Annotation Detail

Information
Associated Genes
ALK
Associated Variants
ALK EML4-ALK E2;A20
Associated Disease
lung non-small cell carcinoma
Source Database
CIViC Evidence
Description
Multiplex RT-PCR to detect in-frame fusions of EML4 to ALK was performed on total RNA from 253 lung adenocarcinomas, and 9 samples were found to contain such fusions, one of which was a novel fusion containing EML4 exon 2 and exon 20 of ALK. This was called variant 5. Two versions of this variant were seen: 5a consisted of EML4 exon 2 fused to ALK exon 20 while 5b contained a 117bp intronic ALK region between the two exons. Genomic PCR showed that EML4-ALK variant 5 tumor cells contained a single EML4-ALK fusion, suggesting 5a and 5b arise from alternate splicing. 5a and 5b showed in-vitro kinase activity and transformed 3T3 cells in cell culture. 5a and 5b transformed 3T3 cells formed tumors when injected in 8/8 nude mice, but 3T3 transformed with ALK alone did not. These results suggest that EML4-ALK variant 5 is a driver mutation in lung adenocarcinoma targetable by ALK inhibitors like crizotinib.
Variant Origin
somatic
Variant Origin
Somatic
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/1190
Gene URL
https://civic.genome.wustl.edu/links/genes/1
Variant URL
https://civic.genome.wustl.edu/links/variants/501
Rating
4
Evidence Type
Predictive
Disease
Lung Non-small Cell Carcinoma
Evidence Direction
Supports
Drug
Crizotinib
Evidence Level
E
Clinical Significance
Sensitivity/Response
Pubmed
18927303
Drugs
Drug NameSensitivitySupported
CrizotinibSensitivitytrue