Prevalence of DNA damage response and repair, cellular signaling, tumor suppressor, and immune checkpoint gene mutations in gastrointestinal cancers.

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e15149 Background: The prevalence of genetic mutations in gastrointestinal (GI) cancers is not well characterized. Molecular targeted therapies have substantial potential to improve outcomes. As next-generation sequencing (NGS) has become more commercially available, there may be additional opportunities to find novel targets for therapy or identify predictors of response to chemotherapy and radiotherapy. Commercially available DNA sequencing was conducted on patients with GI cancers to identify novel therapeutic and prognostic factors. Methods: A total of 86 solid tumor biopsy specimens from GI cancers were submitted for molecular profiling with NGS. Tumor molecular profiles were reviewed to identify frequently occurring pathogenic mutations in DNA damage and repair (DDR), cell cycle (CC), tumor suppressor (TS) and immune checkpoint (IC) pathways. DDR genes included MGMT, MSH 2/6 and ERCC1. CC genes included cMET, EGFR and KRAS. TS genes included APC, PTEN and TP53. IC genes included PD-1 and PDL-1. The overall frequency of mutations as well as the frequency of mutations for each primary site was analyzed. Results: Samples from colorectal (CRC, n=36), gastroesophageal (GE, n=5), liver and bile duct (LBD, n=14), pancreatic (PC, n=26) and other (OC, n=5) GI cancers were analyzed. Overall 46.3% of samples had at least one DDR mutation and commonly occurred in PC (57.7%) and CRC (50.0%).The most commonly mutated DDR genes were MGMT, TOPO1 and TOP2A. 55.2% of samples had at least one CC mutation and were most common in PC (69.2%), CRC (61.1%) and LBD (42.9%). The most common CC mutations were PTEN, P53 and KRAS. 65.5% of samples had at least one TS mutation with TP52 and PTEN being the most common. TS mutations occurred commonly in CRC (80.6%) and GE (60.0%). Mutations in PD-1 and PD-L1 (IC) were present in 25.3% of samples and occurred most frequently in GE (80.0%) and LBD (28.6%). Conclusions: Mutations were commonly seen in DDR (46.3%), CC (55.2%), TS (65.5%) and IC (25.3%) genes in GI primaries, providing a path to explore the role of novel therapeutic agents and how these mutations might be used to predict clinical outcomes.