancer Risks and Management for more information about this study.)

In a later Polish study of more than 12,529 unselected women with breast cancer and 4,702 controls, PALB2 pathogenic variants were detected in 116 cases (0.93%; 95% CI, 0.76%–1.09%) and 10 controls (0.21%; 95% CI, 0.08%–0.34%), with an OR for breast cancer of 4.39 (95% CI, 2.30–8.37).[126] The study findings confirm a substantially elevated risk of breast cancer (24%–40%) among women with a PALB2 pathogenic variant up to age 75 years. The 5-year cumulative incidence of CBC was 10% among those with a PALB2 pathogenic variant, compared with 17% among those with a BRCA1 pathogenic variant and 3% among those without a variant in either gene. Furthermore, the 10-year survival for women with a PALB2 pathogenic variant and breast cancer was 48% (95% CI, 36.5%–63.2%), compared with 72.0% among those with a BRCA1 pathogenic variant and 74.7% among those without a variant in either gene. Among PALB2 carriers, breast tumors 2 cm or larger had substantially worse outcomes (32.4% 10-year survival), compared with tumors smaller than 2 cm (82.4% 10-year survival). Approximately one-third of those with a PALB2 pathogenic variant had TNBC, and the average age at breast cancer diagnosis was 53.3 years.

A similar case-control study from China enrolled 16,501 unselected patients with breast cancer and 5,890 controls. These patients were screened for PALB2, BRCA1, and BRCA2 pathogenic variants. The prevalence of PALB2 pathogenic variants was 0.97% in the cases and 0.19% in the controls. The OR for breast cancer for carriers was 5.23 (95% CI, 2.84–9.65; P > .0001). PALB2 carriers were more likely to be age 30 years or younger (6.88% vs. 3.56%; P = .04). PALB2 carriers were also more likely to have TNBCs (22.83% vs. 13.56%; P = .004), larger tumors (tumor size ≥2 cm, 55.93% vs. 45.93%; P = .04), node-positive tumors (49.60% vs. 38.80%; P = .018), and CBCs (6.29% vs. 2.01%; P = .003). Additionally, PALB2 carriers were more likely to have a family history of breast and/or ovarian cancers (20.63% vs. 7.96%; P < .0001).[127]

In the largest study to date, 524 families with pathogenic variants in PALB2 recruited through an international effort, the RR of breast cancer in women was reported to be 7.18 (95% CI, 5.82–8.85), with a 53% risk (95% CI, 44%–63%) of breast cancer to age 80 years.[128] Additional elevated risks reported included ovarian cancer (RR, 2.91; 95% CI, 1.40–6.04) with a lifetime risk of 5% (95% CI, 2%–10%), pancreatic cancer (RR, 2.37; 95% CI, 1.24–4.50) with a lifetime risk of 2% to 3% (95% CI for women, 1%–4%; 95% CI for men, 2%–5%), and male breast cancer (RR, 7.34; 95% CI, 1.28–42.18) with a lifetime risk of 1% (95% CI, 0.2%–5%). These findings confirm the role of PALB2 as an inherited breast cancer gene in women, while firmly establishing an association with ovarian, pancreatic, and male breast cancers.

Male breast cancer has been observed in PALB2 pathogenic variant–positive breast cancer families.[105,111,124] In a study of 115 male breast cancer cases in which 18 men had BRCA2 pathogenic variants, an additional two men had either a pathogenic or predicted pathogenic PALB2 variant (accounting for about 10% of germline variants in the study and 1%–2% of the total sample).[105] The RR of breast cancer for male carriers of PALB2 pathogenic variants compared with that seen in the general population was estimated to be 8.30 (95% CI, 0.77–88.56; P = .08) in the study of 154 families.[124]

After the identification of PALB2 pathogenic variants in pancreatic tumors and the detection of germline pathogenic variants in 3% of 96 familial pancreatic patients,[129] numerous studies have pointed to a role for PALB2 in pancreatic cancer. PALB2 pathogenic variants were detected in 3.7% of 81 familial pancreatic cancer families [130] and in 2.1% of 94 BRCA1/BRCA2 pathogenic variant–negative breast cancer patients who had either a personal or family history of pancreatic cancer.[131] Two relatively small studies—one of 77 BRCA1/BRCA2 pathogenic variant–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of AJ descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer—failed to detect any PALB2 pathogenic variants.[132,133] A sixfold increase in pancreatic cancer was observed in the relatives of 33 BRCA1/BRCA2-negative, PALB2 pathogenic variant–positive breast cancer probands.[111]

Overall, the observed prevalence of PALB2 pathogenic variants in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed pathogenic variant rate was lower than 4%. Data suggest that the RR of breast cancer may overlap with that of BRCA2, particularly in those with a strong family history; thus, it remains important to refine cancer risk estimates in larger studies. Furthermore, the risk of other cancers (e.g., pancreatic) is poorly defined. Given the low PALB2 pathogenic variant prevalence in the population, additional data are needed to define best candidates for testing and appropriate management.

De Novo Pathogenic Variant Rate

Until the 1990s, the diagnosis of genetically inherited breast and ovarian cancer syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, PJS, PTEN hamartoma syndromes, and LFS are all thought to have high rates of spontaneous pathogenic variants, in the 10% to 30% range,[134-137] while estimates of de novo pathogenic variants in the BRCA genes are thought to be low, primarily on the basis of the few case reports published.[138-146] Additionally, there has been only one case series of breast cancer patients who were tested for BRCA pathogenic variants in which a de novo variant was identified. Specifically, in this study of 193 patients with sporadic breast cancer, 17 pathogenic variants were detected, one of which was confirmed to be a de novo pathogenic variant.[138] As such, the de novo pathogenic variant rate appears to be low and fall into the 5% or less range, based on the limited studies performed.[138-146] Similarly, estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range.[147-149] However, these estimates of spontaneous pathogenic variant rates in the BRCA genes and Lynch syndrome genes seem to overlap with the estimates of nonpaternity rates in various populations (0.6%–3.3%),[150-152] making the de novo pathogenic variant rate for these genes relatively low.

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Background

Pathogenic variants in BRCA1, BRCA2, PALB2, and the genes involved in other rare syndromes discussed in the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary account for less than 25% of the familial risk of breast cancer.[1] Despite intensive genetic linkage studies, there do not appear to be other high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters.[2] However, several moderate-penetrance genes associated with breast and/or gynecologic cancers have been identified. Genes such as CHEK2 and ATM are associated with a 20% or higher lifetime risk of breast cancer;[3,4] similarly, genes such as RAD51C, RAD51D, and BRIP1 are associated with a 5% to 10% risk of ovarian cancer.[5,6] Many of these genes are now included on multigene panels, although the clinical actionability of these findings remains uncertain and under investigation.

Breast and Gynecologic Cancer Susceptibility Genes Identified Through Candidate Gene Approaches

There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.

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56. van Os NJ, Roeleveld N, Weemaes CM, et al.: Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clin Genet 90 (2): 105-17, 2016. [PubMed: 26662178]
57. Moslemi M, Moradi Y, Dehghanbanadaki H, et al.: The association between ATM variants and risk of breast cancer: a systematic review and meta-analysis. BMC Cancer 21 (1): 27, 2021. [PMC free article: PMC7786920] [PubMed: 33402103]
58. Bernstein JL, Teraoka S, Southey MC, et al.: Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry. Hum Mutat 27 (11): 1122-8, 2006. [PubMed: 16958054]
59. Goldgar DE, Healey S, Dowty JG, et al.: Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res 13 (4): R73, 2011. [PMC free article: PMC3236337] [PubMed: 21787400]
60. Lu HM, Li S, Black MH, et al.: Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing. JAMA Oncol 5 (1): 51-57, 2019. [PMC free article: PMC6439764] [PubMed: 30128536]
61. Pennington KP, Walsh T, Harrell MI, et al.: Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20 (3): 764-75, 2014. [PMC free article: PMC3944197] [PubMed: 24240112]
62. Hsu FC, Roberts NJ, Childs E, et al.: Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene. JAMA Oncol 7 (11): 1664-1668, 2021. [PMC free article: PMC8446906] [PubMed: 34529012]
63. Suwaki N, Klare K, Tarsounas M: RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin Cell Dev Biol 22 (8): 898-905, 2011. [PubMed: 21821141]
64. Vaz F, Hanenberg H, Schuster B, et al.: Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42 (5): 406-9, 2010. [PubMed: 20400963]
65. Meindl A, Hellebrand H, Wiek C, et al.: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42 (5): 410-4, 2010. [PubMed: 20400964]
66. Clague J, Wilhoite G, Adamson A, et al.: RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PLoS One 6 (9): e25632, 2011. [PMC free article: PMC3182241] [PubMed: 21980511]
67. Thompson ER, Boyle SE, Johnson J, et al.: Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat 33 (1): 95-9, 2012. [PubMed: 21990120]
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69. Romero A, Pérez-Segura P, Tosar A, et al.: A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. Breast Cancer Res Treat 129 (3): 939-46, 2011. [PubMed: 21537932]
70. Osorio A, Endt D, Fernández F, et al.: Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum Mol Genet 21 (13): 2889-98, 2012. [PubMed: 22451500]
71. Ramus SJ, Song H, Dicks E, et al.: Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst 107 (11): , 2015. [PMC free article: PMC4643629] [PubMed: 26315354]
72. Blanco A, Gutiérrez-Enríquez S, Santamariña M, et al.: RAD51C germline mutations found in Spanish site-specific breast cancer and breast-ovarian cancer families. Breast Cancer Res Treat 147 (1): 133-43, 2014. [PubMed: 25086635]
73. Norquist BM, Harrell MI, Brady MF, et al.: Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2 (4): 482-90, 2016. [PMC free article: PMC4845939] [PubMed: 26720728]
74. Kushnir A, Laitman Y, Shimon SP, et al.: Germline mutations in RAD51C in Jewish high cancer risk families. Breast Cancer Res Treat 136 (3): 869-74, 2012. [PubMed: 23117857]
75. Wong MW, Nordfors C, Mossman D, et al.: BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res Treat 127 (3): 853-9, 2011. [PubMed: 21409391]
76. Zheng Y, Zhang J, Hope K, et al.: Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat 124 (3): 857-61, 2010. [PubMed: 20697805]
77. Akbari MR, Tonin P, Foulkes WD, et al.: RAD51C germline mutations in breast and ovarian cancer patients. Breast Cancer Res 12 (4): 404, 2010. [PMC free article: PMC2949649] [PubMed: 20723205]
78. De Leeneer K, Van Bockstal M, De Brouwer S, et al.: Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast Cancer Res Treat 133 (1): 393-8, 2012. [PubMed: 22370629]
79. Thomas G, Jacobs KB, Kraft P, et al.: A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41 (5): 579-84, 2009. [PMC free article: PMC2928646] [PubMed: 19330030]
80. Figueroa JD, Garcia-Closas M, Humphreys M, et al.: Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20 (23): 4693-706, 2011. [PMC free article: PMC3209823] [PubMed: 21852249]
81. Osher DJ, De Leeneer K, Michils G, et al.: Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. Br J Cancer 106 (8): 1460-3, 2012. [PMC free article: PMC3326673] [PubMed: 22415235]
82. Pelttari LM, Kiiski J, Nurminen R, et al.: A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer. J Med Genet 49 (7): 429-32, 2012. [PMC free article: PMC5426530] [PubMed: 22652533]
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86. He XF, Su J, Zhang Y, et al.: Need for clarification of data in the recent meta-analysis about RAD51 135G>C polymorphism and breast cancer risk. Breast Cancer Res Treat 129 (2): 649-51; author reply 652-3, 2011. [PubMed: 21537934]
87. Lu W, Wang X, Lin H, et al.: Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer 11 (3): 381-5, 2012. [PMC free article: PMC3418444] [PubMed: 22476429]
88. Wang WW, Spurdle AB, Kolachana P, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10 (9): 955-60, 2001. [PubMed: 11535547]
89. Wang Z, Dong H, Fu Y, et al.: RAD51 135G>C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects. Breast Cancer Res Treat 124 (3): 765-9, 2010. [PubMed: 20396943]
90. Zhou GW, Hu J, Peng XD, et al.: RAD51 135G>C polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 125 (2): 529-35, 2011. [PubMed: 20623332]
91. Yu KD, Yang C, Fan L, et al.: RAD51 135G>C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies. Breast Cancer Res Treat 126 (2): 365-71, 2011. [PubMed: 20461453]
92. Dickersin GR, Kline IW, Scully RE: Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer 49 (1): 188-97, 1982. [PubMed: 6274502]
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94. Callegaro-Filho D, Gershenson DM, Nick AM, et al.: Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): A review of 47 cases. Gynecol Oncol 140 (1): 53-7, 2016. [PMC free article: PMC5990049] [PubMed: 26546963]
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96. Jelinic P, Mueller JJ, Olvera N, et al.: Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet 46 (5): 424-6, 2014. [PMC free article: PMC5699446] [PubMed: 24658004]
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Genome-Wide Searches

In contrast to assessing candidate genes and/or alleles, GWAS involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of as many as 5 million SNVs that are chosen to capture a large portion of common variation within the genome based on the HapMap and the 1000 Genomes Project.[4,5] By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[6-8] The strong correlation between many SNVs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNVs. Although this between-SNV correlation allows one to interrogate the majority of the genome without having to assay every SNV, when a validated association is obtained, it is not usually obvious which of the many correlated variants is causal.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases,[9] including breast cancer.[10-13] The first study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the Breast Cancer Association Consortium (BCAC).[10] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. The 8q region and others may harbor multiple independent loci associated with risk. Subsequent genome-wide studies have replicated these loci and identified additional ones.[11,12,14-19] Numerous SNVs identified through large studies of sporadic breast cancer appear to be associated more strongly with estrogen receptor (ER)–positive disease;[20] however, some are associated primarily or exclusively with other subtypes, including triple-negative disease.[21,22] An online catalog is available of SNV-trait associations from published GWAS for use in investigating genomic characteristics of trait/disease-associated SNVs.

Although the statistical evidence for an association between genetic variation at these loci and breast and ovarian cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk (typically, an odds ratio [OR] <1.5), with more risk variants likely to be identified. No interaction between the SNVs and epidemiologic risk factors for breast cancer have been identified.[23,24] Furthermore, theoretical models have suggested that common moderate-risk SNVs have limited potential to improve models for individualized risk assessment.[25-27] These models used receiver operating characteristic (ROC) curve analysis to calculate the area under the curve (AUC) as a measure of discriminatory accuracy. A subsequent study used ROC curve analysis to examine the utility of SNVs in a clinical dataset of more than 5,500 breast cancer cases and nearly 6,000 controls, using a model with traditional risk factors compared with a model using both standard risk factors and ten previously identified SNVs. The addition of genetic information modestly changed the AUC from 58% to 61.8%, a result that was not felt to be clinically significant. Despite this, 32.5% of patients were in a higher quintile of breast cancer risk when genetic information was included, and 20.4% were in a lower quintile of risk. Whether such information has clinical utility is unclear.[25,28]

More limited data are available regarding ovarian cancer risk. Three GWAS involving staged analysis of more than 10,000 cases and 13,000 controls have been carried out for ovarian cancer.[29-31] As in other GWAS, the ORs are modest, generally about 1.2 or weaker but implicate a number of genes with plausible biological ties to ovarian cancer, such as BABAM1, whose protein complexes with and may regulate BRCA1, and TIRAPR, which codes for a poly (ADP-ribose) polymerase, molecules that may be important in BRCA1/BRCA2-deficient cells.

Whole-Genome and Whole-Exome Sequencing

In addition to GWAS interrogating common genetic variants, sequencing-based studies involving whole-genome or whole-exome sequencing [51] are also identifying genes associated with breast cancer, such as XRCC2, a rare, moderate-penetrance breast cancer susceptibility gene.[52] (Refer to the Clinical Sequencing section in Cancer Genetics Overview for more information about whole-exome sequencing.)

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BRCA1 and BRCA2

For more information, see the Management of Cancer Risks in BRCA1/2 Carriers section in BRCA1 and BRCA2: Cancer Risks and Management.

Lynch Syndrome

As mismatch repair genes were identified as the genetic basis of Lynch syndrome, microsatellite instability was identified as a common molecular marker of mismatch repair deficiency. Approximately 15% of sporadic colorectal cancers show microsatellite instability, while up to 28% of sporadic endometrial cancers have this molecular change.[1,2] Most frequently, sporadic tumors with microsatellite instability have hypermethylation of the MLH1 promoter. In Lynch syndrome–related tumors showing microsatellite instability, there is typically loss of one or more of the proteins associated with the mismatch repair genes.

Certain histopathologic features are also strongly suggestive of a microsatellite instability phenotype, including the presence of tumor infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated carcinomas, and lower uterine segment tumors. Use of clinical criteria is one strategy of selection criteria for tumor testing. Computer models have also been used to predict the probability of a mismatch repair genetic variant and can be used in the absence of microsatellite instability or immunohistochemistry information.[3-6] Overall, however, there is a move towards universal testing of colorectal and endometrial tumors when tumor tissue is available. (Refer to the Universal tumor testing to screen for Lynch syndrome section in Genetics of Colorectal Cancer for more information.)

References

1. Vilar E, Gruber SB: Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7 (3): 153-62, 2010. [PMC free article: PMC3427139] [PubMed: 20142816]
2. Nakamura A, Osonoi T, Terauchi Y: Relationship between urinary sodium excretion and pioglitazone-induced edema. J Diabetes Investig 1 (5): 208-11, 2010. [PMC free article: PMC4020723] [PubMed: 24843434]
3. Balmaña J, Stockwell DH, Steyerberg EW, et al.: Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296 (12): 1469-78, 2006. [PubMed: 17003395]
4. Barnetson RA, Tenesa A, Farrington SM, et al.: Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354 (26): 2751-63, 2006. [PubMed: 16807412]
5. Kastrinos F, Allen JI, Stockwell DH, et al.: Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy. Am J Gastroenterol 104 (6): 1508-18, 2009. [PMC free article: PMC3584339] [PubMed: 19491864]
6. Khan O, Blanco A, Conrad P, et al.: Performance of Lynch syndrome predictive models in a multi-center US referral population. Am J Gastroenterol 106 (10): 1822-7; quiz 1828, 2011. [PMC free article: PMC3804147] [PubMed: 21747416]

Introduction

Psychosocial research in the context of cancer genetic testing helps to define psychological outcomes, interpersonal and familial effects, and cultural and community responses. This type of research also identifies behavioral factors that encourage or impede screening and other health behaviors. It can enhance decision making about risk-reduction interventions, evaluate psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification and genetic testing, provide data to help resolve ethical concerns, and predict the interest in testing of various groups.

Psychosocial and screening issues related to gynecologic cancers associated with Lynch syndrome are discussed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section in Genetics of Colorectal Cancer.

Uptake of Genetic Counseling and Genetic Testing

What People Bring to Genetic Testing: Impact of Risk Perception, Health Beliefs, and Personality Characteristics

The emerging literature in this area suggests that risk perceptions, health beliefs, psychological status, and personality characteristics are important factors in decision making about breast/ovarian cancer genetic testing. Many women presenting at academic centers for BRCA1/BRCA2 testing arrive with a strong belief that they have a pathogenic variant, having decided they want genetic testing, but possessing little information about the risks or limitations of testing.[61] Most mean scores of psychological functioning at baseline for subjects in genetic counseling studies were within normal limits.[62] Nonetheless, a subset of subjects in many genetic counseling studies present with elevated anxiety, depression, or cancer worry.[63,64] Identification of these individuals is essential to prevent adverse outcomes. In a study of 205 women pursuing genetic counseling, interactions among cancer worry, breast cancer risk perception, and perceived severity of having a breast cancer genetic variant were found such that those with high worry, high breast cancer risk perception, and low perceived severity were twice as likely to follow through with BRCA1/BRCA2 testing than others.[65]

A general tendency to overestimate inherited risk of breast and ovarian cancer has been noted in at-risk populations,[66-69] in cancer patients,[67,70,71] in spouses of breast and ovarian cancer patients,[72] and among women in the general population.[73-75] but underestimation of breast cancer risk in higher-risk and average-risk women also has been reported.[76] This overestimation may encourage a belief that BRCA1/BRCA2 genetic testing will be more informative than it is currently thought to be. Some evidence exists that even counseling does not dissuade women at low to moderate risk from the belief that BRCA1 testing could be valuable.[32] Overestimation of both breast and ovarian cancer risk has been associated with nonadherence to physician-recommended screening practices.[77,78] A meta-analysis of 12 studies of outcomes of genetic counseling for breast/ovarian cancer showed that counseling improved the accuracy of risk perception.[79]

Women appear to be the prime communicators within families about the family history of breast cancer.[80] Higher numbers of maternal versus paternal transmission cases are reported,[81] likely due to family communication patterns, to the misconception that breast cancer risk can only be transmitted through the mother, and to the greater difficulty in recognizing paternal family histories because of the need to identify more distant relatives with cancer. In an analysis of 2,505 women participating in the Family Healthware Impact Trial,[82] not only was evidence of underreporting of paternal family history identified, but also women reported a lower level of perceived breast cancer risk with a paternal versus maternal breast cancer family history.[83] Physicians and counselors taking a family history are encouraged to elicit paternal and maternal family histories of breast, ovarian, or other associated cancers.[80]

The accuracy of reported family history of breast or ovarian cancer varies; some studies found levels of accuracy above 90%,[84,85] with others finding more errors in the reporting of cancer in second-degree relatives (SDRs) or more distant relatives [86] or in age of onset of cancer.[87] Less accuracy has been found in the reporting of cancers other than breast cancer. Ovarian cancer history was reported with 60% accuracy in one study compared with 83% accuracy in breast cancer history.[88] Providers should be aware that there are a few published cases of Munchausen syndrome in reporting of false family breast cancer history.[89] Much more common is erroneous reporting of family cancer history due to unintentional errors or gaps in knowledge, related in some cases to the early death of potential maternal informants about cancer family history.[80] (Refer to the Documenting the Family History section in Cancer Genetics Risk Assessment and Counseling for more information.)

Targeted written,[90,91] video, CD-ROM, interactive computer programs and websites,[92-99] and culturally targeted educational materials [100-102] may be effective and efficient methods of increasing knowledge about the pros and cons of genetic testing. Such supplemental materials may allow more efficient use of the time allotted for pretest education and counseling by genetics and primary care providers and may discourage individuals without appropriate indication of risk from seeking genetic testing.[90]

Genetic Counseling for Hereditary Predisposition to Breast Cancer

Counseling for breast cancer risk typically involves individuals with family histories that are potentially attributable to BRCA1 or BRCA2. It also, however, may include individuals with family histories of Li-Fraumeni syndrome, ataxia-telangiectasia, Cowden syndrome, or Peutz-Jeghers syndrome.[103] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary for more information.)

Management strategies for carriers may involve decisions about the nature, frequency, and timing of screening and surveillance procedures, chemoprevention, risk-reducing surgery, and use of hormone replacement therapy (HRT). The utilization of breast conservation and radiation as cancer therapy for women who are carriers may be influenced by knowledge of pathogenic variant status. (Refer to the Management of Cancer Risks in BRCA1/2 Carriers section in BRCA1 and BRCA2: Cancer Risks and Management for more information.)

Counseling also includes consideration of related psychosocial concerns and discussion of planned family communication and the responsibility to warn other family members about the possibility of having an increased risk of breast, ovarian, and other cancers. Data suggest that individual responses to being tested as adults are influenced by the results status of other family members.[104,105] Management of anxiety and distress are important not only as quality-of-life factors, but also because high anxiety may interfere with the understanding and integration of complex genetic and medical information and adherence to screening.[106-108] Formal, objective evaluation of these outcomes are well documented. (Refer to the Emotional Outcomes and Behavioral Outcomes sections of this summary for more information.)

Published descriptions of counseling programs for BRCA1 (and subsequently for BRCA2) testing include strategies for gathering a family history, assessing eligibility for testing, communicating the considerable volume of relevant information about breast/ovarian cancer genetics and associated medical and psychosocial risks and benefits, and discussion of specialized ethical considerations about confidentiality and family communication.[109-116] Participant distress, intrusive thoughts about cancer, coping style, and social support were assessed in many prospective testing candidates. The psychosocial outcomes evaluated in these programs have included changes in knowledge about the genetics of breast/ovarian cancer after counseling, risk comprehension, psychological adjustment, family and social functioning, and reproductive and health behaviors.[117] A Dutch study of communication processes and satisfaction levels of consultands going through cancer genetic counseling for inherited cancer syndromes indicated that asking more medical questions (by the counselor), providing more psychosocial information, and longer eye contact by the counselor were associated with lower satisfaction levels. The provision of medical information by the counselor was most highly related to satisfaction and perception that needs have been fulfilled.[118]

Many of the psychosocial outcome studies involve specialized, highly selected research populations, some of which were utilized to map and clone BRCA1 and BRCA2. One such example is K2082, an extensively studied kindred of more than 800 members of a Utah Mormon family in which a BRCA1 pathogenic variant accounts for the observed increased rates of breast and ovarian cancer. A study of the understanding that members of this kindred have about breast/ovarian cancer genetics found that, even in breast cancer research populations, there was incomplete knowledge about associated risks of colon and prostate cancer, the existence of options for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), and the complexity of existing psychosocial risks.[109] A meta-analysis of 21 studies found that genetic counseling was effective in increasing knowledge and improved the accuracy of perceived risk. Genetic counseling did not have a statistically significant long-term impact on affective outcomes including anxiety, distress, or cancer-specific worry and the behavioral outcome of cancer surveillance activities.[62] These prospective studies, however, were characterized by a heterogeneity of measures of cancer-specific worry and inconsistent findings in effects of change from baseline.[62]

Emotional Outcomes

Although there were initial concerns about the possibility of adverse emotional consequences from BRCA testing, most studies conducted over the years have shown low levels of psychological distress among both carriers and noncarriers, particularly over the longer term.[119-121] In a meta-analysis examining cancer-specific distress over short (0–4 weeks), moderate (5–24 weeks), and long (25–52 weeks) periods of time since the receipt of testing results, carriers were found to demonstrate increased levels of distress shortly after receiving results, with levels returning to baseline within moderate and long periods of time.[119] In contrast, noncarriers and those with inconclusive results showed reduced levels of distress over time.[119,122] Psychological distress patterns were found to vary as a function of several factors, including the cancer history of the individual and the country within which the study was conducted. Carriers with a personal history of cancer experienced small decreases in distress over time, whereas no changes were observed among carriers without a personal history of cancer. Among individuals with inconclusive results, greater decreases in distress were observed among those without a cancer history than among those with a cancer history. Among noncarriers, those in the United States experienced significantly greater decreases in psychological distress than noncarriers from Europe and Australia. A study conducted in Austria noted that certain subgroups of consultands experienced greater distress, including those who were older, had a more recent cancer diagnosis, or those who had received counseling but declined BRCA testing.[123]

Several studies have reported on emotional outcomes over longer follow-up periods (i.e., greater than 12 months after disclosure) than those reported in the meta-analysis described above.[119] In a U.K. study, cancer-related worry did not differ between carriers and noncarriers at 3 years of follow-up.[124] Two U.S.-based studies published since the meta-analytic review [119] have reported similar findings among women who were surveyed more than 3 years after receipt of BRCA test results.[125,126] In a cross-sectional study,[125] 167 women who were surveyed more than 4 years after receiving BRCA test results reported low levels of genetic testing–specific concerns, as measured using the Multidimensional Impact of Cancer Risk Assessment Scale.[127] In multivariate regression models, carriers of pathogenic variants were significantly more likely to experience distress than were noncarriers. In a second study,[126] 464 women were followed prospectively for a median of 5 years (range, 3.4–9.1 y) after testing. Among both affected and unaffected participants, BRCA carriers reported significantly higher levels of distress, uncertainty (affected only), perceived stress (affected only), and lower positive testing experiences (unaffected only) than women who received negative results for a known pathogenic variant in the family.[126] Although both studies [125,126] reported greater distress among BRCA carriers than among noncarriers, the level of distress was not reflective of clinically significant dysfunction.

Although most studies have reported that a positive BRCA test result has a relatively minimal impact on psychological distress, many of these studies were conducted among families with a strong family history of breast or ovarian cancer who underwent extensive pretest genetic counseling. Therefore, emotional responses may not generalize to individuals who test under different contexts. For example, individuals who are tested with population BRCA screening may not have a family history of cancer.[128-130] Although pretest genetic counseling is recommended, this is not always done when genetic testing is ordered by nongenetic providers [131] or directly through commercial companies.[132,133]

For example, in a Canadian study of 2,080 Jewish women who participated in a population-based genetic screening study to test for three BRCA pathogenic variants common in families of Jewish heritage, women were not offered in-person genetic counseling but were given a pamphlet on genetic testing for BRCA1/BRCA2 before they provided a DNA sample. One year after genetic testing, women who were positive for a pathogenic variant (n = 18) showed significant increases in cancer-specific distress, whereas no changes in distress were observed among women who were negative for a pathogenic variant.[129] The mean distress score on the Impact of Event Scale for the 18 women with a known pathogenic variant was 25.3 (range, 2–51); 10 of 18 women (56%) scored within moderate (26–43) (n = 7) or severe (44+) (n = 3) ranges. It is unclear from this study whether the increase in distress observed at 1 year of follow-up was due to the lack of in-person genetic counseling, or whether the lower levels of distress at baseline observed were because the women in the study were low risk but eligible for testing because of their ancestry. A follow-up study with this cohort found that distress decreased between 1 to 2 years after testing and that changes in distress varied by risk-reduction options undertaken by carriers. Specifically, those who had undergone RRM or risk-reducing oophorectomy experienced significant decreases in distress compared with those who did not have either surgery.[130] Another smaller qualitative study also supports these findings.[134]

Similarly, the impact of direct-to-consumer (DTC) BRCA testing through commercial companies requires further evaluation. Case studies have reported adverse emotional responses after receipt of a positive BRCA result from DTC genetic testing, suggesting the need for further evaluation of the emotional outcomes of women undergoing genetic testing through commercial companies.[132,133] Only one study, conducted by a commercial company, has attempted to evaluate the impact of BRCA testing in this context.[135] A total of 32 individuals (16 women and 16 men) who tested positive for one of three BRCA founder pathogenic variants common in AJs completed semi-structured interviews. None of the carriers reported extreme anxiety, although some experienced moderate anxiety (13%) or initial disappointment and anxiety that dissipated over time (28%). These findings should be interpreted with caution given that only 24% (32 of 136) of invited carriers of BRCA pathogenic variants participated in the study, raising concerns about selection bias.

Despite evidence of a short-term increase in distress after the receipt of genetic testing results, any adverse responses to a positive carrier status dissipate within 12 months.[119] Additional research is needed to examine emotional outcomes for those who are not provided genetic counseling before testing.[131]

Family Effects

Cultural/Community Effects

The recognition that BRCA1/BRCA2 pathogenic variants are prevalent, not only in breast/ovarian cancer families but also in some ethnic groups,[196] has led to considerable discussion of the ethical, psychological, and other implications of having one’s ethnicity be a factor in determination of disease predisposition. Concerns that people will think everything is solely determined by genetic factors and the creation of a genetic underclass [197] have been voiced. Questions about the impact on the group of being singled out as having genetic vulnerability to breast cancer have been raised. There is also confusion about who gives or withholds permission for the group to be involved in studies of their genetic identity. These issues challenge traditional views on informed consent as a function of individual autonomy.[198]

A growing literature on the unique factors influencing a variety of cultural subgroups suggests the importance of developing culturally specific genetic counseling and educational approaches.[100,199-203] The inclusion of members within the community of interest (e.g., breast cancer survivors, advocates, and community leaders) may enhance the development of culturally tailored genetic counseling materials.[101] One study showed that participation in any genetic counseling (culturally mediated or standard approaches) reduced perceived risk of developing breast cancer.[204]

Ethical Concerns

The human implications of the ethical issues raised by the advent of genetic testing for breast/ovarian cancer susceptibility are described in case studies,[205] essays,[206,207] and research reports. Issues about rights and responsibilities in families concerning the spread of information about genetic risk promise to be major ethical and legal dilemmas in the coming decades.

Studies have shown that 62% of studied family members were aware of the family history and that 88% of hereditary breast/ovarian cancer family members surveyed have significant concerns about privacy and confidentiality. Concern about cancer in third-degree relatives, or relatives further removed, did not differ from concern about cancer in the proband's FDRs or SDRs.[208] Only half of surveyed FDRs of women with breast or ovarian cancer felt that written permission should be required to disclose BRCA1/BRCA2 test results to a spouse or immediate family member. Attitudes toward testing varied by ethnicity, previous exposure to genetic information, age, optimism, and information style. Altruism is a factor motivating genetic testing in some people.[209] Many professional groups have made recommendations regarding informed consent.[113,209-212] There is some evidence that not all practitioners are aware of or follow these guidelines.[213] Research shows that many BRCA1/BRCA2 genetic testing consent forms do not fulfill recommendations by professional groups about the 11 areas that should be addressed,[214] and they omit highly relevant points of information.[213] In a study of women with a history of breast or ovarian cancer, the interviews yielded that the women reported feeling inadequately prepared for the ethical dilemmas they encountered when imparting genetic information to family members.[215] These data suggest that more preparation about disclosure to family members before testing reduces the emotional burden of disseminating genetic information to family members. Patients and health care providers would benefit from enhanced consideration of the ethical issues of warning family members about hereditary cancer risk. (Refer to the PDQ summaries Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information about the ethics of cancer genetics and genetic testing.)

Psychosocial Aspects of Cancer Risk Management for Hereditary Breast and Gynecologic Cancers

Psychosocial Outcome Studies

Behavioral Outcomes

A study [253] of screening behaviors of 216 self-referred, high-risk (>10% risk of carrying a BRCA1/BRCA2 pathogenic variant) women who are members of hereditary breast cancer families found a range of screening practices. Even the presence of known pathogenic variants in their families was not associated with good adherence to recommended screening practices. Sixty-nine percent of women aged 50 to 64 years and 83% of women aged 40 to 49 years had had a screening mammogram in the previous year. Twenty percent of participants had ever had a CA-125 test and 31% had ever had a pelvic ultrasound or TVUS. Further analysis of this study population [253] looking specifically at 107 women with informative BRCA test results found good use of breast cancer screening, though the uptake rate in younger carriers is lower. The reason for the lower uptake rate was not explored in this study.[254] One survey of screening behaviors among women at increased risk of breast/ovarian cancer identified physician recommendations as a significant factor in adherence to screening.[255]

While motivations cited for pursuing genetic testing often include the expectation that carriers of pathogenic variants will be more compliant with breast and/or ovarian screening recommendations,[253,256-258] limited data exist about whether participants in genetic testing alter their screening behaviors over time and about other variables that may influence those behaviors, such as insurance coverage and physician recommendations or attitudes. The impact of cancer genetic counseling on screening behaviors was assessed in a U.K. study of 293 women followed for 12 months postcounseling at four cancer genetics clinics.[259] BSE, CBE, and mammography were significantly increased after counseling; however, gaps in adherence to recommendations were noted: 38% of women aged 35 to 49 years had not had a mammogram by 12 months postcounseling. BSE was not done by most women at the recommended time and frequency.

This is a critical issue not only for women testing positive, but also for adherence to screening for those testing negative and those who have received indeterminate results or choose not to receive their results. It is possible that adherence actually diminishes with a decrease in the perceived risk that may result from a negative genetic test result.

In addition, while there is still some question regarding the link between cancer-related worry and breast cancer screening behavior, accumulating evidence appears to support a linear rather than a curvilinear relationship. That is, for some time, the data were not consistent; some data supported the hypothesis that mild-to-moderate worry may increase adherence, while excessive worry may actually decrease the utilization of recommended screening practices. Other reports support the notion that a linear relationship is more likely; that is, more worry increases adherence to screening recommendations. Few studies, however, have followed women to assess their health behaviors after genetic testing. Thus, a negative test result leading to decreased worry could theoretically result in decreased screening adherence. A large study found that patient compliance with screening practices was not related to general or screening-specific anxiety—with the exception of BSE, for which compliance is negatively associated with procedure-specific anxiety.[77] Further research designed to clarify this potential concern would highlight the need for comprehensive genetic counseling to discuss the need for follow-up screening.

Further complicating this area of research are issues such as the baseline rate of mammography adherence among women older than 40 or 50 years before genetic testing. More specifically, the ability to note a significant difference in adherence on this measure may be affected by the high adherence rate to this screening behavior before genetic testing by women undergoing such testing. It may be easier to find significant changes in mammography use among women with a family history of breast cancer who test positive. Finally, adherence over time will likely be affected by how women undergoing genetic testing and their caregivers perceive the efficacy of many of the screening options in question, such as mammography for younger women, BSE, and ovarian cancer screening (periodic vaginal ultrasound and serum CA-125 measurements), along with the value of preventive interventions.

The issue of screening decision-making and adherence among women undergoing genetic testing for breast and ovarian cancer is the subject of several ongoing trials, and an area of much needed ongoing study.

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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of breast and gynecologic cancers. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The lead reviewers for Genetics of Breast and Gynecologic Cancers are:

• Doreen Agnese, MD (The Ohio State University)
• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Ilana Cass, MD (Dartmouth-Hitchcock Medical Center)
• Lee-may Chen, MD (UCSF Helen Diller Family Comprehensive Cancer Center)
• Mary B. Daly, MD, PhD (Fox Chase Cancer Center)
• Megan Frone, MS, CGC (National Cancer Institute)
• Joanne Kotsopoulos, PhD (University of Toronto and Women's College Hospital)
• Suzanne C. O'Neill, PhD (Georgetown University)
• Tuya Pal, MD, FACMG, FCCMG (Vanderbilt-Ingram Cancer Center)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• John M. Quillin, PhD, MPH, MS (Virginia Commonwealth University)
• Padma Sheila Rajagopal, MD, MPH, MSC (National Cancer Institute)
• Charite Ricker, MS, CGC (University of Southern California)
• Mary Beth Terry, PhD (Columbia University Mailman School of Public Health)
• Catharine Wang, PhD, MSc (Boston University School of Public Health)

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PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Breast and Gynecologic Cancers. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389210]

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