No evidence that HLA genotype influences the driver mutations that occur in cancer patients

Abstract

The major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumour. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

A simple approach for detecting HLA‐A*02 alleles in archival formalin‐fixed paraffin‐embedded tissue samples and an application example for studying cancer immunoediting

“…After validating the accuracy of the developed classification approach, we aimed to demonstrate its applicability in current molecular biology research. A central controversy in the context of tumor immunology is whether the individual's HLA type influences the mutational landscape of cancers 12–14,37 . With the developed approach, we determined the HLA‐A *02 status of an independent cohort of 73 MSI CRC samples.…”

“…A central controversy in the context of tumor immunology is whether the individual's HLA type influences the mutational landscape of cancers. [12][13][14]37 With the developed approach, we determined the HLA-A*02 status of an independent cohort of 73 MSI CRC samples. Thirty-six of these had at least one HLA-A*02 allele (group G pr , 12 hereditary and 24 sporadic cases) and 37 samples did not possess any HLA-A*02 allele (group G non , 19 hereditary and 17 sporadic cases, one patient without information on etiology of MSI, see Table S2a).…”

Hypothesis: Mutations and Immunosurveillance in Obesity-Associated Colorectal Cancer

“…Emerging data support the concept that obesity-related cancer derives from complex interactions between deregulated cell signaling and immune response to tumors, the latter of which is modulated in part by the expression of MHC-1 gene variants. Controversy still exists concerning the association between the MHC-I genotype and the cancer mutational landscape [28], and the experimental approaches proposed here can assist in ascertaining the role of MHC-1 variability. The acquired knowledge can assist in developing approaches that restore MHC-1 expression and function to promote better tumor immunosurveillance [29].…”