Linkage of DNA Methylation Quantitative Trait Loci to Human Cancer Risk

• We provide a comprehensive meQTL catalog of cancer-risk polymorphisms
• Genotype-epitype-phenotype associations can facilitate GWAS interpretation
• Differentially methylated loci relate to yet unidentified cancer genes
• meQTLs are potential integral components of cancer-risk biology

SummaryEpigenetic regulation and, in particular, DNA methylation have been linked to the underlying genetic sequence. DNA methylation quantitative trait loci (meQTL) have been identified through significant associations between the genetic and epigenetic codes in physiological and pathological contexts. We propose that interrogating the interplay between polymorphic alleles and DNA methylation is a powerful method for improving our interpretation of risk alleles identified in genome-wide association studies that otherwise lack mechanistic explanation. We integrated patient cancer risk genotype data and genome-scale DNA methylation profiles of 3,649 primary human tumors, representing 13 solid cancer types. We provide a comprehensive meQTL catalog containing DNA methylation associations for 21% of interrogated cancer risk polymorphisms. Differentially methylated loci harbor previously reported and as-yet-unidentified cancer genes. We suggest that such regulation at the DNA level can provide a considerable amount of new information about the biology of cancer-risk alleles.

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