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

Noor Kherreh,Cathal Seoighe,Siobhán Cleary

doi:10.1007/s00262-021-03028-w

Noor Kherreh, Cathal Seoighe + Show 1 more

Open Access

https://doi.org/10.1007/s00262-021-03028-w

Copy DOI

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 tumor. 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.

Highlights

The immune system has evolved to recognize aberrant and non-self molecules, resulting from pathogen infection, somatic mutations and malformed proteins
Higher values of the patient harmonic mean best rank (PHBR) score in the patients in which the driver mutations occur were presented as evidence that driver mutations preferentially arise in patients who lack the major histocompatibility complex (MHC) alleles that are capable of presenting them to T cells
It is still conceivable that MHC genotype affects the driver mutation landscape at the population level, such that poorly presented driver mutations are relatively common; it is implausible that the population level effect could arise in the absence of any association between PHBR score and driver mutation occurrence within individual patients

Summary

Introduction

The immune system has evolved to recognize aberrant and non-self molecules, resulting from pathogen infection, somatic mutations and malformed proteins. The major histocompatibility complex (MHC) plays a key role in this process. There are two classes of MHC molecules, class I (MHC-I) and class II (MHC-II), encoded, in human, by a cluster of genes on chromosome 6. The human MHC genes and proteins, which are often termed human leukocyte antigens (HLA), are diverse, with over 15,000 alleles identified [1]. Somatic mutations in genes encoding self-proteins can.

Methods

Results

Conclusion