The ALK gene is associated with autosomal dominant neuroblastoma susceptibility (MedGen UID: 414083).
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The ALK gene encodes anaplastic lymphoma kinase, one of a family of receptor tyrosine kinases involved in cell signaling that is important for cell growth, proliferation and differentiation. The ALK gene is expressed in the developing nervous system and is thought to be involved in the regulation of neuronal differentiation.
MedGen UID: 414083
The ALK gene is associated with autosomal dominant neuroblastoma susceptibility. Neuroblastoma is a tumor that forms among developing nerve cells, and therefore most often affects infants and young children (PMID: 18242317). Studies have identified variants in the ALK gene in families exhibiting a predisposition neuroblastoma (PMID: 18724359, 18923523, 18923524, 22071890). Individuals with a pathogenic variant in ALK are at increased risk of developing a spectrum of neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is often malignant while ganglioneuroma is typically benign; ganglioneuroblastoma can behave similarly to a neuroblastoma or a ganglioneuroma (PMID: 20301782).
Individuals with pathogenic variants in ALK also have an increased risk of developing of multiple primary tumors. The multiple primary tumors may be bilateral adrenal or multiple primary extra-adrenal tumors that can occur either synchronously or metachronously (PMID: 18724359, 18242317, 22071890).
The risk of developing a neuroblastoma is highest in infancy and decreases by late childhood. Individuals with a pathogenic variant in ALK tend to develop tumors at a younger age (average 9 months) compared with sporadic tumors (age 2-3 years) (PMID: 18242317). Due to the rarity of these cases, precise lifetime risks are not well-established. It has been suggested that the overall penetrance for this cancer predisposition syndrome is approximately 57% (PMID: 18923503, 18724359, 18923523, 18923524).
The ALK gene encodes a tyrosine kinase receptor which belongs to the insulin receptor superfamily. This protein plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system (NCBI. Gene. Gene ID: 238. http://www.ncbi.nlm.nih.gov/gene/238. Accessed March 2016). If there is a pathogenic variant in this gene that prevents it from normally functioning, there may be an increased risk to develop certain types of cancers.
Hereditary predisposition to cancer due to pathogenic variants in the ALK gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it).
There is currently no clear consensus regarding a screening and surveillance protocol for individuals with pathogenic ALK variants. In the absence of published guidelines, noninvasive measures including physical examination, abdominal ultrasound, and measurement of urine catecholamine metabolite levels have been suggested, although less frequent intervals may also be appropriate (PMID: 20301782, 26539795).
For children who develop neuroblastic tumors, evaluation and treatment should be performed by a pediatric oncologist at a pediatric cancer center (PMID: 20301782). The treatment is the same standard risk-stratified therapy used to treat all neuroblastic tumors (PMID: 20301782). The management guidelines for treating neuroblastoma and ganglioneuroblastoma are complex and depend upon the age of the affected individual, tumor stage and biologic characteristics (PMID: 25435121).
After successful treatment of a neuroblastic tumor, surveillance should continue in children with pathogenic variants in ALK due to the risk of developing multiple primary tumors. There is no consensus on the duration of this screening, however (PMID: 22071890).
Ultimately, an individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.
Review date: March 2016
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|