RT Journal Article
SR Electronic
T1 Allelic imbalance reveals widespread germline-somatic regulatory differences and prioritizes risk loci in Renal Cell Carcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 631150
DO 10.1101/631150
A1 Alexander Gusev
A1 Sandor Spisak
A1 Andre P. Fay
A1 Hallie Carol
A1 Kevin C Vavra
A1 Sabina Signoretti
A1 Viktoria Tisza
A1 Mark Pomerantz
A1 Forough Abbasi
A1 Ji-Heui Seo
A1 Toni K. Choueiri
A1 Kate Lawrenson
A1 Matthew L Freedman
YR 2019
UL http://biorxiv.org/content/early/2019/05/08/631150.abstract
AB Determining the function of non-coding regulatory variants in cancer is a key challenge transcriptional biology. We investigated genetic (germline and somatic) determinants of regulatory mechanisms in renal cell carcinoma (RCC) using H3K27ac ChIP-seq data in 10 matched tumor/normal samples and RNA-seq data from 496/66 tumor/normal samples from The Cancer Genome Atlas (TCGA). Unsupervised clustering of H3K27ac activity cleanly separated tumor from normal individuals, highlighting extensive epigenetic reprogramming during transformation. We developed a novel method to test each chromatin feature for evidence of an allele-specific quantitative trait locus (asQTL) and evaluate tumor/normal differences in allele-specificity (d-asQTLs) while modelling local structural variation and read overdispersion. At an FDR of 5%, we identified 1,356 unique asQTL chromatin peaks in normal tissues; 2,868 in tumors; and 1,054 d-asQTLs (primarily imbalanced in tumor). The d-asQTL peaks were significantly enriched for RCC genome-wide association study (GWAS) heritability (32x, P=1.8×10−3), more so than any other functional feature including all H3K27ac peaks (12x), super-enhancers (5x), and asQTL genes (4x). Intersection of asQTLs with RCC GWAS loci identified putative functional features for 6/17 known loci including tumor-specific activity at SCARB1, a cholesterol metabolism mediator, which has recently been implicated in RCC progression. We validated the asQTL variant through CRISPR interference (CRISPRi) and demonstrated a concomitant allelic effect on the overlapping enhancer and on downstream SCARB1 expression. Knockdowns of master transcription factors (TFs) involved in the hypoxia pathway altered the expression of SCARB1 in a kidney cancer cell line, consistent with a variant-TF interaction. Genome-wide, d-asQTLs were significantly enriched for tumor-specific binding of hypoxic transcription factors, implicating a more general mechanism for polygenic germline-somatic interaction.