ALK Gene Mutation

Approximately 3 to 5% of non-small cell lung carcinomas (NSCLC) have a rearrangement of the ALK (Anaplastic Lymphoma Kinase) gene, resulting in fusion between ALK and another gene, ALK activation, impaired apoptosis, and abnormal cell proliferation. The most common gene that fuses with ALK is EML4. Tumors expressing ALK fusions are likely to respond to ALK kinase inhibitor drugs such as crizotinib, alectinib, brigatinib, lorlatinib, and ceritinib.

The National Comprehensive Cancer Network (NCCN) guidelines recommend ALK testing for patients with recurrent or metastatic NSCLC with histological subtypes of adenocarcinoma, large cell carcinoma, or NSCLC NOS (not otherwise specified), and for squamous cell carcinoma in never-smokers or when biopsy specimens are small. 

FISH is preferred over immunohistochemistry or molecular testing for ALK testing because it detects all known gene rearrangements. The ALK gene has more than 20 known rearrangement partner genes. The most common EML4-ALK fusion has at least 15 variants. Vysis ALK Break Apart FISH Probe Kit is an FDA approved companion diagnostic tests to identify patients for this therapy. Another option is next-generation sequencing. 

In addition to the proven role it plays in select lung cancers, ALK has been found to have a pathogenic role in many cancers including diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor, esophageal squamous cell carcinoma, colorectal cancer and breast cancer. It is estimated that more than 250,000 new cancer diagnoses in the United States each year can be linked to ALK mutations and fusions.

References

Shackelford RE, Vora M, Mayhall K, Cotelingam J. ALK-rearrangements and testing methods in non-small cell lung cancer: a review. Genes Cancer. 2014 Apr;5(1-2):1-14. doi: 10.18632/genesandcancer.3. PMID: 24955213; PMCID: PMC4063252.

Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. 2018 Apr;9(4):423-430. doi: 10.1111/1759-7714.12613. Epub 2018 Feb 28. PMID: 29488330; PMCID: PMC5879058.