A FISH study reveals ALK gains in colon cancer patients

Abstract

The identification of oncogenic chromosomal alterations of anaplastic lymphoma kinase (ALK) in lung cancer and neuroblastoma has revealed ALK as a potential candidate for anticancer targeted therapy. Thus, ongoing clinical trials with ALK inhibitors are showing promising results. ALK chromosomal alterations in other solid tumors are controversial. The aim of this study was to analyze ALK translocations and gene copy number status in a series of colorectal cancer patients and correlate these findings with tumor pathological features including TNM staging, KRAS and BRAF mutations, as well as clinical outcome. ALK status was retrospectively evaluated by fluorescence in situ hybridization (FISH) with a break-apart ALK (2p23) probe (Abbott Molecular, Des Plaines, IL, USA) and centromeric probe of chromosome 2 (Abbott Molecular) in biopsies from colorectal cancer primary tumors, as were KRAS and BRAF by mutational analysis. Survival was analyzed by KaplaneMeier method. One hundred and four colorectal cancer patients were evaluated. ALK translocations were not observed; however, 39/104 (37%) of the patients had an increase in ALK gene copy number (3e5 copies), with the percentage of cells with ALK copy gain within a tumor ranging between 6% and 46% (mean 22%). There was no correlation between ALK gene copy number and KRAS mutational status, but BRAF mutations and ALK gain appear to be mutually exclusive, since the five patients with BRAF mutation had ALK disomic pattern. ALK gain was correlated with nodal status. Forty-three per cent of patients with positive nodal status had an increase in ALK copy number, while only 15% of patients with negative lymph nodes had ALK gain (p 5 0.05). The increase in ALK gene copy number was not correlated with overall survival. As a conclusion, the identification of ALK gene gain in colorectal cancer patients seems to be a relatively frequent genetic abnormality and is associated with tumors that have a more aggressive phenotype. Taking into account that ALK inhibitors are showing promising results in other types of tumors, it could be interesting to study ALK as a potential new therapeutic target for this tumor. Further evaluation of the biological meaning of ALK gain in colorectal cancer is ongoing. GERMLINE EPIMUTATION OF THE TUMOR SUPPRESSOR GENE PTPRJ IN EARLY ONSET FAMILIAL COLORECTAL CANCER