NTHL1 Tumor Syndrome

Clinical characteristics.

NTHL1 tumor syndrome is characterized by an increased lifetime risk for colorectal cancer (CRC), breast cancer, and colorectal polyposis. Colorectal polyps can be adenomatous, hyperplastic, and/or sessile serrated. Duodenal polyposis has also been reported. Additional cancers reported in individuals with NTHL1 tumor syndrome include endometrial cancer, cervical cancer, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies. The cumulative lifetime risk of developing extracolonic cancer by age 60 years has been estimated at 35% to 78%.

Diagnosis/testing.

The diagnosis is established in a proband by identification of germline biallelic pathogenic variants in NTHL1 on molecular genetic testing.

Management.

Treatment of manifestations: Colorectal polyps should be removed (polypectomy) until polypectomy alone cannot manage the large size and density of the polyps. At that point, either subtotal colectomy or proctocolectomy is performed based on polyp features and location. Large duodenal polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.

Surveillance: Due to the limited number of affected individuals reported, surveillance recommendations are likely to evolve. They currently include: colonoscopy with polypectomy every two years beginning at age 18-20 years; breast MRI examination annually between ages 30 and 60 years; mammography annually between ages 40 and 50 years, then every two years between ages 50 and 75 years; transvaginal ultrasound examination and endometrial biopsy to screen for endometrial cancer every two years between ages 40 and 60 years; upper endoscopy and side-viewing duodenoscopy every five years beginning at age 25 years.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual who has germline biallelic NTHL1 pathogenic variants in order to identify as early as possible those who would benefit from appropriate surveillance, early diagnosis, and treatment of NTHL1-associated tumors.

Genetic counseling.

NTHL1 tumor syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

NTHL1 tumor syndrome should be suspected in an individual with the following clinical findings, family history, and/or molecular genetic findings on tumor tissue.

Clinical findings

• Presence of multiple primary cancers before age 50 years, especially including breast, colon, or urothelial cell cancer, brain tumors, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma
• Colorectal cancer (CRC) diagnosed before age 40 years
• One or more colorectal adenomas in an individual age ≤40 years
• A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
• A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age

Family history is consistent with autosomal recessive inheritance of multiple cancers (especially when including breast, colorectal, or urothelial cell cancer, brain tumors, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma).

Molecular genetic findings on tumor tissue. A specific mutational signature due to a high percentage of somatic C>T transversions (e.g., COSMIC Signature 30) is identified on tumor tissue testing [Grolleman et al 2019].

Establishing the Diagnosis

The diagnosis of NTHL1 tumor syndrome is established in a proband with biallelic germline NTHL1 pathogenic variants identified on molecular genetic testing [Weren et al 2015] (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of NTHL1 tumor syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of NTHL1 tumor syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

When the diagnosis of NTHL1 tumor syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, an exome array (when clinically available) may be considered to detect the known pathogenic variants as well as (multi)exon deletions or duplications. Thus far, NTHL1 copy number aberrations have not been described in individuals with NTHL1 tumor syndrome.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in NTHL1 Tumor Syndrome

Clinical Description

NTHL1 tumor syndrome has been described in 20 families including 33 affected individuals [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Broderick et al 2017, Fostira et al 2018, Altaraihi et al 2019, Belhadj et al 2019, Grolleman et al 2019, Groves et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Colon polyps. The 24 individuals reported by Grolleman et al [2019] who had been evaluated by colonoscopy were all found to have adenomatous polyps (range 1-100). Seven of these individuals had hyperplastic/sessile serrated polyps.

Colorectal cancer (CRC). Nineteen of 33 individuals reported to date developed CRC. The median age of onset was 61 years (range 33-73 years). Nine individuals were diagnosed with CRC before age 50 years [Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019]. CRC in individuals with NTHL1 tumor syndrome was mostly right-sided, but has been observed throughout the colon, from the rectum to the appendix [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019]. Metachronous or synchronous tumors were identified in six individuals [Grolleman et al 2019]. The limited number of families and the presence of a selection bias in the individuals reported to date hamper accurate cancer risk analysis. In the absence of timely surveillance, the lifetime risk for CRC in individuals with NTHL1 tumor syndrome is likely to be high.

Breast cancer was observed in nine of 15 women with NTHL1 tumor syndrome with a median age of onset of 49 years (range 38-63 years) [Grolleman et al 2019]. Three women had bilateral breast cancer. The reported subtypes included ductal, lobular, and mixed ductal/papillary. Hormone receptor status (triple negative) was reported in one individual.

Duodenal polyps and cancer. Multiple duodenal polyps were reported in two individuals with NTHL1 tumor syndrome [Weren et al 2015, Fostira et al 2018]. One individual also developed esophageal polyps. Another individual developed duodenal cancer at age 52 years [Weren et al 2015].

Other cancers. Endometrial cancer has been diagnosed in five of the 17 women with NTHL1 tumor syndrome reported thus far, with a median age of diagnosis of 57 years (range 47-74 years). Additional cancers reported in individuals with NTHL1 tumor syndrome include cervical cancer, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019]. Grolleman et al [2019] reported the presence of multiple primary tumors in 16 of 29 individuals (55%). Based on these findings, the cumulative lifetime risk of developing extracolonic cancer by age 60 years was estimated at 35% to 78% (95% CI) [Grolleman et al 2019].

Benign extraintestinal manifestations reported in some individuals include: skin hemangiomas, seborrheic keratosis, and intradermal nevi; ovarian and hepatic cysts; and breast papillomas. To date, the number of individuals reported with these features is low and an association with NTHL1 tumor syndrome is as yet unclear.

NTHL1 heterozygotes. The risk of developing CRC or other malignancy in individuals with a heterozygous germline NTHL1 pathogenic variant is unclear. In the eleven families reported by Grolleman et al [2019], three confirmed heterozygotes developed cancer. A previously reported individual with breast cancer was found to have a germline heterozygous NTHL1 variant (p.Gln287Ter) and loss of heterozygosity in tumor tissue [Nik-Zainal et al 2016, Drost et al 2017].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

This condition has been referred to as NTHL1 polyposis and familial adenomatous polyposis 3 (OMIM 616415), terms which emphasize the similarity with MUTYH polyposis [Belhadj et al 2017, Groves et al 2019, Valle et al 2019]. Considering the broad tumor spectrum reported in individuals with biallelic NTHL1 pathogenic variants, and the fact that the diagnosis has been identified in individuals without CRC and/or (suspected) polyposis, the term NTHL1 tumor syndrome is preferred.

Prevalence

The prevalence of NTHL1 tumor syndrome is unknown. Based on the prevalence of NTHL1 pathogenic variants in the population, it has been estimated that in Europeans, NTHL1 tumor syndrome would occur with a frequency approximately one fifth (1:114,770) that of MUTYH polyposis (1:19,079) [Weren et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NTHL1 tumor syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Due to the lifelong increased cancer risk and the diversity of tumors associated with NTHL1 tumor syndrome, evaluations for cancer in individuals with NTHL1 tumor syndrome need to be ongoing and comprehensive (see Surveillance). Individuals with NTHL1 tumor syndrome should seek a cancer genetics consultation to review the diagnosis and medical management recommendations.

Treatment of Manifestations

In general, the treatment regarding gastrointestinal tumors is similar to that of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (see APC-Associated Polyposis Conditions).

Colon polyps and colon cancer. Colonoscopy is effective surveillance for colon cancer; polyps should be removed (polypectomy) until polypectomy alone cannot manage the large size and density of the polyps. At that point, either subtotal colectomy or proctocolectomy is performed based on polyp features and location [Lipton & Tomlinson 2006, Sampson & Jones 2009].

Breast cancer, endometrial cancer, and other cancers. The treatment for these cancers in individuals with NTHL1 tumor syndrome is the same as for that of the general population.

Duodenal polyps. Management of polyps is similar to that in individuals with FAP. In particular, large polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.

Surveillance

Table 3.

Recommended Surveillance for Individuals with NTHL1 Tumor Syndrome

Individuals heterozygous for a germline NTHL1 pathogenic variant. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for cancer and there are no specific screening recommendations for heterozygous relatives of individuals with NTHL1 tumor syndrome. NTHL1 heterozygotes are advised to participate in population screening measures for colorectal cancer and breast cancer, or could be offered screening based on their family history (e.g., incidence of CRC and/or breast cancer in family members who do not have biallelic NTHL1 pathogenic variants).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual who has biallelic germline NTHL1 pathogenic variants in order to identify as early as possible those who would benefit from appropriate surveillance (beginning at age 18 years), early diagnosis, and treatment of NTHL1-associated tumors.

In general, molecular genetic testing for NTHL1 tumor syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with biallelic NTHL1 pathogenic variants, screening should begin by age 18 years, or two to five years earlier than the earliest diagnosis in the family [NCCN 2016]. Therefore, a history of early cancers in the family may warrant testing prior to age 18.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

NTHL1 tumor syndrome is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one NTHL1 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an NTHL1 pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• The risk for cancer in individuals with a heterozygous germline NTHL1 pathogenic variant is unclear; however, available data do not suggest that heterozygous individuals are at increased risk for colorectal cancer or breast cancer (see Management, Surveillance).

Sibs of a proband

• If each parent is known to be heterozygous for an NTHL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of not being a carrier.
• The risk of cancer in individuals with a heterozygous germline NTHL1 pathogenic variant is unclear; however, available data do not suggest that heterozygous individuals have an increased risk for colorectal cancer or breast cancer (see Management, Surveillance).

Offspring of a proband. Provided the reproductive partner of the proband is not a carrier of an NTHL1 pathogenic variant, the offspring of an individual with NTHL1 tumor syndrome are obligate heterozygotes (carriers) for a pathogenic variant in NTHL1. Given the very low carrier frequency of NTHL1 pathogenic variants (see Prevalence), it is unlikely that the reproductive partner of the proband is a carrier of an NTHL1 pathogenic variant unless consanguinity is a factor.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a NTHL1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the NTHL1 pathogenic variants in the family.

Note: If consanguinity is a factor, the reproductive partner of an individual with one or two NTHL1 pathogenic variants can be offered NTHL1 sequence analysis to clarify the risk for NTHL1 tumor syndrome in their offspring.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of appropriate surveillance, early diagnosis, and treatment of NTHL1-associated tumors.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – Health Professional Version (part of PDQ^®, National Cancer Institute).

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the NTHL1 pathogenic variants have been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• In general, genetic testing for NTHL1 tumor syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. In asymptomatic individuals with biallelic NTHL1 pathogenic variants, screening is recommended beginning at age 18 years, or two to five years prior to the earliest diagnosis in the family [NCCN 2016]. Therefore, a history of early cancers in the family may warrant testing prior to age 18.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Prenatal Testing and Preimplantation Genetic Testing

If the reproductive partner of a proband (or carrier) is also known to have one or two NTHL1 pathogenic variants, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The protein encoded by NTHL1 is a DNA glycosylase of the base-excision-repair pathway that removes endogenously damaged nucleotides in DNA [Robertson et al 2009]. Various DNA glycosylases target different types of damage caused by oxidation, deamination, or alkylation. NTHL1 specifically targets oxidized pyrimidine residues in DNA and has apurinic/apyrimidinic lyase activity [Wallace et al 2012]. Subsequently, the repair process completes with the incorporation of the correct nucleotide or elongation of multiple nucleotides by a DNA polymerase and sealing of the remaining nick by a DNA ligase [Svilar et al 2011, Wallace et al 2012, Krokan et al 2014].

NTHL1 tumor syndrome is an autosomal recessive condition caused by biallelic NTHL1 pathogenic variants. Thus far, all nine identified variants are either stop-gain, frameshift-, or splice site variants, likely resulting in disruption of both alleles. Therefore, in affected individuals every cell is NTHL1 deficient, resulting in slow but progressive accumulation of somatic pathogenic variants, thereby increasing the risk of cancer in tissues that are most vulnerable to this type of damage.

Mechanism of disease causation. Currently, the nine different NTHL1 pathogenic variants identified in NTHL1 tumor syndrome lead to premature stop codons (see Table 4).

Individuals with biallelic NTHL1 loss-of-function pathogenic variants develop tumors that have somatic pathogenic variants strongly biased towards C>T transitions, predominantly at non-CpG sites [Weren et al 2015]. Analysis of the somatic mutational patterns in NTHL1-deficient colon organoid clones and in multiple tumors of persons with biallelic germline NTHL1 pathogenic variants revealed that loss of NTHL1 function elicits a specific mutational signature [Grolleman et al 2019]. The resulting mutational process is most prominent in tissues with higher proliferation rates and/or higher rates of oxidative damage, and increases the chance that cancer-driver genes are hit by a pathogenic variant. Establishing the mutational pattern in tumor tissue can be of help in proving the pathogenicity of (novel) NTHL1 variants.

Table 4.

Notable NTHL1 Pathogenic Variants

Revision History

• 2 April 2020 (sw) Review posted live
• 17 June 2019 (nh/rk) Original submission

Literature Cited

• Altaraihi M, Gerdes AM, Wadt K. A new family with a homozygous nonsense variant in NTHL1 further delineated the clinical phenotype of NTHL1-associated polyposis. Hum Genome Var. 2019;6:46. [PMC free article: PMC6804823] [PubMed: 31645984]

• Belhadj S, Mur P, Navarro M, González S, Moreno V, Capellá G, Valle L. Delineating the phenotypic spectrum of the NTHL1-associated polyposis. Clin Gastroenterol Hepatol. 2017;15:461–2. [PubMed: 27720914]

• Belhadj S, Quintana I, Mur P, Munoz-Torres PM, Alonso MH, Navarro M, Terradas M, Piñol V, Brunet J, Moreno V, Lázaro C, Capellá G, Valle L. NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. Sci Rep. 2019;9:9020. [PMC free article: PMC6588610] [PubMed: 31227763]

• Broderick P, Dobbins SE, Chubb D, Kinnersley B, Dunlop MG, Tomlinson I, Houlston RS. Validation of recently proposed colorectal cancer susceptibility gene variants in an analysis of families and patients-a systematic review. Gastroenterology. 2017;152:75–7.e4. [PMC free article: PMC5860724] [PubMed: 27713038]

• Chubb D, Broderick P, Dobbins SE, Frampton M, Kinnersley B, Penegar S, Price A, Ma YP, Sherborne AL, Palles C, Timofeeva MN, Bishop DT, Dunlop MG, Tomlinson I, Houlston RS. Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nat Commun. 2016;7:11883. [PMC free article: PMC4917884] [PubMed: 27329137]

• Drost J, van Boxtel R, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, de Ligt J, Behjati S, Grolleman JE, van Wezel T, Nik-Zainal S, Kuiper RP, Cuppen E, Clevers H. Use of CRIPSR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science. 2017;358:234–8. [PMC free article: PMC6038908] [PubMed: 28912133]

• Fostira F, Kontopodis E, Apostolou P, Fragkaki M, Androulakis N, Yannoukakos D, Konstantopoulou I, Saloustros E. Extending the clinical phenotype associated with biallelic NTHL1 germline mutations. Clin Genet. 2018;94:588–9. [PubMed: 30248171]

• Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA, Palles C, Ligtenberg MJL, Vos JR, Ten Broeke SW, de Miranda NFCC, et al. Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype. Cancer Cell. 2019;35:256–66. [PubMed: 30753826]

• Groves A, Gleeson M, Spigelman AD. NTHL1-associate polyposis: first Australian case report. Fam Cancer. 2019;18:179–82. [PubMed: 30859360]

• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, et al. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]

• Krokan HE, Saetrom P, Aas PA, Pettersen HS, Kavli B, Slupphaug G. Error-free versus mutagenic processing of genomic uracil - relevance to cancer. DNA Repair. 2014;19:38–47. [PubMed: 24746924]

• Lipton L, Tomlinson I. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006;5:221–6. [PubMed: 16998667]

• NCCN. National Comprehensive Cancer Network guidelines for colorectal cancer screening. 2016.

• Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, Martincorena I, Alexandrov LB, Martin S, Wedge DC, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54. [PMC free article: PMC4910866] [PubMed: 27135926]

• Rivera B, Castellsagué E, Bah I, van Kempen LC, Foulkes WD. Biallelic NTHL1 mutations in a woman with multiple primary tumors. N Engl J Med. 2015;373:1985–6. [PubMed: 26559593]

• Robertson AB, Klungland A, Rognes T, Leiros I. DNA repair in mammalian cells: Base excision repair: the long and short of it. Cell Mol Life Sci. 2009;66:981–93. [PubMed: 19153658]

• Sampson JR, Jones N. MUTYH-associated polyposis. Best Pract Res Clin Gastroenterol. 2009;23:209–18. [PubMed: 19414147]

• Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet. 1989;2:783–5. [PubMed: 2571019]

• Svilar D, Goellner EM, Almeida KH, Sobol RW. Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage. Antioxid Redox Signal. 2011;14:2491–507. [PMC free article: PMC3096496] [PubMed: 20649466]

• Valle L, de Voer RM, Goldberg Y, Sjursen W, Försti A, Ruiz-Ponte C, Caldés T, Garré P, Olsen MF, Nordling M, Castellvi-Bel S, Hemminki K. Update on genetic predisposition to colorectal cancer and polyposis. Mol Aspects Med. 2019;69:10–26. [PubMed: 30862463]

• Wallace SS, Murphy DL, Sweasy JB. Base excision repair and cancer. Cancer Lett. 2012;327:73–89. [PMC free article: PMC3361536] [PubMed: 22252118]

• Weren RDA, Ligtenberg MJL, Kets CM, de Voer RM, Verwiel ET, Spruijt L, van Zelst-Stams WA, Jongmans MC, Gilissen C, Hehir-Kwa JY, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015;47:668–71. [PubMed: 25938944]

• Weren RD, Ligtenberg MJ, Geurts van Kessel A, de Voer RM, Hoogerbrugge N, Kuiper RP. NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 2018;244:135–42. [PubMed: 29105096]