Clinical Diagnosis

Individuals with ALK-related neuroblastoma susceptibility (i.e., heterozygous for an ALK mutation) are at risk of developing neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Often the family history is positive for one or more relatives with one of these tumors [Mossé et al 2008] with both benign and malignant forms occurring in the same family.

Molecular Genetic Testing

Gene. ALK is the only gene associated with ALK-related neuroblastoma susceptibility.

Clinical testing

Sequence analysis of select exons. Mutations in the ALK tyrosine kinase domain are seen in the vast majority of familial neuroblastoma.

• In families with two or more first-degree relatives with neuroblastoma, the incidence of ALK germline mutations is high. In eight families in which at least three members had neuroblastoma, six (75%) had heterozygous ALK germline mutations [Mossé et al 2008].

• In families in which two second-degree or more distant relatives have neuroblastoma, the incidence of ALK germline mutation is much lower.

Molecular diagnostic laboratories currently evaluate only the tyrosine kinase domain (exons 21-28) of the ALK gene. To date all reported disease-associated ALK mutations are located in the tyrosine kinase domain and the majority are thought to be drivers of an oncogenic process [Mossé et al 2008].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Summary of Molecular Genetic Testing Used in ALK-Related Neuroblastoma Susceptibility

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1			Test Availability
			Familial 2	Simplex 3
ALK	Sequence analysis of select exons 4	Sequence variants in the selected exons	75% 5		Rare 6	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Familial ALK-related neuroblastoma susceptibility is defined as a proband with neuroblastoma plus a minimum of one first-degree relative with neuroblastoma, ganglioneuroblastoma, or ganglioneuroma.

3. Simplex is defined as a single case of neuroblastoma in a family.

4. Select exons 21-28 that encode the tyrosine kinase domain. All reported disease-associated ALK mutations are located in the tyrosine kinase domain, and all of these have been found to be oncogenic [Mossé et al 2008].

5. Mossé et al [2008]

6. Mossé et al [2008] tested 167 tumors from simplex cases with high-risk neuroblastomas and found 14 somatic missense mutations that were predicted to be activating mutations. From the 14 individuals with somatic mutations, germline DNA was available from nine. One of the nine, the ALK mutation Ile1250Thr, was identified in germline DNA as well as in tumor DNA.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis of ALK-related neuroblastoma susceptibility in a proband requires identification of a sequence variant in the tyrosine kinase domain of ALK that is known or suspected to cause altered kinase function.

• Guidelines for appropriate use of this test in individuals with neuroblastoma are currently under development. No consensus opinion currently exists on the criteria for testing. Some institutions are currently screening all children with neuroblastoma; others are screening only individuals with a strong family history of neuroblastoma.

• Testing a proband for an ALK germline mutation is definitely recommended if at least two first-degree relatives in a family (including the index case) have neuroblastoma, ganglioneuroma, or ganglioneuroblastoma.

  • Testing of probands with more distant relatives (≥2^nd degree) with a history of neuroblastoma, ganglioneuroma, or ganglioneuroblastoma may be considered, but the mutation detection frequency is expected to be much lower [Mossé et al 2008].

  • ALK testing should be considered particularly in families with no history of neural crest disorder (e.g., Hirschsprung disease or central hypoventilation syndrome), the presence of which would suggest a PHOX2B mutation [Mossé et al 2008]. (See also Differential Diagnosis.)

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Germline ALK mutations. No phenotypes other than hereditary predisposition to neuroblastoma are known to be associated with germline ALK mutations.

Somatic ALK mutations. Fusion proteins resulting from somatic translocations involving the ALK gene have been implicated in several types of cancer. In all these tumors, aberrant ALK signaling occurs as a result of a chromosomal translocation involving the ALK locus at 2p23; germline and somatic mutations in the ALK gene have only been discovered in neuroblastoma. The frequency of mutations involving ALK in neuroblastoma tumor (i.e., somatic) tissue is 6%-12% [Santani & Maris 2009, personal communication].

Anaplastic large-cell lymphomas harbor a characteristic chromosome 2;5 translocation involving ALK and NPM1, the gene encoding nucleophosmin. This translocation can be referred to as ALK/NPM1 [Morris et al 1994].

• ALK/EML4 fusion transcripts are found in a subset of patients with no-small cell lung cancer, all of whom lack EGFR mutations [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].

Preliminary evidence suggests that response to ALK inhibitors in neuroblastoma may vary by somatic alteration (differing mutations vs high-level amplification). For example, human neuroblastoma-derived cell lines harboring p.Arg1275Gln mutations were more sensitive to the small molecule inhibitor PF-02341066 than cell lines with p.Phe1174Leu mutations 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).

Natural History

Individuals with ALK-related neuroblastoma susceptibility (i.e., heterozygous for ALK mutations) are at risk of developing neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. The risk of tumor development is highest in infancy and decreases by late childhood. 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]. Individuals with familial neuroblastoma also have a higher incidence of multiple primary tumors [Mossé et al 2008, Park et al 2008]. There are no data at present regarding the specific percentage of individuals with germline mutations in ALK who will develop tumors in their lifetime.

Probands with ALK-related neuroblastoma susceptibility often present with a family history of neuroblastoma, but they usually do not have a family history of dysmorphic features or co-morbid illnesses, such as Hirschsprung disease.

Statistically significant long-term outcome data are not yet available for individuals with ALK-related neuroblastoma susceptibility. Although long term survivors of neuroblastoma who are heterozygous for familial ALK mutations have been reported [Carén et al 2008], no prospective studies have evaluated the survival of persons with germline ALK mutations compared to those with neuroblastoma not associated with germline ALK mutations.

Since neuroblastoma outcome is heavily dependent on biologic characteristics and stage of the tumor, it is likely that survival from neuroblastoma depends more upon tumor type, tumor stage, and appropriate medical intervention than on the presence or absence of a germline ALK mutation [Park et al 2008]. The potential prognostic impact of ALK genomic aberrations on outcome, especially within risk subsets, has yet to be determined.

In addition to germline mutations, ALK activation by somatic mutation or gene amplification has been found in up to 12% of sporadic neuroblastomas [Mossé et al 2008]. Disruption of normal ALK signaling is likely to play a critical role in neuroblastoma pathogenesis, but the prognostic significance of ALK mutation or overexpression has yet to be verified in large studies [Chen et al 2008; Mossé et al 2008; Santani & Maris 2009, personal communication].

Cancer risk. Data from the ten reported families with ALK-related neuroblastoma susceptibility suggest that the overall penetrance of this cancer predisposition syndrome is around 57% [Eng 2008]. One large family with a Gly1128Ala mutation appeared to have lower penetrance, with 40% of heterozygotes developing a neuroblastoma during childhood [Mossé et al 2008]. Adult heterozygotes in this kindred were healthy; no tumor types other than neuroblastoma were reported. Penetrance among families with all other mutations was 61%. These data are preliminary, as the number of reported cases remains small [Eng 2008].

Genotype-Phenotype Correlations

The vast majority (91%) of ALK disease-causing mutations fall within the kinase domain [Chen et al 2008]. All reported mutations in the kinase domain appear to be oncogenic [Mossé et al 2008].The most commonly reported germline mutation is p.Arg1275Gln, found in approximately 45% of cases [Wood et al 2009]; it is also the most common somatic mutation.

The Gly1128Ala mutation may be associated with somewhat decreased penetrance compared with all other reported mutations (40% vs. 61%, respectively) [Eng 2008].

No reported ALK mutations are associated with either increased frequency of tumor formation or more aggressive disease behavior.

Penetrance

Inheritance is autosomal dominant with incomplete penetrance. Several asymptomatic adults who are obligate heterozygotes have been identified [Mossé et al 2008]. It is possible that the reduced penetrance is associated either with intragenic ALK variants or variants elsewhere in the genome that contribute to altering susceptibility to neuroblastoma.

Prevalence

About 1%-2% of index cases of neuroblastoma have a close relative with neuroblastoma. ALK germline mutations are found in kindreds with familial neuroblastoma and in rare cases of simplex neuroblastoma (i.e., a single occurrence in a family) [Mossé et al 2008].

Evaluations Following Initial Diagnosis

No guidelines have been established for initial screening for individuals diagnosed with ALK-related neuroblastoma susceptibility.

Treatment of Manifestations

Children who develop neuroblastomas or other tumors of neural crest origin should be evaluated and treated by a pediatric oncologist at a pediatric cancer center.

The management guidelines for neuroblastoma are complex:

• Depending on the age of the patient, stage of the tumor, and biologic characteristics of the tumor, treatment may involve observation or surgical resection.

• Tumors with risk for metastatic spread require chemotherapy and sometimes radiation therapy.

Surveillance

Large-scale, population-based studies in Japan, Europe, Canada, and the US that screened healthy infants to identify early-stage neuroblastomas found no improvement in survival in children diagnosed before symptoms occurred [Schilling et al 2002, Woods et al 2002].

Because no data are available as yet on the effect of screening in families with germline ALK mutations and because surveillance at the population level does not improve neuroblastoma outcome, there is currently no consensus on the proper frequency or type of tumor surveillance for individuals with ALK germline mutations. In the absence of published guidelines, noninvasive measures with limited toxicity are currently recommended for screening of asymptomatic children with known ALK germline mutations.

Surveillance is at the discretion of the medical provider. Abdominal ultrasound examination and measurement of urine catecholamine metabolite levels, which are noninvasive and relatively safe screening methods, have been performed on the following schedule; less frequent intervals may also be appropriate.

• Every 1-2 months in infants age ≤12 months

• Every 3-4 months during childhood age ≤10 years

Screening should continue even after the diagnosis of a tumor, since individuals with ALK-related neuroblastoma are at risk of developing multiple primary tumors.

Agents/Circumstances to Avoid

There is currently no evidence that individuals with ALK-related neuroblastoma susceptibility have increased sensitivity to chemotherapeutic agents or radiation therapy. Medical and surgical management of tumors should not differ from that of the general population.

Testing of Relatives at Risk

In families with documented ALK-related neuroblastoma susceptibility (i.e., a known disease-causing ALK mutation is segregating in the family), testing of all first-degree relatives, including minors, is indicated because heterozygotes are at significant risk of developing cancer at a young age.

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

Therapies Under Investigation

Small molecule inhibitors targeting the ALK tyrosine kinase domain are currently under development; oral preparations have shown clinical activity in early clinical trials in adults [Kwak et al 2009]. Translocations involving ALK are found in several types of sporadic cancer including anaplastic large cell lymphoma and a subset of patients with nonsmall cell lung carcinoma [Kwak et al 2009]. These agents show promise for treating tumors with ALK deregulation, including neuroblastoma; one such agent is currently in clinical trials in the Children’s Oncology Group: “A Phase I/II study of PF-02341066, an oral small-molecule inhibitor of anaplastic lymphoma kinase (ALK) and C-Met, in children with relapsed/refractory solid tumors and anaplastic large-cell lymphoma.” (ADVL0912) [Wood et al 2009].

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

ALK-related neuroblastoma susceptibility is inherited in an autosomal dominant manner, with incomplete penetrance [Mossé et al 2008].

Risk to Family Members

Parents of a proband

• Some, but not all, individuals diagnosed with ALK-related neuroblastoma susceptibility have an affected parent. Because of incomplete penetrance, a parent may have the ALK mutation without having had neuroblastoma [Janoueix-Lerosey et al 2008, Mossé et al 2008].

• Parents of a proband should be offered molecular genetic testing for the ALK mutation identified in their child.

• As yet, no data regarding the cancer risk for adults with ALK germline mutations have been published. However, in other familial cancer syndromes where the proband is a child (e.g., hepatoblastoma, familial adenomatous polyposis), adult family members who are heterozygous for a germline mutation may be at risk for other tumors even if they did not develop a tumor during childhood [Aretz et al 2006].

• A proband with ALK-related neuroblastoma susceptibility may have the disorder as the result of a new gene mutation. Although the proportion of cases caused by de novo mutations is unknown, new mutations have been reported. In at least one family, a child with neuroblastoma inherited a de novo p.Arg1275Gln mutation from an unaffected father [Mossé et al 2008].

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported to date, it remains a possibility.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include testing for the mutation detected in the proband. Evaluation of parents may determine that one is heterozygous for an ALK mutation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although some individuals diagnosed with ALK-related neuroblastoma susceptibility have an affected parent, the family history may appear to be negative because of incomplete penetrance or failure to recognize the disorder in family members. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may never have had neuroblastoma or a related tumor, although this has not been reported for ALK-related neuroblastoma susceptibility.

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 an ALK mutation, the risk to the sibs of inheriting the mutation is 50%. Because ALK-related neuroblastoma susceptibility is a recently described condition, the likelihood that a sib who inherits the ALK mutation will develop neuroblastoma is not yet known.

• The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of incomplete penetrance in a parent.

• 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 familial germline mutations in ALK in children with neuroblastoma.

• If the ALK mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population, because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with ALK-related neuroblastoma susceptibility has a 50% chance of inheriting the mutation. The likelihood that a child who inherits the ALK mutation will develop neuroblastoma is unknown, though the penetrance is high (~60%) and the relative risk is substantial.

Other family members. The risk to other family members depends upon the status of the proband's parents. If a parent is affected or has an ALK mutation, his or her family members may be at risk for neuroblastoma or related tumors. The degree of this risk can be estimated by pedigree analysis or determined by molecular genetic testing.

Related Genetic Counseling Issues

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

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

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 an ALK mutation, or are at risk of having an ALK mutation.

DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for ALK-related neuroblastoma susceptibility is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The ALK mutation in the family must be identified before prenatal testing can be performed.

Although molecular genetic testing can identify the presence of an ALK mutation, it cannot predict whether neuroblastoma will develop.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Molecular Genetic 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 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 disease-causing mutations are found exclusively within the tyrosine kinase domain of ALK. These mutations 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.

Normal allelic variants. The ALK gene consists of 29 coding exons.

Pathologic allelic variants. Missense mutations in the tyrosine kinase domain of ALK are associated with ALK-related neuroblastoma susceptibility [Mossé et al 2008].

Normal gene product. The ALK gene encodes a 1620-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. Mutations in the tyrosine kinase domain of ALK result in constitutive phosphorylation [Mossé et al 2008], and they are predicted with high probability to be oncogenic drivers [Mossé et al 2008]. Both ALK mutations and amplifications have been shown to have direct oncogenic effect, as evidenced by autophosphorylation of mutant strains and activation of downstream targets in neuroblastoma cell lines harboring ALK mutations 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 mutant cell lines, rapid tumor growth in nude mice, and increased apoptosis in response to siRNA or small hairpin RNA targeted against the ALK gene [Chen et al 2008, George et al 2008, Park et al 2008].

Literature Cited

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8. Janoueix-Lerosey I, Lequin D, Brugières L, Ribeiro A, de Pontual L, Combaret V, Raynal V, Puisieux A, Schleiermacher G, Pierron G, Valteau-Couanet D, Frebourg T, Michon J, Lyonnet S, Amiel J, Delattre O. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008;455:967–70. [PubMed: 18923523]
9. Kwak EL, Carnidge DR, Clark J, Lauwers G, Shapiro RG, Maki MJ, Ratain B, Solomon Y, Bang S, Ou R, Salgia R (2009) Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066. American Society of Clinical Oncology Annual Meeting, Abstract 3509.
10. Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263:1281–4. [PubMed: 8122112]
11. Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008;455:930–5. [PMC free article: PMC2672043] [PubMed: 18724359]
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13. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am. 2008;55:97–120. [PubMed: 18242317]
14. Schilling FH, Spix C, Berthold F, Erttmann R, Fehse N, Hero B, Klein G, Sander J, Schwarz K, Treuner J, Zorn U, Michaelis J. Neuroblastoma screening at one year of age. N Engl J Med. 2002;346:1047–53. [PubMed: 11932471]
15. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6. [PubMed: 17625570]
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Published Statements and Policies Regarding Genetic Testing

1. ASCO; Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, adopted February 20, 1996. J Clin Oncol. 1996;14:1730–6. [PubMed: 8622094]

Revision History

• 5 January 2010 (me) Review posted live

• 14 August 2009 (rhg) Original submission