Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

On behalf of the AGO Study Group, On behalf of the Australian Ovarian Cancer Study Group

Research output: Contribution to journalArticle

18 Citations (Scopus)

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. 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. 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). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novelEOCtherapies.

Original languageEnglish (US)
Pages (from-to)5264-5276
Number of pages13
JournalClinical Cancer Research
Volume21
Issue number23
DOIs
StatePublished - Dec 1 2015

Fingerprint

Ovarian Neoplasms
Single Nucleotide Polymorphism
Genome
Long Noncoding RNA
Disease-Free Survival
Drug Therapy
Survival
Histone Code
Atlases
Carboplatin
HDL Lipoproteins
Paclitaxel
Ovary
Neoplasms
Research Design
Lipids
Gene Expression
Therapeutics
Genes
Ovarian epithelial cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes : Findings from the Ovarian Cancer Association Consortium. / On behalf of the AGO Study Group; On behalf of the Australian Ovarian Cancer Study Group.

In: Clinical Cancer Research, Vol. 21, No. 23, 01.12.2015, p. 5264-5276.

Research output: Contribution to journalArticle

On behalf of the AGO Study Group ; On behalf of the Australian Ovarian Cancer Study Group. / Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes : Findings from the Ovarian Cancer Association Consortium. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 23. pp. 5264-5276.
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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. 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. 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). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novelEOCtherapies.",
author = "{On behalf of the AGO Study Group} and {On behalf of the Australian Ovarian Cancer Study Group} and Johnatty, {Sharon E.} and Tyrer, {Jonathan P.} and Siddhartha Kar and Jonathan Beesley and Yi Lu and Bo Gao and Fasching, {Peter A.} and Alexander Hein and Ekici, {Arif B.} and Beckmann, {Matthias W.} and Diether Lambrechts and {Van Nieuwenhuysen}, Els and Ignace Vergote and Sandrina Lambrechts and Rossing, {Mary Anne} and Doherty, {Jennifer A.} and Jenny Chang-Claude and Francesmary Modugno and Ness, {Roberta B.} and Moysich, {Kirsten B.} and Levine, {Douglas A.} and Kiemeney, {Lambertus A.} and Massuger, {Leon F A G} and Jacek Gronwald and Jan Lubiński and Anna Jakubowska and Cezary Cybulski and Louise Brinton and Jolanta Lissowska and Nicolas Wentzensen and Honglin Song and Valerie Rhenius and Ian Campbell and Diana Eccles and Weiva Sieh and Whittemore, {Alice S.} and Valerie McGuire and Rothstein, {Joseph H.} and Rebecca Sutphen and Hoda Anton-Culver and Argyrios Ziogas and Gayther, {Simon A.} and Aleksandra Gentry-Maharaj and Usha Menon and Ramus, {Susan J.} and Pearce, {Celeste L.} and Pike, {Malcolm C.} and Winham, {Stacey J} and Cunningham, {Julie M} and Goode, {Ellen L}",
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TY - JOUR

T1 - Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes

T2 - Findings from the Ovarian Cancer Association Consortium

AU - On behalf of the AGO Study Group

AU - On behalf of the Australian Ovarian Cancer Study Group

AU - Johnatty, Sharon E.

AU - Tyrer, Jonathan P.

AU - Kar, Siddhartha

AU - Beesley, Jonathan

AU - Lu, Yi

AU - Gao, Bo

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Ekici, Arif B.

AU - Beckmann, Matthias W.

AU - Lambrechts, Diether

AU - Van Nieuwenhuysen, Els

AU - Vergote, Ignace

AU - Lambrechts, Sandrina

AU - Rossing, Mary Anne

AU - Doherty, Jennifer A.

AU - Chang-Claude, Jenny

AU - Modugno, Francesmary

AU - Ness, Roberta B.

AU - Moysich, Kirsten B.

AU - Levine, Douglas A.

AU - Kiemeney, Lambertus A.

AU - Massuger, Leon F A G

AU - Gronwald, Jacek

AU - Lubiński, Jan

AU - Jakubowska, Anna

AU - Cybulski, Cezary

AU - Brinton, Louise

AU - Lissowska, Jolanta

AU - Wentzensen, Nicolas

AU - Song, Honglin

AU - Rhenius, Valerie

AU - Campbell, Ian

AU - Eccles, Diana

AU - Sieh, Weiva

AU - Whittemore, Alice S.

AU - McGuire, Valerie

AU - Rothstein, Joseph H.

AU - Sutphen, Rebecca

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Gayther, Simon A.

AU - Gentry-Maharaj, Aleksandra

AU - Menon, Usha

AU - Ramus, Susan J.

AU - Pearce, Celeste L.

AU - Pike, Malcolm C.

AU - Winham, Stacey J

AU - Cunningham, Julie M

AU - Goode, Ellen L

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. 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. 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). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novelEOCtherapies.

AB - Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. 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. 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). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novelEOCtherapies.

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