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Grant Details

Grant Number: 7R01CA211574-03 Interpret this number
Primary Investigator: Schildkraut, Joellen
Organization: Emory University
Project Title: Genomic and Transcriptomic Analysis of Breast and Ovarian Cancers
Fiscal Year: 2020


ABSTRACT Ovarian and breast cancers share common genetic and lifestyle/environmental factors. GWAS have identified more than a hundred genomic regions containing common variants associated with risks of these cancers, several of which confer risks to both cancers. The molecular features of the aggressive subtypes of these cancers--high grade serous ovarian cancer (HGSOC) and estrogen receptor (ER) negative breast cancer—are also remarkably similar, suggesting common genetic and biological mechanisms driving disease development. In the current proposal, we aim to focus on pleiotropic mechanisms underlying susceptibility to ovarian and breast cancer, through tissue-specific transcription-wide analysis of gene expression associated with common variant risk alleles for ovarian and breast cancer identified by GWAS. We will apply a new gene-based association method, PrediXcan, to test the molecular mechanisms through which genetic variation affects ovarian and breast cancer development. The proposed integration of germline genetic data with annotation of whole genome transcription in the relevant tissue types effectively reduces the multiple testing burden faced by GWAS by grouping together multiple risk loci at the gene-level, and further simplifies additional characterization of implicated pathways. We hypothesize that the biological relevance of predictors provided by PrediXcan will allow us to overcome tumor heterogeneity and identify novel genes/pathways for ovarian and breast cancer. We then propose performing functional analyses in experimental models of breast and ovarian cancer to validate the genes and pathways we identify using PrediXcan. This proposal incorporates novel methodology integrating multiple sources of genomic and transcriptomic data to identify the role of genetically regulated gene expression traits in the pathogenesis of ovarian and breast cancers. Mortality is highest for the specific subtypes of these cancers that we will focus on, since the mechanisms underlying the pathogenesis of these cancer subtypes are poorly understood. Genotype and phenotype data from the GAME-ON, OCAC and BCAC consortia, along with the publicly available datasets, TCGA, METABRIC and GTEx, represent a unique opportunity to apply the PrediXcan approach in a large- scale for a well-defined group of cases and controls with high quality epidemiologic data resources .


Mapping inherited genetic variation with opposite effects on autoimmune disease and cancer identifies candidate drug targets associated with the anti-tumor immune response.
Authors: Chen J. , Epstein M.P. , Schildkraut J.M. , Kar S.P. .
Source: medRxiv : the preprint server for health sciences, 2023-12-28; , .
EPub date: 2023-12-28.
PMID: 38234717
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Cis- and trans-eQTL TWAS of breast and ovarian cancer identify more than 100 risk associated genes in the BCAC and OCAC consortia.
Authors: Head S.T. , Dezem F. , Todor A. , Yang J. , Plummer J. , Gayther S. , Kar S. , Schildkraut J. , Epstein M.P. .
Source: bioRxiv : the preprint server for biology, 2023-11-13; , .
EPub date: 2023-11-13.
PMID: 38014246
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The tumor multi-omic landscape of endometrial cancers developed on a germline genetic background of adiposity.
Authors: Richenberg G. , Francis A. , Owen C.N. , Gray V. , Robinson T. , Gabriel A.A. , Lawrenson K. , Crosbie E.J. , Schildkraut J.M. , Mckay J.D. , et al. .
Source: medRxiv : the preprint server for health sciences, 2023-10-10; , .
EPub date: 2023-10-10.
PMID: 37873386
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Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility.
Authors: Gregga I. , Pharoah P.D.P. , Gayther S.A. , Manichaikul A. , Im H.K. , Kar S.P. , Schildkraut J.M. , Wheeler H.E. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2023-09-01; 32(9), p. 1198-1207.
PMID: 37409955
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POIROT: a powerful test for parent-of-origin effects in unrelated samples leveraging multiple phenotypes.
Authors: Head S.T. , Leslie E.J. , Cutler D.J. , Epstein M.P. .
Source: Bioinformatics (Oxford, England), 2023-04-03; 39(4), .
PMID: 37067493
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Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.
Authors: Kar S.P. , Considine D.P.C. , Tyrer J.P. , Plummer J.T. , Chen S. , Dezem F.S. , Barbeira A.N. , Rajagopal P.S. , Rosenow W.T. , Moreno F. , et al. .
Source: HGG advances, 2021-07-08; 2(3), .
EPub date: 2021-06-16.
PMID: 34317694
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Transcription factors in epithelial ovarian cancer: histotype-specific drivers and novel therapeutic targets.
Authors: Nameki R. , Chang H. , Reddy J. , Corona R.I. , Lawrenson K. .
Source: Pharmacology & therapeutics, 2021 Apr; 220, p. 107722.
EPub date: 2020-11-01.
PMID: 33137377
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Genetically predicted circulating protein biomarkers and ovarian cancer risk.
Authors: Considine D.P.C. , Jia G. , Shu X. , Schildkraut J.M. , Pharoah P.D.P. , Zheng W. , Kar S.P. , Ovarian Cancer Association Consortium .
Source: Gynecologic oncology, 2021 Feb; 160(2), p. 506-513.
EPub date: 2020-11-25.
PMID: 33246661
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Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites.
Authors: Jones M.R. , Peng P.C. , Coetzee S.G. , Tyrer J. , Reyes A.L.P. , Corona R.I. , Davis B. , Chen S. , Dezem F. , Seo J.H. , et al. .
Source: American journal of human genetics, 2020-10-01; 107(4), p. 622-635.
EPub date: 2020-09-17.
PMID: 32946763
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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
Authors: Lu Y. , Beeghly-Fadiel A. , Wu L. , Guo X. , Li B. , Schildkraut J.M. , Im H.K. , Chen Y.A. , Permuth J.B. , Reid B.M. , et al. .
Source: Cancer research, 2018-09-15; 78(18), p. 5419-5430.
EPub date: 2018-07-27.
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