Abstract 4384: Targeted sequencing reveals distinct and rare pathogenic variants in Caucasians with colorectal cancer

Abstract

Abstract PURPOSE: Next-generation sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC) which is on the rise in many parts of the developing World including in the Middle East. Little is known about its genetic hallmarks in these populations. AIM: To identify variants in 15 CRC-associated genes in patients of Iranian descent. METHODS: CRC specimens from 63 patients were used to establish the variants’ profile on an Ion Torrent platform by targeted exome sequencing. To rule out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established. RESULTS: There were 51 validated variants distributed on 12 genes: 22% MSH3 (n=11/51), 10% MSH6 (n=5/51), 8% AMER1 (n=4/51), 20% APC (n=10/51), 2% BRAF (n=1/51), 2% KRAS (n=1/51), 12% PIK3CA (n=6/51), 8% TGFβR2A (n=4/51), 2% SMAD4 (n=1/51), 4% SOX9 (n=2/51), 6% TCF7L2 (n=3/51), and 6% TP53 (n=3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%). MSH3 variants were more frequent and predominantly homozygous in the analyzed population. CONCLUSION: These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. This is especially true for MSH3 variants that were very frequent and predominantly homozygous as these will associate with the EMAST phenotype that has prognostic implications. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies. Citation Format: Pooneh Mokarram, Sudhir Varma, Hamed Azimi, Hasti Olumi, Ali reza Safarpour, Michael Nickerson, Hassan Brim, Hassan Ashktorab. Targeted sequencing reveals distinct and rare pathogenic variants in Caucasians with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4384. doi:10.1158/1538-7445.AM2017-4384