Allelic imbalance of chromatin accessibility in cancer identifies candidate causal risk variants and their mechanisms
Menée à partir de données de séquençage ATAC-seq du projet "The Cancer Genome Atlas" portant sur 406 échantillons tumoraux issus de 23 types de cancer et menée à l'aide d'une analyse du déséquilibre allélique, cette étude identifie des variants constitutionnels influençant l'accessibilité de la chromatine ainsi que des mécanismes par lesquels ces variants peuvent favoriser le développement d'un cancer
While many germline cancer risk variants have been identified through genome-wide association studies (GWAS), the mechanisms by which these variants operate remain largely unknown. Here we used 406 cancer ATAC-Seq samples across 23 cancer types to identify 7,262 germline allele-specific accessibility QTLs (as-aQTLs). Cancer as-aQTLs had stronger enrichment for cancer risk heritability (up to 145 fold) than any other functional annotation across seven cancer GWAS. Most cancer as-aQTLs directly altered transcription factor (TF) motifs and exhibited differential TF binding and gene expression in functional screens. To connect as-aQTLs to putative risk mechanisms, we introduced the regulome-wide associations study (RWAS). RWAS identified genetically associated accessible peaks at >70% of known breast and prostate loci and discovered new risk loci in all examined cancer types. Integrating as-aQTL discovery, motif analysis and RWAS identified candidate causal regulatory elements and their probable upstream regulators. Our work establishes cancer as-aQTLs and RWAS analysis as powerful tools to study the genetic architecture of cancer risk.