ALK-related neuroblastic tumor susceptibility results from heterozygosity for a germline ALK activating pathogenic variant in the tyrosine kinase domain that predisposes to neuroblastic tumors. The spectrum of neuroblastic tumors includes 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. At present there are no data regarding the lifetime risk to an individual with a germline ALK pathogenic variant of developing a neuroblastic tumor. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest that the overall penetrance is around 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood.
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.
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.
- Asymptomatic children. Because no data are available as yet on the effect of screening in families with a germline ALK activating pathogenic variant and because tumor 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 asymptomatic children with a germline ALK activating pathogenic variant. In the absence of published guidelines, some healthcare providers perform the noninvasive measures of physical examination, abdominal ultrasound examination, and measurement of urine catecholamine metabolite levels every 1-2 months in infants age ≤12 months and every 3-4 months in children age ≤10 years; however, less frequent intervals may also be appropriate.
- 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. Although no consensus exists, some recommend screening until age six years.
Evaluation of relatives at risk: It is appropriate to test relatives at risk (i.e., sibs who are younger than age ten 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).
ALK-related neuroblastic tumor susceptibility is inherited in an autosomal dominant manner, with incomplete penetrance. Some (not all) individuals diagnosed with ALK-related neuroblastic susceptibility have an affected parent who may have had any one of the three neuroblastic tumor types. Although 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 for pregnancies at increased risk is possible; however, requests for prenatal testing for conditions which (like ALK-related neuroblastic tumor susceptibility) do not affect intellect and have some treatment available are not common.
ALK-related neuroblastic tumor susceptibility should be suspected in an individual 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 [Mossé et al 2008]. Note: Both benign and malignant tumors can occur in the same family.
Establishing the Diagnosis
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 (see Table 1).
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].
Strong recommendations regarding testing for germline ALK pathogenic variants:
- All children with documented somatic ALK pathogenic variants within a neuroblastic tumor
- An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor
*Note: Germline ALK pathogenic variants are equally likely to be identified in individuals with any of the three neuroblastic tumor types and with any stage of malignant neuroblastoma [Liu & Thiele 2012].
Moderate recommendation regarding testing for germline ALK pathogenic variants:
- A simplex case (i.e., a single occurrence in a family) with bilateral neuroblastoma or multifocal primary neuroblastic tumors [Bourdeaut et al 2012]
No recommendation for testing for germline ALK pathogenic variants:
- An individual with a neuroblastic tumor and distant relatives (≥2nd degree) with a history of neuroblastic tumors, as such an individual is unlikely to have a germline ALK pathogenic variant [Mossé et al 2008]
Considerations for testing for somatic ALK pathogenic variants. Some institutions are currently screening tumors of all children with neuroblastoma and others are screening tumors at the time of recurrence or progression, primarily for potential for ALK-directed therapy (see Molecular Genetics, Cancer and Benign Tumors) rather than identifying those at increased risk for having a germline ALK pathogenic variant.
The approach to molecular testing for a germline ALK pathogenic variant is sequence analysis to detect heterozygous germline ALK activating pathogenic variants in the tyrosine kinase domain that are known or suspected to cause altered kinase function.
Individuals with ALK-related neuroblastic tumor susceptibility (i.e., who are heterozygous for a germline ALK activating pathogenic variant) are at risk of developing a spectrum of neuroblastic tumors that includes 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.
There are no data at present regarding the percentage of individuals with a germline ALK pathogenic variant who will develop a neuroblastic tumor in their lifetime.
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]. These data remain preliminary, as the numbers are small.
Risk for neuroblastic 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].
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 neuroblastoma outcome is heavily dependent on biologic 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].
Aside from the following three 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.Phe1174Leu.The one individual reported with this germline pathogenic variant experienced early lethality [De Brouwer et al 2010].
Penetrance is incomplete. Several asymptomatic adults who are obligate heterozygotes 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.
About 1%-2% of probands with neuroblastoma have a close relative with neuroblastoma [Mossé et al 2008].
Genetically Related (Allelic) Disorders
Germline ALK pathogenic variants. The majority of individuals with a germline ALK pathogenic variant have no obvious phenotype other than predisposition to neuroblastoma. The exceptions are the pathogenic variants (p.Phe1174Val and p.Phe1245Val) identified in the germline in two unrelated children with congenital neuroblastoma, severe developmental delay, and structural brain stem abnormalities. Although these pathogenic variants have been reported as somatic mutations in neuroblastoma tumors, they have not been reported in the germline of phenotypically normal individuals with neuroblastoma [de Pontual et al 2011].
Sporadic tumors (including neuroblastoma) occurring as single tumors in the absence of any other findings of this syndrome frequently harbor somatic variants in ALK that are not present in the germline; thus, predisposition to these tumors is not heritable. For more details see Molecular Genetics, Cancer and Benign Tumors.
Germline pathogenic variants in ALK and PHOX2B are the etiologic agents for familial neuroblastoma susceptibility.
- Heterozygous germline ALK pathogenic variants are the main cause of familial susceptibility to neuroblastoma in otherwise healthy individuals.
PHOX2B. Germline PHOX2B pathogenic variants 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 a heterozygous germline PHOX2B pathogenic variant 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 medical history of the individual is positive for disorders of neural crest development or the individual has characteristic facial features, it is likely that a germline PHOX2B pathogenic variant (rather than a germline ALK variant) is causative [Mossé et al 2008].
KIF1B. A germline KIF1B pathogenic variant has been reported in a three-generation family with a predisposition to neuronal and non-neuronal tumors. Of the three individuals in the family who developed tumors, one had bilateral pheochromocytomas, a ganglioneuroma, and a leiomyosarcoma; one had bilateral pheochromocytoma; and one had adenocarcinoma of the lung [Yeh et al 2008]. None of the individuals with a germline KIF1B pathogenic variant 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 multiple café-au-lait macules, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. NF1 is inherited in an autosomal dominant manner. Half of affected individuals have NF1 as the result of a de novo NF1 pathogenic variant.
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 ), Wilms tumor, hepatoblastoma, and rhabdomyosarcoma. In addition, BWS is a growth disorder characterized by macrosomia, macroglossia, visceromegaly, omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. Of these physical findings, only the hemihypertrophy is independently associated with increased tumor risk.
BWS is associated with abnormal regulation of gene transcription in the imprinted domain on chromosome 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. BWS usually occurs in simplex cases, but can also be inherited in an autosomal dominant manner.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ALK-related neuroblastic tumor susceptibility, the following evaluations are recommended based on the author’s personal experience as no guidelines have been established for initial evaluation of individuals diagnosed with a germline ALK pathogenic variant.
- 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 radiograph and ultrasound examination of the abdomen, the most common sites for neuroblastic tumor development
- Measurement of urine cathecholamines, as homovanillic acid and vanillylmendelic acid may be elevated in the presence of a neuroblastic tumor
- Medical genetics consultation
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.
Asymptomatic children at risk. Large-scale, population-based studies in Japan, Europe, Canada, and the US that screened healthy infants with urinary catecholamines to identify 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 a germline ALK activating pathogenic variant and because tumor 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 a germline ALK activating pathogenic variant. In the absence of published guidelines, the noninvasive measures of physical examination, abdominal ultrasound examination, and measurement of urine catecholamine metabolite levels 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 in children age ≤10 years
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. Although no consensus exists, some recommend screening until age six years [Bourdeaut et al 2012].
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 relatives at risk* for the ALK pathogenic variant found in the proband to identify those 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).
*Sibs who are younger than age ten years at the time of diagnosis of the proband, as well as sibs born subsequently.
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, ceritinib) 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 ALK pathogenic variants, including a complete response in at least one individual [Mossé et al 2012].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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 neuroblastic tumor 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 neuroblastic susceptibility have an affected parent who may have had any one of the three associated tumor types (neuroblastoma, ganglioneuroma, or ganglioneuroblastoma). Because of incomplete penetrance, a parent may have a germline ALK activating pathogenic variant without having developed a neuroblastic tumor [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 adults with a germline ALK activating pathogenic variant have been published.
- Parents of a proband should be offered molecular genetic testing for the germline ALK activating pathogenic variant identified in their child.
- A proband with ALK-related neuroblastic tumor susceptibility may have the disorder as the result of a de novo germline ALK activating pathogenic variant. Although de novo germline pathogenic variants have been reported, the proportion of de novo pathogenic variants is unknown.
- If the germline ALK activating pathogenic variant 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 pathogenic variant 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 germline ALK activating pathogenic variant include testing for the ALK pathogenic variant detected in the proband.
- The family history of some individuals diagnosed with ALK-related neuroblastic tumor susceptibility may appear to be negative because of incomplete 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.
Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the variant and may never have developed neuroblastoma or a related tumor, although this has not been reported for ALK-related neuroblastic tumor susceptibility.
Sibs of a proband
- The risk to sibs for ALK-related neuroblastic tumor susceptibility 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%. Because ALK-related neuroblastic tumor susceptibility is a recently described condition, the likelihood that a sib who inherits the ALK pathogenic variant will develop a neuroblastic tumor is not yet known.
- 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 incomplete penetrance in a parent.
- If the ALK pathogenic variant 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 theoretic possibility of germline mosaicism.
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.
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 any child from 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, his or her family members may be at risk for neuroblastoma or related tumors.
- Whether or not an individual is at risk for ALK-related neuroblastic tumor susceptibility can be determined by pedigree analysis and 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 pathogenic variant. When neither parent of a proband with this autosomal dominant condition has the ALK pathogenic variant identified in the proband, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or 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.
- 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 a germline ALK activating pathogenic variant, or are at risk of having a germline ALK activating pathogenic variant.
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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
If the germline ALK activating pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.
Requests for prenatal testing for conditions which (like ALK-related neuroblastic tumor susceptibility) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Note: Although molecular genetic testing can identify the presence of a germline ALK activating pathogenic variant, it cannot predict whether neuroblastoma will develop.
Preimplantation genetic diagnosis (PGD) may be an option for some families in which a germline ALK activating pathogenic variant has been identified.
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.
- My46 Trait Profile
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
|Gene||Chromosome Locus||Protein||Locus Specific||HGMD|
|ALK||2p23||ALK tyrosine kinase receptor||ALK database||ALK|
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 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 allelic variants. The vast majority (91%) of ALK pathogenic variants fall within the kinase domain [Chen et al 2008]. Missense mutations 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 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. 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 mutant 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 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].
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 chromosomal 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 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].
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 patients whose tumor harbors a somatic ALK activating pathogenic variant or ALK amplification (i.e., >10 copies of ALK) have a poorer prognosis than patients 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 mutant 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].
Published Guidelines/Consensus Statements
- American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online; registration or institutional access required. 2010. Accessed 6-11-15.
- Bourdeaut F, Ferrand S, Brugières L, Hilbert M, Ribeiro A, Lacroix L, Bénard J, Combaret V, Michon J, Valteau-Couanet D, Isidor B, Rialland X, Poirée M, Defachelles AS, Peuchmaur M, Schleiermacher G, Pierron G, Gauthier-Villars M, Janoueix-Lerosey I, Delattre O. Comité Neuroblastome of the Société Francaise de Cancérologie. ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome. Eur J Hum Genet. 2012;20:291–7. [PMC free article: PMC3283184] [PubMed: 22071890]
- Brems H, Beert E, de Ravel T, Legius E. Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol. 2009;10:508–15. [PubMed: 19410195]
- Carén H, Abel F, Kogner P, Martinsson T. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours. Biochem J. 2008;416:153–9. [PubMed: 18990089]
- Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang L, Soda M, Kikuchi A, Igarashi T, Nakagawara A, Hayashi Y, Mano H, Ogawa S. Oncogenic mutations of ALK kinase in neuroblastoma. Nature. 2008;455:971–4. [PubMed: 18923524]
- DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr. 1998;132:398–400. [PubMed: 9544889]
- De Brouwer S, De Preter K, Kumps C, Zabrocki P, Porcu M, Westerhout EM, Lakeman A, Vandesompele J, Hoebeeck J, Van Maerken T, De Paepe A, Laureys G, Schulte JH, Schramm A, Van Den Broecke C, Vermeulen J, Van Roy N, Beiske K, Renard M, Noguera R, Delattre O, Janoueix-Lerosey I, Kogner P, Martinsson T, Nakagawara A, Ohira M, Caron H, Eggert A, Cools J, Versteeg R, Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res. 2010;16:4353–62. [PubMed: 20719933]
- de Pontual L, Kettaneh D, Gordon CT, Oufadem M, Boddaert N, Lees M, Balu L, Lachassinne E, Petros A, Mollet J, Wilson LC, Munnich A, Brugière L, Delattre O, Vekemans M, Etchevers H, Lyonnet S, Janoueix-Lerosey I, Amiel J. Germline gain-of-function mutations of ALK disrupt central nervous system development. Hum Mutat. 2011;32:272–6. [PubMed: 21972109]
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Emily G Greengard, MD (2015-present)
Rebecca H Johnson, MD; Seattle Children’s Hospital (2009-2015)
Julie R Park, MD (2009-present)
- 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
Initial Posting: January 5, 2010; Last Update: April 9, 2015.
University of Washington, Seattle, Seattle (WA)
Greengard EG, Park JR. ALK-Related Neuroblastic Tumor Susceptibility. 2010 Jan 5 [Updated 2015 Apr 9]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.