2022年6月13日，《自然—遗传学》杂志在线发表了美国丹娜-法伯癌症研究所Alexander Gusev小组的最新成果。该研究发现，癌症中染色质可及性的等位基因不平衡可确定候选因果风险变异及其机制。

Author: Grishin, Dennis, Gusev, Alexander

Issue&Volume: 2022-06-13

Abstract: 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.

DOI: 10.1038/s41588-022-01075-2

Source: https://www.nature.com/articles/s41588-022-01075-2