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Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2015 Dec 01; Vol. 21 (23), pp. 5264-76. Date of Electronic Publication: 2015 Jul 07. - Publication Year :
- 2015
-
Abstract
- Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.<br />Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.<br />Results: Five SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)).<br />Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- Alleles
Carcinoma, Ovarian Epithelial
Computational Biology methods
Female
Genotype
Humans
Kaplan-Meier Estimate
Meta-Analysis as Topic
Neoplasms, Glandular and Epithelial genetics
Neoplasms, Glandular and Epithelial mortality
Neoplasms, Glandular and Epithelial pathology
Ovarian Neoplasms pathology
Ovarian Neoplasms therapy
Patient Outcome Assessment
Polymorphism, Single Nucleotide
Prognosis
Genome-Wide Association Study
Ovarian Neoplasms genetics
Ovarian Neoplasms mortality
Quantitative Trait Loci
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 21
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 26152742
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-15-0632