Abstract
BackgroundAnaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements have been reported in 2-13% of patients with non-small cell lung cancer (NSCLC). Patients with ALK rearrangements do not respond to EGFR-specific tyrosine kinase inhibitors (TKIs); however, they do benefit from small molecule inhibitors targeting ALK.ResultsIn this study, fluorescence in situ hybridization (FISH) using a break-apart probe for the ALK gene was performed on formalin fixed paraffin-embedded tissue to determine the incidence of ALK rearrangements and hybridization patterns in a large unselected cohort of 1387 patients with a referred diagnosis of non-small cell lung cancer (1011 of these patients had a histologic diagnosis of adenocarcinoma). The abnormal FISH signal patterns varied from a single split signal to complex patterns. Among 49 abnormal samples (49/1387, 3.5%), 32 had 1 to 3 split signals. Fifteen samples had deletions of the green 5′ end of the ALK signal, and 1 of these 15 samples showed amplification of the orange 3′ end of the ALK signal. Two patients showed a deletion of the 3′ALK signal. Thirty eight of these 49 samples (38/1011, 3.7%) were among the 1011 patients with confirmed adenocarcinoma. Five of 8 patients with ALK rearrangements detected by FISH were confirmed to have EML4-ALK fusions by multiplex RT-PCR. Among the 45 ALK-rearranged samples tested, only 1 EGFR mutation (T790M) was detected. Two KRAS mutations were detected among 24 ALK-rearranged samples tested.ConclusionsIn a large unselected series, the frequency of ALK gene rearrangement detected by FISH was approximately 3.5% of lung carcinoma, and 3.7% of patients with lung adenocarcinoma, with variant signal patterns frequently detected. Rare cases with coexisting KRAS and EGFR mutations were seen.
Highlights
Anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements have been reported in 2-13% of patients with non-small cell lung cancer (NSCLC)
We examined the frequency and patterns of ALK rearrangements in clinical specimens from a large cohort of lung cancer patients from both primary and tertiary settings across the United States referred for molecular profiling
ALK fluorescence in situ hybridization (FISH) was performed on an unselected series that included 1387 samples from patients with NSCLC
Summary
Anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements have been reported in 2-13% of patients with non-small cell lung cancer (NSCLC). Patients with ALK rearrangements do not respond to EGFR-specific tyrosine kinase inhibitors (TKIs); they do benefit from small molecule inhibitors targeting ALK. The use of targeted kinase inhibitors is based on the presence of specific genetic alterations, such as activating mutations in the epidermal growth factor receptor (EGFR) or activating chromosomal fusions involving the ALK kinase, and can be highly effective if the tumors harbor these associated molecular alterations [2]. Molecular tests are routinely performed to identify mutations in oncogenes in lung cancer, including EGFR and ALK; to identify those patients with a high likelihood of response to targeted therapy; and reduce unnecessary side effects of ineffective treatments. The mutation status of KRAS is usually assessed since tumors that show such mutations do not respond to targeted kinase therapies
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