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Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

ABSTRACT: We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

SUBMITTER: Glubb DM

PROVIDER: S-EPMC5630285 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

Glubb Dylan M DM Johnatty Sharon E SE Quinn Michael C J MCJ O'Mara Tracy A TA Tyrer Jonathan P JP Gao Bo B Fasching Peter A PA Beckmann Matthias W MW Lambrechts Diether D Vergote Ignace I Velez Edwards Digna R DR Beeghly-Fadiel Alicia A Benitez Javier J Garcia Maria J MJ Goodman Marc T MT Thompson Pamela J PJ Dörk Thilo T Dürst Matthias M Modungo Francesmary F Moysich Kirsten K Heitz Florian F du Bois Andreas A Pfisterer Jacobus J Hillemanns Peter P Karlan Beth Y BY Lester Jenny J Goode Ellen L EL Cunningham Julie M JM Winham Stacey J SJ Larson Melissa C MC McCauley Bryan M BM Kjær Susanne Krüger SK Jensen Allan A Schildkraut Joellen M JM Berchuck Andrew A Cramer Daniel W DW Terry Kathryn L KL Salvesen Helga B HB Bjorge Line L Webb Penny M PM Grant Peter P Pejovic Tanja T Moffitt Melissa M Hogdall Claus K CK Hogdall Estrid E Paul James J Glasspool Rosalind R Bernardini Marcus M Tone Alicia A Huntsman David D Woo Michelle M Group Aocs A deFazio Anna A Kennedy Catherine J CJ Pharoah Paul D P PDP MacGregor Stuart S Chenevix-Trench Georgia G

Oncotarget 20170615 39

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter reg ...[more]

PMID: 29029385

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Project description:Annotating and interpreting the results of genome-wide association studies (GWAS) remains challenging. Assigning function to genetic variants as expression quantitative trait loci is an expanding and useful approach, but focuses exclusively on mRNA rather than protein levels. Many variants remain without annotation. To address this problem, we measured the steady state abundance of 441 human signaling and transcription factor proteins from 68 Yoruba HapMap lymphoblastoid cell lines to identify novel relationships between inter-individual protein levels, genetic variants, and sensitivity to chemotherapeutic agents. Proteins were measured using micro-western and reverse phase protein arrays from three independent cell line thaws to permit mixed effect modeling of protein biological replicates. We observed enrichment of protein quantitative trait loci (pQTLs) for cellular sensitivity to two commonly used chemotherapeutics: cisplatin and paclitaxel. We functionally validated the target protein of a genome-wide significant trans-pQTL for its relevance in paclitaxel-induced apoptosis. GWAS overlap results of drug-induced apoptosis and cytotoxicity for paclitaxel and cisplatin revealed unique SNPs associated with the pharmacologic traits (at p<0.001). Interestingly, GWAS SNPs from various regions of the genome implicated the same target protein (p<0.0001) that correlated with drug induced cytotoxicity or apoptosis (p ≤ 0.05). Two genes were functionally validated for association with drug response using siRNA: SMC1A with cisplatin response and ZNF569 with paclitaxel response. This work allows pharmacogenomic discovery to progress from the transcriptome to the proteome and offers potential for identification of new therapeutic targets. This approach, linking targeted proteomic data to variation in pharmacologic response, can be generalized to other studies evaluating genotype-phenotype relationships and provide insight into chemotherapeutic mechanisms.

Dataset Information

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

Publications

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

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