Gad Rennert

Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Abstract Alternative polyadenylation (APA) modulates mRNA processing in the 3′-untranslated regions (3′ UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA sequencing data from 1,337 samples from the Genotype-Tissue Expression project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European ancestry populations: breast, ovarian, prostate, colorectal, lung, and pancreatic cancers. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3′-UTR APA quantitative trait loci and colocalization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3′-UTR variants demonstrated that the risk alleles of 3′-UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the posttranscriptional activities of their target genes compared with reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers. Significance: Systematic evaluation of associations of alternative polyadenylation with cancer risk reveals 58 putative susceptibility genes, highlighting the contribution of genetically regulated alternative polyadenylation of 3′UTRs to genetic susceptibility to cancer.

Genomic Landscapes of Endometrioid and Mucinous Ovarian Cancers and Morphologically Similar Tumor Types

Abstract Endometrioid and mucinous ovarian carcinomas represent nearly a fifth of ovarian cancers, but their molecular characteristics and pathologic origins are poorly understood. To identify the genomic and epigenomic alterations characteristic of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed a combination of sequence, copy number, mutation signature, and rearrangement analyses from tumor samples and matched normal tissues of 133 patients, as well as methylation analyses of these tumors and tissues of 150 patients from The Cancer Genome Atlas. Genomic analyses included samples from patients with ovarian endometrioid (n = 44), ovarian mucinous (n = 43), uterine endometrioid (n = 15), and gastrointestinal mucinous carcinomas (n = 31), including mucinous carcinomas of the stomach, colon, and pancreas. In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4, and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous carcinomas. Whole-genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid carcinomas and NF1 and MED1 in ovarian mucinous carcinomas. The number of alterations, affected genes, and genome-wide methylation profiles were not distinguishable between ovarian and uterine endometrioid carcinomas, supporting the hypothesis that these tumors share a tissue of origin. In contrast, mutation and methylation patterns in ovarian mucinous carcinomas were different from gastrointestinal mucinous carcinomas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers. Significance: Integrative multi-omic analyses support a common tissue of origin between ovarian endometrioid and uterine endometrioid carcinomas but not between ovarian mucinous and gastric or pancreatic mucinous carcinomas.