Abstract

PurposeAfrican Americans have a higher incidence and mortality from colorectal cancer. This disparity might be due, in part, to the type of mutations in driver genes. In this study, we examined alterations specific to APC, MSH3, and MSH6 genes using targeted exome sequencing to determine distinctive variants in the course of neoplastic transformation.Experimental DesignA total of 140 African American colon samples (30 normal, 21 adenomas, 33 advanced adenomas and 56 cancers) were used as our discovery set on an Ion Torrent platform. A 36 samples subset was resequenced on an Illumina platform for variants’ validation. Bioinformatics analyses were performed and novel validated variants are reported.ResultsTwo novel MSH6 variants were validated and mapped to the MutS-V region near the MSH2 binding site. For MSH3, 4 known variants were validated and were located in exon 10 (3 non-synonymous) and exon 18 (1 synonymous). As for APC, 20 variants were validated with 4 novel variants: 3 stopgain and 1 non-synonymous. These variants mapped prior to and on the Armadillo repeats region, to the 15-amino acid repeat region, and to the 20-amino acid repeats region, respectively.ConclusionWe defined novel variants that target DNA mismatch repair and APC genes in African Americans with colorectal lesions. A greater frequency of variants in genes encoding DNA mismatch repair functions and APC likely plays major roles in colorectal cancer initiation and higher incidence of the disease in African Americans.

Highlights

  • Colorectal cancer (CRC) is the third most commonly diagnosed malignancy in the World [1]

  • We examined alterations specific to APC, MSH3, and MSH6 genes using targeted exome sequencing to determine distinctive variants in the course of neoplastic transformation

  • Experimental Design: A total of 140 African American colon samples (30 normal, 21 adenomas, 33 advanced adenomas and 56 cancers) were used as our discovery set on an Ion Torrent platform

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Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy in the World [1]. Despite advances in early detection and therapies, CRC still has a lethal outcome in nearly 40% of all diagnosed cases [2, 3]. CRC is an important contributor to cancer mortality [4]. The significant clinical heterogeneity within a given pathologic stage reflects the underlying molecular heterogeneity in CRC pathogenesis [3]. CRCs are categorized into those with microsatellite instability (MSI) which are primarily proximal and frequently associate with the CpG island methylator phenotype (CIMP) and hypermutation, and those that are microsatellite stable (MSS) but are chromosomally unstable [3, 7, 8].

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