Clinical characteristics.

ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings, ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest an overall penetrance of approximately 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.

Diagnosis/testing.

ALK-related neuroblastic tumor susceptibility is established by identification of a heterozygous germline ALK activating pathogenic variant in the tyrosine kinase domain that is known or suspected to cause altered kinase function.

Management.

Treatment of manifestations: Children who develop neuroblastic tumors should be evaluated and treated by a pediatric oncologist at a pediatric cancer center. Treatment for individuals with neuroblastoma and ganglioneuroblastoma who have a germline ALK activating pathogenic variant is the same standard risk-stratified therapy used to treat all neuroblastoma. Ganglioneuromas are typically removed by surgical resection and require no further therapy.

Surveillance:

• Asymptomatic children. Physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every three months between birth and age six years. Physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) every six months between age six years and ten years. Screening beyond age ten years is not indicated.
• After successful treatment of a neuroblastic tumor. Screening for neuroblastoma should continue since children with ALK-related neuroblastoma are at risk of developing multiple primary tumors. Screening should continue as described above until age ten years.

Evaluation of relatives at risk: It is appropriate to test relatives at risk (i.e., sibs age <10 years at the time of diagnosis of the proband, as well as sibs born subsequently) for the ALK pathogenic variant found in the proband to identify those for whom early detection of neuroblastoma and initiation of therapy would likely improve quality of life and possibly affect outcome (if therapy is started prior to end organ damage).

Genetic counseling.

ALK-related neuroblastic tumor susceptibility is inherited in an autosomal dominant manner, with reduced penetrance. Some individuals diagnosed with ALK-related neuroblastic susceptibility have an affected parent who may have had any one of the three neuroblastic tumor types. De novo germline pathogenic variants have been reported; the proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with ALK-related neuroblastic tumor susceptibility has a 50% chance of inheriting the ALK pathogenic variant; however, the likelihood that a child who inherits the ALK pathogenic variant will develop a neuroblastic tumor is unknown. Prenatal testing is possible for pregnancies at increased risk in families in which the pathogenic variant has been identified.

Suggestive Findings

ALK-related neuroblastic tumor susceptibility should be suspected in individuals with:

• A neuroblastic tumor including neuroblastoma, ganglioneuroblastoma, or ganglioneuroma;
• Multiple primary neuroblastic tumors that arise either synchronously or metachronously;
• A family history of one or more relatives with one of these three neuroblastic tumors. Note: Both benign and malignant tumors can occur in the same family.

Written guidelines for selection of individuals with a neuroblastic tumor to be tested for germline ALK pathogenic variants are under development, and no consensus opinion currently exists.

Considerations for testing for germline ALK pathogenic variants include the following strong and moderate recommendations [Bourdeaut et al 2012, Brodeur et al 2017].

Establishing the Diagnosis

ALK-related neuroblastic tumor susceptibility is established in a proband by identification of a heterozygous germline ALK activating pathogenic variant in the tyrosine kinase domain that is known or suspected to cause altered kinase function (see Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of ALK may detect heterozygous germline activating pathogenic variants in the tyrosine kinase domain that are known or suspected to cause altered kinase function.
  Note: ALK-related neuroblastic tumor susceptibility is postulated to occur through a gain-of-function mechanism. Large intragenic deletion or duplication has not been reported; testing for intragenic deletions or duplication is not indicated.
• A multigene panel that includes ALK and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Individuals with ALK-related neuroblastic tumor susceptibility are at risk of developing a spectrum of neuroblastic tumors that include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Within this spectrum, neuroblastoma represents a more malignant tumor and ganglioneuroma a more benign tumor. The three neuroblastic tumor types are defined histologically. Depending on the histologic findings, ganglioneuroblastoma can behave in a benign fashion, like ganglioneuroma, or in a more aggressive fashion, like neuroblastoma.

Data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest that the overall penetrance of this cancer predisposition syndrome is around 57% [Eng 2008]. A recent study showed that 45%-50% of individuals with a germline ALK pathogenic variant will develop a neuroblastic tumor in their lifetime [Brodeur et al 2017].

Risk for neuroblastic tumor development is highest in infancy and decreases by late childhood, with 98% of neuroblastic tumors occurring by age ten years [Brodeur et al 2017]. Individuals with familial neuroblastoma tend to develop tumors at a younger age (average 9 months) than those without familial predisposition (age 2-3 years) [Park et al 2008].

Multiple primary tumors. Individuals with familial neuroblastoma also have a higher-than-average incidence of multiple primary tumors [Mossé et al 2008, Park et al 2008]. The multiple primary tumors may be bilateral adrenal tumors or multiple primary extra-adrenal tumors arising at sites of sympathetic ganglions. The tumors can occur either synchronously or metachronously [Bourdeaut et al 2012].

Outcome. Given the rarity of familial neuroblastic tumors, statistically significant long-term outcome data are not yet available for individuals with ALK-related neuroblastic tumor susceptibility. Although long-term survivors of neuroblastoma who are heterozygous for an inherited germline ALK pathogenic variant have been reported [Carén et al 2008], no prospective studies have evaluated the survival of persons with a germline ALK pathogenic variant compared to those with neuroblastoma not associated with a germline ALK pathogenic variant.

Since neuroblastomic tumor outcome is heavily dependent on biological characteristics and stage of the tumor, it is likely that survival from a neuroblastic tumor depends more on tumor type (neuroblastoma having the poorest outcome), tumor stage, and appropriate medical intervention than on the presence or absence of a germline ALK activating pathogenic variant [Park et al 2008].

Genotype-Phenotype Correlations

Aside from the following pathogenic variants, no associations between specific germline ALK pathogenic variants and risk of developing neuroblastoma or outcome of neuroblastoma have been established [Azarova et al 2011].

• p.Arg1275Gln, found in approximately 45% of individuals with a germline ALK pathogenic variant [Wood et al 2009], may be associated with somewhat decreased penetrance (40%).
• p.Gly1128Ala, reported as a germline ALK pathogenic variant in one large family, appeared to have lower penetrance: 40% of heterozygotes developed a neuroblastoma during childhood [Mossé et al 2008]. Adult heterozygotes were healthy; no tumor types other than neuroblastoma were reported.

Penetrance

The overall penetrance of a germline ALK pathogenic variant is approximately 50% [Brodeur et al 2017]. Several obligate heterozygous asymptomatic adults have been identified [Mossé et al 2008, Bourdeaut et al 2012]. In at least one family, a child with neuroblastoma inherited the p.Arg1275Gln pathogenic variant from an unaffected father [Mossé et al 2008].

See also Genotype-Phenotype Correlations for information on penetrance.

Prevalence

Familial neuroblastoma occurs in approximately 1%-2% of all individuals with neuroblastoma [Weiss et al 2016]. Of those familial cases, gain-of-function pathogenic variants in ALK account for 75% [Ritenour et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ALK-related neuroblastic tumor susceptibility, the evaluations summarized in this section are recommended:

• Physical examination to assess for clinical manifestations of neuroblastic tumors such as an abdominal mass, Horner syndrome, and/or cutaneous lesions
• Radiograph of the chest and ultrasound examination of the abdomen, the most common sites for neuroblastic tumor development
• Measurement of urine catecholamines, as homovanillic acid and vanillylmandelic acid may be elevated in the presence of a neuroblastic tumor
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Children who develop neuroblastic tumors (neuroblastomas, ganglioneuroblastoma, or ganglioneuroma) should be evaluated and treated by a pediatric oncologist at a pediatric cancer center.

Neuroblastoma and ganglioneuroblastoma. The treatment for individuals with a neuroblastic tumor who have a germline ALK activating pathogenic variant is the same standard risk-stratified therapy used to treat all neuroblastic tumors. Clinical trials are ongoing to study the efficacy of ALK-targeted therapy in the setting of relapsed and refractory neuroblastoma and ganglioneuroblastoma (see Therapies Under Investigation).

The management guidelines for neuroblastoma or ganglioneuroblastoma are complex [Irwin & Park 2015]:

• Depending on the age of the affected individual, stage of the tumor, and biologic characteristics of the tumor, treatment may involve observation or surgical resection.
• Tumors with risk for metastatic spread or those that have already metastasized require chemotherapy and sometimes radiation therapy, stem cell transplantation, and immunotherapy.

Ganglioneuromas are typically removed by surgical resection and require no further therapy.

Surveillance

Asymptomatic children at risk. Guidelines for the screening of individuals with familial neuroblastoma – including those with germline ALK activating pathogenic variants – were published in 2017 [Brodeur et al 2017]. These surveillance recommendations include physical examination, abdominal ultrasound examination, chest x-ray, and measurement of urine catecholamine metabolite levels (homovanillic acid and vanillylmandelic acid) at the following frequency:

• Birth to age 6 years. Every three months
• Age 6-10 years. Every six months

Screening beyond age ten years is not indicated.

After successful treatment of a neuroblastic tumor, screening for neuroblastic tumors should continue since children with ALK-related neuroblastic tumor susceptibility are at risk of developing multiple primary tumors. Screening should continue as described above until ten years of age.

Agents/Circumstances to Avoid

There is currently no evidence that individuals with ALK-related neuroblastoma tumor susceptibility have increased sensitivity to chemotherapeutic agents or radiation therapy; thus, medical and surgical management of tumors should be the same as for the general population.

Evaluation of Relatives at Risk

It is appropriate to test sibs younger than age ten years at the time of the proband's diagnosis as well as sibs born subsequently for the ALK pathogenic variant found in the proband. Genetic testing identifies sibs at high risk for neuroblastoma, for whom early detection of neuroblastoma and initiation of therapy would likely improve quality of life and may affect outcome (if therapy is started prior to end organ damage).

Note: Sibs of all probands with neuroblastoma have an increased chance of developing neuroblastoma themselves, with a standardized incidence ratio of 9.7 compared to the general population [Mossé et al 2008]. This increased risk is likely due in part to the possibility of inherited germline ALK pathogenic variants in some children with neuroblastoma.

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

Therapies Under Investigation

Several early-phase clinical trials of small-molecule inhibitors targeting the ALK tyrosine kinase domain have been completed in individuals with ALK-aberrant neuroblastoma. In addition, several trials are ongoing. The role of these agents for the treatment of ALK-aberrant neuroblastoma is yet to be elucidated. Currently, the Children's Oncology Group Phase III trial for children with high-risk neuroblastoma is incorporating the ALK inhibitor crizotinib into the frontline treatment for individuals whose tumors harbor an ALK aberration.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

ALK-related neuroblastic tumor susceptibility is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with ALK-related neuroblastic susceptibility inherited an ALK pathogenic variant from a heterozygous parent.
  • Because of reduced penetrance, a parent may have a germline ALK activating pathogenic variant without having developed a neuroblastic tumor (neuroblastoma, ganglioneuroma, or ganglioneuroblastoma) [Janoueix-Lerosey et al 2008, Mossé et al 2008].
  • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline ALK activating pathogenic variants and no data regarding the cancer risk for heterozygous adult parents of a child with ALK-related neuroblastic susceptibility have been published.
• Some individuals diagnosed with ALK-related neuroblastic tumor susceptibility may have the disorder as the result of a de novo germline ALK activating pathogenic variant. De novo germline pathogenic variants have been reported; their proportion is unknown.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo germline ALK activating pathogenic variant.
• If the germline ALK activating pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.
• The family history of some individuals diagnosed with ALK-related neuroblastic tumor susceptibility may appear to be negative because of reduced penetrance or failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither of the parents has the germline ALK pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected or has a germline ALK activating pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. The likelihood that a sib who inherits the ALK pathogenic variant will develop a neuroblastic tumor is not yet definitively known, but likely a 45%-50% chance.
• If the proband has a known ALK pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• The sibs of a proband with clinically unaffected parents whose ALK variant status is unknown are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual with ALK-related neuroblastic tumor susceptibility has a 50% chance of inheriting the ALK pathogenic variant.
• The likelihood that a child who inherits the ALK pathogenic variant will develop a neuroblastic tumor is unknown, though the penetrance is high (57%) [Eng 2008] and the relative risk (compared to a child in the general population) of developing a neuroblastic tumor is substantial.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a germline ALK activating pathogenic variant, members of the parent's family may be at risk for neuroblastoma or related tumors.

Related Genetic Counseling Issues

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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Testing of at-risk asymptomatic relatives of individuals with ALK-related neuroblastic tumor susceptibility is possible after molecular genetic testing has identified the specific germline ALK pathogenic variant in the family. Although molecular genetic testing can identify the presence of an ALK pathogenic variant, it cannot predict whether neuroblastoma, ganglioneuroma, or ganglioneuroblastoma will develop.

Family planning

• The optimal time for determination of genetic risk 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, have a germline ALK activating pathogenic variant, or are at risk of having a germline ALK activating pathogenic variant.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the germline ALK activating pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Note: Although molecular genetic testing can identify the presence of a germline ALK activating pathogenic variant, it cannot predict whether neuroblastoma will develop.

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

ALK is predicted to function as an oncogene in the pathogenesis of neuroblastoma [Chen et al 2008, George et al 2008, Janoueix-Lerosey et al 2008, Mossé et al 2008]. Somatic chromosomal translocations causing constitutive activation of ALK are known to mediate malignant transformation in other types of tumors such as non-small-cell lung cancer (ALK/EML4 fusion protein) and anaplastic large-cell lymphoma (ALK/NPM1) [Palmer et al 2009].

In ALK-related neuroblastoma, both germline and somatic pathogenic variants are found exclusively within the tyrosine kinase domain of ALK. These pathogenic variants lead to constitutive phosphorylation and activation of the ALK protein. Somatic amplification of ALK on chromosome 2p23 has also been identified in a subset of sporadic neuroblastomas with unfavorable biologic characteristics and aggressive clinical course.

Gene structure. ALK comprises 29 coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The vast majority (91%) of ALK pathogenic variants fall within the kinase domain [Chen et al 2008]. Missense variants in the tyrosine kinase domain of ALK are associated with ALK-related neuroblastic tumor susceptibility [Mossé et al 2008].

The variant p.Arg1275Gln, the most commonly reported germline pathogenic variant, is found in approximately 45% of individuals with a germline pathogenic variant [Wood et al 2009]; it is also the most common somatic pathogenic variant.

Normal gene product. ALK encodes a 1,620-amino acid protein that is a single chain receptor tyrosine kinase; its normal function is not known [Mossé et al 2008]. Expression is restricted to the developing central and peripheral nervous system with a postulated role in regulation of neuronal differentiation.

Abnormal gene product. Pathogenic variants in the tyrosine kinase domain of ALK result in constitutive phosphorylation [Mossé et al 2008] and are predicted with high probability to drive oncogenesis [Mossé et al 2008]. Both ALK pathogenic variants and amplifications have been shown to have direct oncogenic effect, as evidenced by autophosphorylation of mutated strains and activation of downstream targets in neuroblastoma cell lines harboring ALK pathogenic variants and amplification [Janoueix-Lerosey et al 2008, Mossé et al 2008]. Tumors with aberrant ALK signaling display transforming potential in vivo, inducing soft agar colony formation in mutated cell lines, rapid tumor growth in nude mice, and increased apoptosis in response to small interfering or small-hairpin RNA targeted against ALK [Chen et al 2008, George et al 2008, Park et al 2008].

Cancer and Benign Tumors

Fusion proteins resulting from somatic translocations involving ALK have been implicated in several types of cancer. In all these tumors, aberrant ALK signaling occurs as a result of a chromosome translocation involving the ALK locus at 2p23. In contrast, germline and somatic ALK pathogenic variants have only been discovered in neuroblastoma.

Fusion proteins

• Anaplastic large-cell lymphomas harbor a characteristic chromosome 2;5 translocation involving ALK and NPM1 (encoding nucleophosmin), which may be referred to as ALK/NPM1 [Morris et al 1994].
• ALK/EML4 fusion transcripts are found in a subset of individuals with non-small-cell lung cancer, all of whom lack EGFR pathogenic variants [Soda et al 2007].
• ALK fusion proteins have also been described in inflammatory myofibroblastic tumors, diffuse large B-cell lymphomas, and squamous cell carcinomas of the esophagus [Palmer et al 2009].

Somatic ALK pathogenic variants. The frequency of somatic ALK pathogenic variants involving neuroblastoma tumor tissue is 6%-12% [Santani A & Maris J, personal communication]. Disruption of normal ALK signaling is likely to play a critical role in neuroblastic tumor pathogenesis. Furthermore, it appears that individuals whose tumor harbors a somatic ALK activating pathogenic variant or ALK amplification (i.e., >10 copies of ALK) have a poorer prognosis than individuals with otherwise similar tumor stage and biology [Chen et al 2008; Mossé et al 2008; Mossé et al 2013; Santani A & Maris J, personal communication].

Preclinical data suggest that responsiveness to crizotinib may depend on the presence or absence and specific type of somatic ALK pathogenic variant (i.e., in the tumor). Specifically, tumors with the somatic ALK pathogenic variants p.Phe1174Leu, p.Gly1128Ala, p.Met1166Arg, p.Phe1245Cys, p.Phe1245Val, and p.Tyr1278Ser are relatively crizotinib resistant, whereas the p.Ile1170Asn, p.Ile1170Ser, p.Ile1171Asn, p.Leu1196Met, and p.Arg1275Gln variants are sensitive to crizotinib. The p.Arg1192Pro variant is intermediate in sensitivity [Mossé et al 2013]. Subsequent Phase II and III clinical trials for neuroblastoma will incorporate ALK molecular genetic testing for the tumors of all individuals enrolled in the trial.

These data have been confirmed in other studies as well. For example, human neuroblastoma-derived cell lines harboring mutated proteins with the p.Arg1275Gln substitution, the most common abnormal protein described in ALK-related neuroblastoma [Azarova et al 2011], were more sensitive to the small-molecule ALK inhibitor PF-02341066 than cell lines harboring proteins with the p.Phe1174Leu substitution or those without ALK aberrations [Wood et al 2009]. The cell line most sensitive to pharmacologic inhibition harbors high-level amplification of ALK (wild type sequence). Clinical correlation in individuals with neuroblastoma has yet to be determined [Wood et al 2009].

The variant p.Phe1174Leu, associated with amplification of the oncogene MYCN, is found as a somatic pathogenic variant in 30% of sporadic neuroblastoma tumors that harbor an ALK pathogenic variant [Carpenter & Mossé 2012]. Individuals with this pathogenic variant have a worse prognosis than individuals with MYCN amplification alone [Azarova et al 2011].

Author History

Emily G Greengard, MD (2015-present)
Rebecca H Johnson, MD; Seattle Children's Hospital (2009-2015)
Julie R Park, MD (2009-present)

Revision History

• 17 January 2019 (sw) Comprehensive update posted live
• 9 April 2015 (me) Comprehensive update posted live
• 9 May 2013 (cd) Revision: ALK sequence analysis available clinically
• 27 September 2012 (me) Comprehensive update posted live
• 5 January 2010 (me) Review posted live
• 14 August 2009 (rhj) Original submission

Published Guidelines / Consensus Statements

• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 5-24-22.

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