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Abstract
Introduction. Microsatellite instability (MSI), a consequence of defective in DNA mismatch repair (dMMR), is manifested by multiple mutations. This phenomenon is particularly common in colorectal tumors, gastric cancer, endometrial cancer, etc. MSI in tumors is often associated with activation of the MAPK pathway, for example with mutations in the KRAS, NRAS and BRAF genes. Recent studies have shown that drugs targeting ALK, ROS1, RET and NTRK1-3 tyrosine kinase translocations occur in tumors with microsatellite instability.
Aim. To study the frequency and spectrum of activating tyrosine kinase translocations in microsatellite unstable tumors of different localization.
Materials and methods. MSI status was determined for 27,408 neoplasms. Detection of rearrangements involving the ALK, ROS1, RET and NTRK1-3 genes in 1,284 samples of MSI-positive tumors was performed using the 5'-3'-end unbalanced expression test, variant-specific PCR and high-throughput RNA next-generation sequencing (RNA-NGS).
Results. Gene fusions were detected in 101/990 (10.2 %) colorectal cancers, 1/108 (1 %) gastric cancers (ALK: 11; RET: 25; NTRK1: 42; NTRK2: 2; NTRK3: 22). These alterations were not observed in endometrial (n = 157), cervical (n = 13), pancreatic (n = 7), cholangiocarcinoma (n = 4) or ovarian (n = 5) cancers. The highest frequency of gene rearrangements was observed in KRAS/NRAS/BRAF-negative colorectal cancer with MSI 93/395 (23.5 %). Much less frequent rearrangements were found in colorectal cancers with KRAS/NRAS/BRAF mutations (8/597, 1.3 %). Patients with colorectal cancer over 50 years of age had a higher frequency of translocations compared to younger patients (97/795 (12.2 %) vs. 3/195 (1.5 %), p = 0.0002).
Conclusion. Tyrosine kinase gene translocations occur with significant frequency in MSI-positive colorectal cancer, especially in KRAS/NRAS/BRAF wild-type tumors.
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