Allelic imbalance reveals widespread germline-somatic regulatory differences and prioritizes risk loci in Renal Cell Carcinoma

Gusev, A.; Spisak, S.; Fay, A. P.; Carol, H.; Vavra, K. C.; Signoretti, S.; Tisza, V.; Pomerantz, M.; Abbasi, F.; Seo, J.-H.; Choueiri, T. K.; Lawrenson, K.; Freedman, M. L.

doi:10.1101/631150

bioRxiv · 10.1101/631150

Allelic imbalance reveals widespread germline-somatic regulatory differences and prioritizes risk loci in Renal Cell Carcinoma

Gusev, A.·Spisak, S.·Fay, A. P.·Carol, H.·Vavra, K. C.·Signoretti, S.·Tisza, V.·Pomerantz, M.·Abbasi, F.·Seo, J.-H.·Choueiri, T. K.·Lawrenson, K.·Freedman, M. L.

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Abstract

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=1.8x10-3), 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.

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Gusev, A., Spisak, S., Fay, A. P., Carol, H., Vavra, K. C., Signoretti, S., Tisza, V., Pomerantz, M., Abbasi, F., Seo, J.-H., Choueiri, T. K., Lawrenson, K., Freedman, M. L.. 2019-05-08. Allelic imbalance reveals widespread germline-somatic regulatory differences and prioritizes risk loci in Renal Cell Carcinoma. https://doi.org/10.1101/631150

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