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ALK-Related Neuroblastoma Susceptibility

, MD and , MD.

Author Information
, MD
Seattle Children’s Hospital
Seattle, Washington
, MD
Seattle Children’s Hospital
Seattle, Washington

Initial Posting: ; Last Revision: May 9, 2013.

Summary

Disease characteristics. ALK-related neuroblastoma susceptibility occurs in individuals who are heterozygous for a germline ALK mutation and is characterized by an increased risk of developing neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. The risk for 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).

Diagnosis/testing. ALK is the only gene in which mutations are known to cause ALK-related neuroblastoma susceptibility. ALK mutations are found in equal frequencies across all neuroblastoma subtypes and risk groups. Oncogenic germline ALK mutations seem to occur only in families with high or moderate degrees of confidence for harboring a predisposing allele. In families with two or more first-degree relatives with neuroblastoma, the incidence of ALK germline mutations is high. In families in which two second-degree or more distant relatives have neuroblastoma, the incidence of ALK germline mutation is much lower.

Management. Treatment of manifestations: Treatment of neuroblastoma is best provided by a pediatric oncologist at a pediatric cancer center. Depending on the age of the child, stage of the tumor, and biologic characteristics of the tumor, treatment may involve observation or surgical resection. Tumors with risk of metastatic spread require chemotherapy and sometimes radiation therapy.

Surveillance: Surveillance is at the discretion of the medical provider because no data are available as yet on the effect of screening in families with germline ALK mutations and surveillance at the population level has not improved neuroblastoma outcome. However, screening with noninvasive techniques such as ultrasonography and measurement of urinary catecholamine metabolites should probably be implemented for unaffected children who have a germline ALK mutation. Abdominal ultrasound examination and measurement of urine catecholamine metabolite levels have been performed every one to two months in infants up to age 12 months and every three to four months during childhood up to age ten years; less frequent intervals may also be appropriate.

Evaluation of relatives at risk: In families with documented ALK-related neuroblastoma susceptibility, testing of all at-risk first-degree relatives including minors is indicated because germline mutations in ALK are highly penetrant and heterozygotes are at significant risk of developing cancer at a young age.

Therapies under investigation: Small molecule inhibitors targeting the ALK tyrosine kinase, such as TAE684 and crizotinib, are currently in preclinical development and early-phase clinical trials. Crizotinib has demonstrated safety and tolerability in children, as well as promising activity in ALK-translocated tumors such as anaplastic large cell lymphoma. Activity in neuroblastoma is still under investigation.

Genetic counseling. ALK-related neuroblastoma susceptibility is inherited in an autosomal dominant manner with incomplete penetrance. Some, but not all, individuals diagnosed with ALK-related neuroblastoma susceptibility have an affected parent; the proportion with de novo mutations is unknown. Each child of an individual with ALK-related neuroblastoma susceptibility has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk for ALK-related neuroblastoma susceptibility is possible; however, such testing cannot predict if neuroblastoma will develop.

Diagnosis

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 in which mutations are known to cause ALK-related neuroblastoma susceptibility.

Clinical testing

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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Familial 4Simplex 5
ALKSequence analysis of select exons 6Sequence variants 7, 8 in select exons80% 9, 10, 11Rare 11, 12
Sequence analysisSequence variants 7, 8 in the entire coding region80% 9, 10, 11Rare 11, 12

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

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

5. Simplex is defined as neuroblastoma in a single individual in a family.

6. Select exons 21-28 encoding the tyrosine kinase domain.

7. 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].

8. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

9. Heterozygous activating mutations in the ALK oncogene are found in the germline of 80% of individuals with familial neuroblastoma [Liu & Thiele 2012].

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

11. Activating mutations of ALK may be found in 7%-8% of sporadic neuroblastoma tumors, but these are only rarely associated with germline mutations [Liu & Thiele 2012]. 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 ALK mutations, p.Ile1250Thr, was identified in germline DNA as well as tumor DNA.

12. Germline ALK mutations have been identified in two unrelated patients with congenital neuroblastoma, severe developmental delay, and structural brain stem abnormalities [de Pontual et al 2011]. The germline mutations identified in these patients, p.Phe1174Val and p.Phe1245Val, have been reported in somatic neuroblastomas but have not been reported as germline mutations in phenotypically normal individuals with neuroblastoma.

Testing Strategy

To confirm/establish 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. Written guidelines for appropriate use of this test in individuals with neuroblastoma are still currently under development, and no consensus opinion exists on the criteria for testing.

  • Testing should be considered in individuals with a family history of neuroblastoma and in simplex cases with bilateral neuroblastoma. [Bourdeaut et al 2012].
    • 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. Germline mutations in ALK occur at equal frequencies in all three of these tumor types and in all neuroblastoma risk groups [Liu & Thiele 2012].
    • Testing of probands with more distant relatives (≥2nd 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 may suggest a PHOX2B mutation [Mossé et al 2008]. (See Differential Diagnosis.)
  • Some institutions are currently screening all children with neuroblastoma; others are screening only individuals with a strong family history of neuroblastoma. All children with documented somatic ALK mutations within a neuroblastoma tumor should subsequently undergo germline testing.

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.

Clinical Description

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 for 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 on 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 p.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. This mutation may be associated with somewhat decreased penetrance (40%) compared with all other reported mutations (61%) [Eng 2008].

No reported ALK mutations are associated with either increased frequency of tumor formation or more aggressive disease behavior. p.Phe1174Leu is associated with amplification of the MYCN oncogene and is found as a somatic mutation in 30% of sporadic neuroblastoma [Carpenter & Mossé 2012]. Affected individuals with this mutation have a worse prognosis than affected individuals with MYCN amplification alone [Azarova et al 2011]. The one reported case of an affected individual with the germline mutation p.Phe1174Leu was associated with early lethality [de Brouwer et al 2010]. No other associations between specific germline (or somatic) ALK mutations and neuroblastoma outcome have been established [Azarova et al 2011].

Penetrance

Inheritance is autosomal dominant with incomplete penetrance. Several asymptomatic adults who are obligate heterozygotes have been identified [Mossé et al 2008, Bourdeaut et al 2012]. It is possible that the reduced penetrance is associated either with intragenic ALK variants or with 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].

Differential Diagnosis

Germline mutations in ALK and PHOX2B are the etiologic agents for familial neuroblastoma susceptibility. Germline mutations in ALK are the main cause of familial susceptibility to neuroblastoma in otherwise healthy families. Heterozygous germline mutations in PHOX2B account for the remainder of families, most of whom also have disorders of neural crest development (see PHOX2B) [Mossé et al 2008, Azarova et al 2011].

PHOX2B. Germline mutations in PHOX2B are found in some kindreds with familial neuroblastoma. Germline mutations in PHOX2B most commonly occur in association with familial neuroblastoma and disorders of neural crest development, such as Hirschsprung disease, decreased esophageal motility, or congenital central hypoventilation syndrome. Persons with PHOX2B germline mutations may also have dysmorphic features, including downslanting palpebral fissures, small nose, triangular shaped mouth, or low-set, posteriorly rotated ears.

If the family history or patient history is positive for disorders of neural crest development or the patient has characteristic facial features, germline PHOX2B mutations are more likely than germline ALK mutations to be identified in the proband [Mossé et al 2008].

KIF1B. A germline mutation in KIF1B, on chromosome 1p36.2, has been reported in a three-generation pedigree with a predisposition to neuronal and non-neuronal tumors. Three individuals in the pedigree developed tumors. One had bilateral pheochromocytomas, a ganglioneuroma, and a leiomyosarcoma. One had bilateral pheochromocytoma, and another had adenocarcinoma of the lung [Yeh et al 2008]. None of the reported individuals with KIF1B germline mutations had neuroblastoma.

Neurofibromatosis 1 (NF1). Compared with the general population, children with NFI are at increased risk of developing malignancies, including neuroblastoma, rhabdomyosarcoma, and peripheral nerve sheath tumors [Brems et al 2009]. Features of NF1 include café-au-lait macules, cutaneous neurofibromas, Lisch nodules of the iris, macrocephaly, and developmental delay. Individuals with NF1 may have affected relatives with similar features, since the disease is inherited in an autosomal dominant manner. However, since 50% of cases of NF1 are caused by new mutations, probands may have no affected relatives.

Beckwith-Weidemann syndrome (BWS). Persons with BWS are at increased risk for embryonal malignancies, including neuroblastoma (relative risk of 197 compared to the general population, as described by DeBaun & Tucker [1998]), Wilms tumor, hepatoblastoma, and rhabdomyosarcoma. BWS usually occurs in simplex cases, but can also be inherited in an autosomal dominant manner. BWS results from aberrant expression of imprinted genes at chromosome locus 11p15.5, which can be caused by different genetic mechanisms: abnormal methylation of one of two differently methylated regions (DMRs), paternal uniparental disomy, or mutation of CDKN1C. Clinical features include macrosomia at birth, hemihypertrophy, coarse facial features, macroglossia, omphalocele, visceromegaly, and neonatal hypoglycemia. Of these physical findings, only the hemihypertrophy is independently associated with increased tumor risk [Shuman et al 2010].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

There is no treatment algorithm recommended for individuals with neuroblastoma who have germline ALK mutations, other than the standard risk-stratified therapy used for treatment of all neuroblastoma. Clinical trials are ongoing to study the efficacy of ALK-targeted therapy in the setting of relapsed and refractory neuroblastoma (see Therapies Under Investigation).

The management guidelines for neuroblastoma are complex:

  • 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 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 be the same as for the general population.

Evaluation 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

Oral preparations of small molecule inhibitors targeting the ALK tyrosine kinase domain (e.g., crizotinib) have shown efficacy and minimal toxicity in children with ALK translocated tumors other than neuroblastoma. Of affected individuals with refractory/relapsed neuroblastoma, response has only been identified in those with tumors resulting from germline mutations in ALK, including a complete response in at least one individual [Mossé et al 2012]. Because responsiveness to crizotinib may depend on the presence or absence and specific type of ALK mutation in the tumor, subsequent Phase 2 clinical trials for relapsed/refractory neuroblastoma will incorporate ALK mutation analysis for the tumors of all individuals enrolled in the trial [Carpenter & Mossé 2012].

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 (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 developed 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 other tumor types have been reported to be associated with germline mutations in ALK and 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 mutation. De novo mutations have been reported; the proportion of cases caused by such mutations is unknown. In at least one family, a child with neuroblastoma inherited the 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 developed 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 whose ALK mutation status is unknown, 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. Testing could be considered on sibs who are younger than age ten years at the time of diagnosis of the proband, as well as sibs born subsequently.
  • 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 on 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, 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. 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 of affected individuals.

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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for ALK-Related Neuroblastoma Susceptibility have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. ALK-Related Neuroblastoma Susceptibility: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ALK2p23​.2-p23.1ALK tyrosine kinase receptorALK homepage - Mendelian genesALK

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for ALK-Related Neuroblastoma Susceptibility (View All in OMIM)

105590ANAPLASTIC LYMPHOMA KINASE; ALK
613014NEUROBLASTOMA, SUSCEPTIBILITY TO, 3; NBLST3

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-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 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. ALK comprises 29 coding exons.

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

Table 2. Selected ALK Pathogenic Germline Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.3824G>Ap.Arg1275Gln (most common)NM_004304​.3
NP_004295​.2
c.3383G>Cp.Gly1128Ala
c.3575G>Cp.Arg1192Pro
c.3260C>Tp.Thr1087Ile
c.3452C>Tp.Thr1151Met 1
c.3749T>Cp.Ile1250Thr 2
c.3520T>Gp.Phe1174Val 3
c.3733T>Gp.Phe1245Val 3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. George et al [2008]

2. Mossé et al [2008]

3. de Pontual et al [2011]

Normal gene product. ALK 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 drive oncogenesis [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 small interfering or small-hairpin RNA targeted against ALK [Chen et al 2008, George et al 2008, Park et al 2008].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 10-31-13.

Literature Cited

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Chapter Notes

Revision History

  • 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 (rhg) Original submission
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