Inactivation of MSH3 in Colorectal Cancer and Race

Abstract
The occurrence of CRC in the United States shows a large disparity among recognized races and
ethnicities, with African Americans demonstrating the highest incidence and mortality from this disease. We
have observed a novel “loss of function” phenotype for the DNA mismatch repair protein MSH3 that is induced
by pro-inflammatory interleukin-6 (IL6) to shuttle MSH3 from the nucleus (where it normally repairs DNA
microsatellites and double strand breaks) to the cytosol, where it no longer can repair DNA with coincident
accumulation of tetranucleotide microsatellite frameshifts (termed EMAST, elevated microsatellite alterations at
selected tetranucleotide repeats). These inflammation-associated microsatellite alterations are observed in
50% of all sporadic CRCs and is associated with advance-staged disease and poor patient survival. This
inflammation-induced somatic MSH3 defect is observed in twice as many African American than Caucasian
rectal cancers, and is associated with poor patient outcome. In this proposal, we hypothesize that MSH3
disruption contributes to the consequence of advanced stage and poor survival in African American CRC
patients. Our preliminary data demonstrates clear evidence that MSH3 participates in Homologous
Recombination repair of DNA double strand breaks as well as prevents aneuploidy. We have identified 6
unique somatic deleterious MSH3 mutations among African American CRCs that have not been reported in
public databases. And we have characterized that chromosome 9p24.2 loss of heterozygosity (LOH) is
associated with EMAST, and dramatically modifies survival of patients whose primary CRC demonstrates
EMAST and 9p24.2 LOH. In this proposal, we will examine the central role of MSH3 dysfunction in its
contribution to the survival outcome of African American CRC patients. Our aim is to assess the role of MSH3-
disrupted double strand break mis-repair among African American CRCs, determine the functionality of 6
unique MSH3 mutations observed in African American CRCs, and ascertain the contribution of MSH3-
deficiency with chromosome 9p24.2 LOH in the aggressiveness of African American CRCs. Overall, this
proposal examines the role and contribution of defective MSH3 protein that likely contributes to the poor
phenotype associated with African American CRC patients.

Grant Number: 5R01CA258519-06
NIH Institute/Center: NIH
Principal Investigator: John Carethers