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Human leukocyte antigen (HLA) class I expression defects and colorectal tumorigenesis

Saturday 1 December 2012

Human leukocyte antigen (HLA) class I expression defects

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.

In one series, Immunohistochemical detection of the expression of HLA class I, beta2-microglobulin (beta2m), and antigen-processing machinery molecules was performed in 37 primary MAP carcinomas and nine metastases resected from 29 MAP patients.

HLA class I expression abnormalities were often concomitant with beta2m expression loss and mutations in the beta2m gene. (19462419)

Loss of HLA class I expression is 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. (19462419)