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. 2017 Oct 7;8(59):99966-99977.
doi: 10.18632/oncotarget.21557. eCollection 2017 Nov 21.

Distinctive DNA mismatch repair and APC rare variants in African Americans with colorectal neoplasia

Hassan Ashktorab  1 , Hamed Azimi  1 , Sudhir Varma  2 , Payaam Tavakoli  1 , Michael L Nickerson  3 , Hassan Brim  4
Affiliations

Distinctive DNA mismatch repair and APC rare variants in African Americans with colorectal neoplasia

Hassan Ashktorab et al. Oncotarget. .

Abstract

Purpose: African 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 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. A 36 samples subset was resequenced on an Illumina platform for variants' validation. Bioinformatics analyses were performed and novel validated variants are reported.

Results: Two 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.

Conclusion: We 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.

Keywords: African Americans; colon; targeted exome sequencing.

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Conflict of interest statement

CONFLICTS OF INTEREST No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1. Flow chart of patient selection for both Discovery and Validation sets for somatic variant analysis
Discovery set: 140 samples (n=123 patients) and Validation set: 36 samples (n=26 patients).
Figure 2
Figure 2. Distribution of confirmed and novel variants in proteins encoded by target genes
(A) MSH3 (B) MSH6, (Arrows show confirmed and asterisks the novel variants, respectively).
Figure 3
Figure 3. Distribution of APC confirmed and novel variants, (Arrows show confirmed and asterisks the novel variants, respectively)
See this image and copyright information in PMC

References

    1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108. https://doi.org/10.3322/caac.21262. - DOI - PubMed
    1. Clark ME, Smith RR. Liver-directed therapies in metastatic colorectal cancer. J Gastrointest Oncol. 2014;5:374–87. https://doi.org/10.3978/j.issn.2078-6891.2014.064. - DOI - PMC - PubMed
    1. Jass JR. Molecular heterogeneity of colorectal cancer: Implications for cancer control. Surg Oncol. 2007;16:S7–9. https://doi.org/10.1016/j.suronc.2007.10.039. - DOI - PubMed
    1. Siegel R, Desantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220–41. https://doi.org/10.3322/caac.21149. - DOI - PubMed
    1. Karahan B, Argon A, Yildirim M, Vardar E. Relationship between MLH-1, MSH-2, PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer. Int J Clin Exp Pathol. 2015;8:4044–53. - PMC - PubMed