Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer.

// Hassan Ashktorab 1 , Pooneh Mokarram 5 , Hamed Azimi 1 , Hasti Olumi 1 , Sudhir Varma 3 , Michael L. Nickerson 4 , Hassan Brim 2 1 Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA 2 Department of Pathology, Howard University College of Medicine, Washington, DC, USA 3 Hithru LLC, Silver Spring, MD, USA 4 Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA 5 Current address: Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran Correspondence to: Hassan Ashktorab, email: hashktorab@howard.edu Michael L. Nickerson, email: nickersonml@od.nih.gov Keywords: targeted exome sequencing, colon, Iranian, Shirazi, Caucasian Received: July 20, 2016      Accepted: December 01, 2016      Published: December 16, 2016 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, Iran. Little is known about its genetic hallmarks in these populations. AIM: To identify variants in 15 CRC-associated genes in patients of Iranian descent. 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%). MATERIALS AND METHODS: CRC specimens from 63 Shirazi patients were used to establish the variant’ 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. 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. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies.