Question ID: WS-29
Submitted by: Allan Hildesheim
February 3, 2011
Question: What are the specific mechanisms of antigen processing and presentation whose variation impact risk of development of infection-related cancers? Background: Results from multiple genome-wide association studies (GWAS) of 1) cancers that are proven to be caused by infections and 2) chronic carriage of infections that have been definitively linked to cancer have repeatedly found that polymorphisms in the Major Histocompatibility Complex (MHC) region of chromosome 6 show the strongest evidence for association. These findings reinforce previous candidate gene studies that have shown clear associations between HLA genes located within the MHC and these same infection and cancer outcomes. It is plausible that genetic predisposition based on HLA genes is among the most consistent genetic factors known to predispose to human cancers. HLA genes are complex, highly variable, have different biological functions, and are in strong linkage disequilibrium with each other. As a result, despite our knowledge that HLAs (and possibly other immune-related genes in the MHC) are important for the development of infection-related cancers, the specific genes/alleles involved and their precise biological role in cancer development remains unproven. Feasibility: GWAS studies have paved the way for large, targeted studies that could for the first time elucidate the specific HLA (or other) genes within the MHC involved in cancer development. HLA-specific and SNP/sequencing-based genotyping approaches exist that can be combined to allow for the evaluation of this question within well-characterized and sufficiently powered epidemiological studies, combined with functional biological studies of resultant associations. Implications of success: If this question can be answered, it will be the first time that a specific immunological mechanism is shown to be involved in the development of multiple cancer types caused by infectious agents and that together account for approximately 20% of all cancers worldwide.
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