Distinct BRAF (V600E) and KRAS mutations in high microsatellite Instability sporadic colorectal cancer in African Americans

Krishan Kumar, Hassan Brim, Francis Giardiello, Duane T. Smoot, Mehdi Nouraie, Edward L. Lee, Hassan Ashktorab

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Abstract

Purpose: Colorectal cancer develops through genetic, epigenetic, and environmental events that result in uncontrolled cell proliferation. Colorectal cancer incidence and mortality is higher in African Americans (AA) than in the general population. Here, we carried out a molecular analysis of sporadic colorectal cancer tumors from AAs to investigate possible explanations for the observed disparities. Experimental Design: A total of 222 AA colorectal cancer tumors were analyzed for micro- satellite instability (MSI) for protein expression of two DNA mismatch repair genes, MLH1 and MSH2, by immunohistochemistry; for the methylation silencing of MLH1, p16, APC, and APC2 promoters by methylation-specific PGR; and for point mutations in two oncogenes, KRAS and BRAF, by sequencing. Results: In our sample, 19.8% of the AAs colorectal cancer tumors were MSI high (MSI-H) and did not associate with any of the clinicopathologic features, except tumor differentiation. Higher levels of inactive DNA mismatch repair proteins MLH1 (41%) and MSH2 (33%) were found by immunohistochemistry. Methylation-specific PGR analysis revealed a high level of methylation for MLH1 (66%), APC (53%), and APC2 (90%), but not for p16 (26%). BRAF mutations were only within the MSI-H tumors, whereas most (64%) of KRAS mutations were found within the non-MSI-H group. Conclusions: ML H1 MSH2, and BRAF alterations are significantly associated with MSI-H phenotype, unlike APC, A PC 2 and KRAS alterations. The prominent role of DNA mismatch repair gene suppression in MSI-H and a distinctive role of BRAF and KRAS mutations with respect to MSI status are supported by this study.

Original languageEnglish (US)
Pages (from-to)1155-1161
Number of pages7
JournalClinical Cancer Research
Volume15
Issue number4
DOIs
StatePublished - Feb 15 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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