Grant Details
Grant Number: |
1R21CA220078-01 Interpret this number |
Primary Investigator: |
Lawrenson, Kate |
Organization: |
Cedars-Sinai Medical Center |
Project Title: |
The Role of Splice Quantitative Traits in Ovarian Cancer Pathogenesis |
Fiscal Year: |
2017 |
Abstract
Abstract
Genome wide association studies (GWAS) have so far identified more than 30 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 with respect to genetic risk variants that target splicing mechanisms of target susceptibility
genes. Specifically we aim to: (1) Integrate the largest GWAS datasets for ovarian cancer with RNA
sequencing data for hundreds of ovarian normal and cancer tissues to identify genetic risk variants
associated specifically with differential splicing; (2) Establish the functional mechanisms associated splice
associated risk variants for ovarian cancer risk loci using functional assays to analyse the effects of splicing
on their target genes on tumor development in novel experimental models of ovarian cancer precursor
tissues. These studies will establish a statistical and functional pipeline to evaluate the contribution of risk
associated splice variants in other complex traits and disorders
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
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.
, RodrĂguez-MalavĂ© 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
Related Citations
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