Beta2‐microglobulin mutations in microsatellite unstable colorectal tumors

Abstract

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 nonpolyposis 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 β2‐microglobulin (β2m) gene. To examine the implications of β2m mutations during MSI‐H colorectal tumor development, we analyzed the prevalence of β2m 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 β2m 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 β2m 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. β2m mutations were positively related to stage in tumors without distant metastases (UICC I‐III), suggesting that loss of β2m expression may promote local progression of colorectal MSI‐H tumors. However, no β2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional β2m may be necessary for distant metastasis formation in CRC patients.