MUTYH-associated polyposis carcinomas frequently lose HLA class I expression - a common event amongst DNA-repair-deficient colorectal cancers

Human leukocyte antigen (HLA) class I expression defects frequently occur in colorectal cancers bearing mismatch repair (MMR) deficiencies and are interpreted as immune evasion mechanisms to avoid cancer cell recognition and elimination by the immune system. MMR-deficient tumours are thought to be more prone to lose HLA class I expression, due to their frequent generation of aberrant peptides which can stimulate a cytotoxic T-cell-mediated response. MUTYH-associated polyposis (MAP) is a colorectal cancer syndrome caused by defects in the MUTYH DNA repair enzyme. Impairment of MUTYH activity could lead to a surplus of mutated peptides which would be presented to cytotoxic T-cells through the HLA class I molecules. We have studied the frequency of HLA class I expression defects in MAP carcinomas and have compared it to those observed in MMR-deficient and -proficient colorectal tumours. Immunohistochemical detection of the expression of HLA class 1, beta 2-microglobulin (beta 2m), and antigen-processing machinery molecules was performed in 37 primary MAP carcinomas and nine metastases resected from 29 MAP patients. Furthermore, we sequenced the beta 2m, TAP1, and TAP2 genes. Defects in HLA class I expression were detected in 65% of primary MAP carcinomas, affecting 72% of patients. HLA class I expression abnormalities were often concomitant with beta 2m expression loss and mutations in the beta 2m gene. Loss of HLA class I expression is thus a frequent event in MAP carcinomas, similarly to MMR-deficient colorectal tumours. The extensive mutagenic background of these tumours most likely triggers a strong selective pressure, exerted by the immune system on the tumour, which favours the outgrowth of tumour cell clones with an immune evasive phenotype. Our data provide additional evidence for a link between DNA repair deficiencies and altered HLA class I phenotypes in colorectal cancer. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.