Beta2-microglobulin mutations in microsatellite unstable colorectal tumors

Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the beta 2-microglobulin (beta 2m) gene. To examine the implications of beta 2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of beta 2m mutations in MSI-H colorectal adenomas (n = 38) and carcinomas (n = 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of beta 2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of beta 2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. beta 2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of beta 2m expression may promote local progression of colorectal MSI-H tumors. However, no beta 2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional beta 2m may be necessary for distant metastasis formation in CRC patients. (C) 2007 Wiley-Liss, Inc.