Research Papers:

Driver genes exome sequencing reveals distinct variants in African Americans with colorectal neoplasia

Hassan Ashktorab _, Hamed Azimi, Sudhir Varma, Edward L. Lee, Adeyinka O. Laiyemo, Michael L. Nickerson and Hassan Brim

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Oncotarget. 2019; 10:2607-2624. https://doi.org/10.18632/oncotarget.26721

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Hassan Ashktorab1, Hamed Azimi1, Sudhir Varma3, Edward L. Lee2, Adeyinka O. Laiyemo1, Michael L. Nickerson4 and Hassan Brim2

1Department of Medicine, Cancer Center, Howard University, Washington, DC, USA

2Department of Pathology, Howard University College of Medicine, Washington, DC, USA

3Hithru Analytics, LLC, Silver Spring, MD, USA

4Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA

Correspondence to:

Hassan Ashktorab, email: hashktorab@howard.edu

Keywords: colon; targeted sequencing; African Americans; actionable; druggable

Received: August 28, 2018    Accepted: January 31, 2019    Published: April 05, 2019


Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. African Americans are disproportionately affected by CRC. Our hypothesis is that driver genes with known and novel mutations have an impact on CRC outcome in this population. Therefore, we investigated the variants’ profiles in a panel of 15 CRC genes.

Patients & Methods: Colorectal specimens (n=140) were analyzed by targeted exome sequencing using an Ion Torrent platform. Detected variants were validated in 36 samples by Illumina sequencing. The novel status of the validated variants was determined by comparison to publicly available databases. Annotated using ANNOVAR and in-silico functional analysis of these variants were performed to determine likely pathogenic variants.

Results: Overall, 121 known and novel variants were validated: APC (27%), AMER1 (3%), ARID1 (7%), MSH3 (12%), MSH6 (10%), BRAF (4%), KRAS (6%), FBXW7 (4%), PIK3CA (6%), SMAD4 (5%), SOX9 (2%), TCF7L2 (2%), TGFBR2 (5%), TP53 (7%). From these validated variants, 12% were novel in 8 genes (AMER1, APC, ARID1A, BRAF, MSH6, PIK3CA, SMAD4, and TCF7L2). Of the validated variants, 23% were non-synonymous, 14% were stopgains, 24% were synonymous and 39% were intronic variants.

Conclusion: We here report the specifics of variants’ profiles of African Americans with colorectal lesions. Validated variants showed that Tumor Suppressor Genes (TSGs) APC and ARID1 and DNA Mismatch repair (MMR) genes MSH3 and MSH6 are the genes with the highest numbers of validated variants. Oncogenes KRAS and PIK3CA are also altered and likely participate in the increased proliferative potential of the mutated colonic epithelial cells in this population.

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