Grant Details
Grant Number: |
1R01CA211707-01 Interpret this number |
Primary Investigator: |
Gayther, Simon |
Organization: |
Cedars-Sinai Medical Center |
Project Title: |
Functional Effects of Ovarian Cancer Risk Variants |
Fiscal Year: |
2017 |
Abstract
Abstract
Genome wide association studies (GWAS) have so far identified more than 20 common low penetrance
variants for ovarian cancer; but it is estimated that thousands more risk variants await discovery. In the
post-GWAS era a complex set of challenges for the identification, functional characterization and utility of
susceptibility alleles have emerged including: (i) Identifying the causal genetic variants and regulatory
targets driving cancer development at risk loci; (ii) Identifying the susceptibility genes associated with risk
variants; (iii) Establishing if there are common biological networks that explain the functional mechanisms
underlying multiple risk loci. Clinically, identifying the genetic risk component of ovarian cancer will likely
lead to improved disease prevention through population screening and disease prevention strategies; and
understanding the function of risk loci may lead to the discovery of clinical biomarkers and novel targeted
therapies, analogous to the paradigm of PARP therapy for BRCA1 or BRCA2 mutation carriers.
The current proposal is designed to address many of these challenges for ovarian cancer in the post-
GWAS era including: (1) Identifying additional novel, common variant susceptibility alleles for the different
histological subtypes of ovarian cancer; (2) Establishing the functional mechanisms driving disease at
ovarian cancer risk loci based on the identification and characterization of the likely casual SNPs and
targets susceptibility genes are risk loci; (3) Using genome wide profiling of functional models based on
perturbation of ovarian cancer susceptibility genes, to identify common mechanisms and biological
pathways driving tumorigenesis; (4) To integrate functional datasets with genetic association datasets to
improve the power of these studies to identify additional ovarian cancer susceptibility loci.
Publications
Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.
Authors: Dareng E.O.
, Coetzee S.G.
, Tyrer J.P.
, Peng P.C.
, Rosenow W.
, Chen S.
, Davis B.D.
, Dezem F.S.
, Seo J.H.
, Nameki R.
, et al.
.
Source: American Journal Of Human Genetics, 2024-05-07 00:00:00.0; , .
EPub date: 2024-05-07 00:00:00.0.
PMID: 38723632
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Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors.
Authors: Tak Y.E.
, Boulay G.
, Lee L.
, Iyer S.
, Perry N.T.
, Schultz H.T.
, Garcia S.P.
, Broye L.
, Horng J.E.
, Rengarajan S.
, et al.
.
Source: Cell Genomics, 2022-04-13 00:00:00.0; 2(4), .
PMID: 35967079
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A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes.
Authors: Mortlock S.
, Corona R.I.
, Kho P.F.
, Pharoah P.
, Seo J.H.
, Freedman M.L.
, Gayther S.A.
, Siedhoff M.T.
, Rogers P.A.W.
, Leuchter R.
, et al.
.
Source: Cell Reports. Medicine, 2022-03-15 00:00:00.0; 3(3), p. 100542.
EPub date: 2022-03-15 00:00:00.0.
PMID: 35492879
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Augmenting and directing long-range CRISPR-mediated activation in human cells.
Authors: Tak Y.E.
, Horng J.E.
, Perry N.T.
, Schultz H.T.
, Iyer S.
, Yao Q.
, Zou L.S.
, Aryee M.J.
, Pinello L.
, Joung J.K.
.
Source: Nature Methods, 2021-08-05 00:00:00.0; , .
EPub date: 2021-08-05 00:00:00.0.
PMID: 34354266
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Single-cell transcriptomics identifies gene expression networks driving differentiation and tumorigenesis in the human fallopian tube.
Authors: Dinh H.Q.
, Lin X.
, Abbasi F.
, Nameki R.
, Haro M.
, Olingy C.E.
, Chang H.
, Hernandez L.
, Gayther S.A.
, Wright K.N.
, et al.
.
Source: Cell Reports, 2021-04-13 00:00:00.0; 35(2), p. 108978.
PMID: 33852846
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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 00:00:00.0; 107(4), p. 622-635.
EPub date: 2020-09-17 00:00:00.0.
PMID: 32946763
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Mutant Allele-Specific CRISPR Disruption in DYT1 Dystonia Fibroblasts Restores Cell Function.
Authors: Cruz L.
, György B.
, Cheah P.S.
, Kleinstiver B.P.
, Eimer W.A.
, Garcia S.P.
, Sharma N.
, Ozelius L.J.
, Bragg D.C.
, Joung J.K.
, et al.
.
Source: Molecular Therapy. Nucleic Acids, 2020-09-04 00:00:00.0; 21, p. 1-12.
EPub date: 2020-05-15 00:00:00.0.
PMID: 32502938
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A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development.
Authors: Lawrenson K.
, Fonseca M.A.S.
, Liu A.Y.
, Segato Dezem F.
, Lee J.M.
, Lin X.
, Corona R.I.
, Abbasi F.
, Vavra K.C.
, Dinh H.Q.
, et al.
.
Source: Cell Reports, 2019-12-10 00:00:00.0; 29(11), p. 3726-3735.e4.
PMID: 31825847
Related Citations
Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.
Authors: Lawrenson K.
, Song F.
, Hazelett D.J.
, Kar S.P.
, Tyrer J.
, Phelan C.M.
, Corona R.I.
, Rodríguez-Malavé N.I.
, Seo J.H.
, Adler E.
, et al.
.
Source: Gynecologic Oncology, 2019 05; 153(2), p. 343-355.
EPub date: 2019-03-19 00:00:00.0.
PMID: 30898391
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A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.
Authors: Gusev A.
, Lawrenson K.
, Lin X.
, Lyra P.C.
, Kar S.
, Vavra K.C.
, Segato F.
, Fonseca M.A.S.
, Lee J.M.
, Pejovic T.
, et al.
.
Source: Nature Genetics, 2019 05; 51(5), p. 815-823.
EPub date: 2019-05-01 00:00:00.0.
PMID: 31043753
Related Citations
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, 2018-07-27 00:00:00.0; , .
EPub date: 2018-07-27 00:00:00.0.
PMID: 30054336
Related Citations
Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells.
Authors: Lakshminarasimhan R.
, Andreu-Vieyra C.
, Lawrenson K.
, Duymich C.E.
, Gayther S.A.
, Liang G.
, Jones P.A.
.
Source: Cancer Letters, 2017-08-10 00:00:00.0; 401, p. 11-19.
EPub date: 2017-05-06 00:00:00.0.
PMID: 28483516
Related Citations
Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.
Authors: Phelan C.M.
, Kuchenbaecker K.B.
, Tyrer J.P.
, Kar S.P.
, Lawrenson K.
, Winham S.J.
, Dennis J.
, Pirie A.
, Riggan M.J.
, Chornokur G.
, et al.
.
Source: Nature Genetics, 2017 May; 49(5), p. 680-691.
EPub date: 2017-03-27 00:00:00.0.
PMID: 28346442
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Enrichment Of Putative Pax8 Target Genes At Serous Epithelial Ovarian Cancer Susceptibility Loci
Authors: Kar S.P.
, Adler E.
, Tyrer J.
, Hazelett D.
, Anton-Culver H.
, Bandera E.V.
, Beckmann M.W.
, Berchuck A.
, Bogdanova N.
, Brinton L.
, et al.
.
Source: British Journal Of Cancer, 2017-02-14 00:00:00.0; 116(4), p. 524-535.
PMID: 28103614
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