E-poster Presentation 2014 World Cancer Congress

Contribution of DNA mismatch repair (MMR) defects and inflammation towards outcome from colorectal cancer in American Blacks (#580)

John M. Carethers 1 , Kathleen L. McGuire
  1. University of Michigan, Ann Arbor, MI, United States

Background:  American Black patients with colorectal cancer (CRC) show higher mortality than their White counterparts; there are several factors that contribute, including a potential role for biology. DNA MMR defects in sporadic CRC include: (a) epigenetic inactivation of hMLH1 expression and subsequent mono/dinucleotide microsatellite instability (MSI) formation observed in 15-20% of all CRC patients and associated with neo-antigen stimulated inflammation that helps achieve improved survival compared to MMR-proficient CRC patients, and (b) inflammation-driven loss of function of hMSH3 and subsequent tetranucleotide MSI observed in 60% of CRC patients and associated with poor survival outcome compared to patients without defective hMSH3.

Aim: Determine frequency of these two DNA MMR defects in American Blacks and examine cytotoxic immunity that might contribute towards racial disparity observed for CRC.

Methods: Over 500 CRCs from a population-based cohort comprising 45% American Blacks were assessed for mono/di and tetranucleotide MSI using five National Cancer Institute recommended markers and five tetranucleotide markers. We utilized immunohistochemistry to determine infiltrating immune biomarkers in specimens.

Results: Among White CRCs, 14% showed mono/dinucleotide MSI (associated with hMLH1 methylation) whereas American Black CRCs demonstrated 7% MSI (P=0.009). White CRCs demonstrated 28% tetranucleotide MSI (associated with hMSH3 loss of function) compared to 49% among Black CRCs (P=0.014). CRCs with mono/dinucleotide MSI had higher CD8+ T cell infiltrates than non-MSI CRCs (88.0 vs 30.4/hpf, P<0.0001); however, we observed no difference between American Black and White CRCs in CD8+, CD57+ and IL-17-expression cell infiltrates. American Black CRCs showed diminished infiltration of cells expressing granzyme B+, with a paucity of representation as “high responders” compared to Whites.

Conclusions: The observed racial disparity for American Blacks with CRC may be in part due to biology as a consequence of (a) reduced classic MSI, (b) increased tetranucelotide MSI, and (c) reduction in cytoprotective responses within CRCs.