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Incidence and patterns of ALK FISH abnormalities seen in a large unselected series of lung carcinomas
Zunyan Dai1, Joann C Kelly, Aurelia Meloni-Ehrig
1Department of Cytogenetics, Quest Diagnostics Nichols Institute, 14225 Newbrook Drive, Chantilly, VA, 20151, USA. Zunyan.X.Dai@questdiagnostics.com.
Background:
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); however, they do benefit from small molecule inhibitors targeting ALK.
Results:
In 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.
Conclusions:
In 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.
Insights
Anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements occur in 3.5% of lung cancers. Fluorescence in situ hybridization (FISH) detected these rearrangements, revealing varied patterns and rare coexisting mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements are identified in 2-13% of non-small cell lung cancer (NSCLC) cases.
- Patients with ALK rearrangements show limited response to EGFR-targeted tyrosine kinase inhibitors (TKIs) but benefit from ALK-specific inhibitors.
Purpose of the Study:
- To determine the incidence and patterns of ALK gene rearrangements in a large, unselected cohort of non-small cell lung cancer (NSCLC) patients.
- To investigate the correlation between ALK rearrangements and other common mutations like EGFR and KRAS.
Main Methods:
- Fluorescence in situ hybridization (FISH) with an ALK break-apart probe was used on formalin-fixed, paraffin-embedded tissues.
- A cohort of 1387 patients with non-small cell lung cancer (NSCLC), including 1011 with adenocarcinoma, were analyzed.
- Multiplex reverse transcription-polymerase chain reaction (RT-PCR) was employed to confirm EML4-ALK fusions in a subset of samples.
Main Results:
- ALK gene rearrangements were detected in 3.5% (49/1387) of all NSCLC cases and 3.7% (38/1011) of adenocarcinoma cases.
- FISH analysis revealed diverse hybridization patterns, including split signals, deletions, and amplification.
- EML4-ALK fusions were confirmed in 5 out of 8 FISH-positive cases; only one EGFR mutation (T790M) and two KRAS mutations were found in ALK-rearranged samples.
Conclusions:
- ALK gene rearrangement occurs in approximately 3.5% of lung carcinomas and 3.7% of lung adenocarcinomas, often presenting with variant FISH patterns.
- The study identified rare instances of coexisting ALK rearrangements with KRAS and EGFR mutations, highlighting the complexity of NSCLC.
- FISH is an effective method for detecting ALK rearrangements in NSCLC, aiding in patient stratification for targeted therapies.
