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

被引：31

作者：

Johnatty, Sharon E. ^{[1
]}

Tyrer, Jonathan P. ^{[2
]}

Kar, Siddhartha ^{[2
]}

Beesley, Jonathan ^{[1
]}

Lu, Yi ^{[1
]}

Gao, Bo ^{[3
,4
]}

Fasching, Peter A. ^{[5
,6
]}

Hein, Alexander ^{[7
]}

Ekici, Arif B. ^{[6
]}

Beckmann, Matthias W. ^{[7
]}

Lambrechts, Diether ^{[8
,9
]}

Van Nieuwenhuysen, Els ^{[10
]}

Vergote, Ignace ^{[10
]}

Lambrechts, Sandrina ^{[10
]}

Rossing, Mary Anne ^{[11
,12
]}

Doherty, Jennifer A. ^{[13
]}

Chang-Claude, Jenny ^{[14
]}

Modugno, Francesmary ^{[15
,16
,17
,18
]}

Ness, Roberta B. ^{[19
]}

Moysich, Kirsten B. ^{[20
]}

Levine, Douglas A. ^{[21
]}

Kiemeney, Lambertus A. ^{[22
]}

Massuger, Leon F. A. G. ^{[23
]}

Gronwald, Jacek ^{[24
]}

Lubinski, Jan ^{[24
]}

Jakubowska, Anna ^{[24
]}

Cybulski, Cezary ^{[24
]}

Brinton, Louise ^{[25
]}

Lissowska, Jolanta ^{[26
,27
]}

Wentzensen, Nicolas ^{[25
]}

Song, Honglin ^{[28
]}

Rhenius, Valerie ^{[28
]}

Campbell, Ian ^{[29
,30
]}

Eccles, Diana ^{[31
]}

Sieh, Weiva ^{[32
]}

Whittemore, Alice S. ^{[32
]}

McGuire, Valerie ^{[32
]}

Rothstein, Joseph H. ^{[32
]}

Sutphen, Rebecca ^{[33
]}

Anton-Culver, Hoda ^{[34
]}

Ziogas, Argyrios ^{[35
]}

Gayther, Simon A. ^{[36
]}

Gentry-Maharaj, Aleksandra ^{[37
]}

Menon, Usha ^{[37
]}

Ramus, Susan J. ^{[36
]}

Pearce, Celeste L. ^{[36
,38
]}

Pike, Malcolm C. ^{[36
,39
]}

Stram, Daniel O. ^{[36
]}

Wu, Anna H. ^{[36
]}

Kupryjanczyk, Jolanta ^{[27
,40
]}

机构：

[1] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia

[2] Univ Cambridge, Dept Oncol, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England

[3] Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia

[4] Univ Sydney, Ctr Canc Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA

[6] Univ Erlangen Nurnberg, Inst Human Genet, Univ Hosp Erlangen, Erlangen, Germany

[7] Univ Erlangen Nurnberg, Dept Gynecol & Obstet, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, D-91054 Erlangen, Germany

[8] VIB, Vesalius Res Ctr, Leuven, Belgium

[9] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium

[10] Univ Leuven, Leuven Canc Inst, Dept Gynecol Oncol, Leuven, Belgium

[11] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA

[12] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[13] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Dept Community & Family Med, Lebanon, NH USA

[14] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[15] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA

[16] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA

[17] Magee Womens Res Inst, Womens Canc Res Program, Pittsburgh, PA USA

[18] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA

[19] Univ Texas Sch Publ Hlth, Houston, TX USA

[20] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA

[21] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA

[22] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands

[23] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Sci, NL-6525 ED Nijmegen, Netherlands

[24] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland

[25] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[26] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland

[27] Inst Oncol, Warsaw, Poland

[28] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England

[29] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Vic, Australia

[30] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia

[31] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton, Hants, England

[32] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA

[33] Univ S Florida, Coll Med, Epidemiol Ctr, Tampa, FL USA

[34] Univ Calif Irvine, Sch Med, Ctr Canc Genet Res & Prevent, Dept Epidemiol, Irvine, CA 92717 USA

[35] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA

[36] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA

[37] UCL EGA Inst Womens Hlth, Womens Canc, London, England

[38] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[39] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[40] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland

[41] Maria Sklodowska Curie Mem Canc Ctr, Dept Gynecol Oncol, Warsaw, Poland

[42] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Prevent & Control, Los Angeles, CA 90048 USA

[43] Cedars Sinai Med Ctr, Dept Biomed Sci, Community & Populat Hlth Res Inst, Los Angeles, CA 90048 USA

[44] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA

[45] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany

[46] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany

[47] Inst Humangenet Wiesbaden, Wiesbaden, Germany

[48] Zentrum Gynakol Onkol, Kiel, Germany

[49] Hannover Med Sch, Dept Obstet & Gynaecol, Hannover, Germany

[50] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 23期

基金：

英国医学研究理事会; 加拿大健康研究院; 美国国家卫生研究院;

关键词：

POLYMORPHISMS; SURVIVAL; EXPRESSION; WOMEN; YAP1; PHARMACOGENOMICS; SUSCEPTIBILITY; METAANALYSIS; PROGRESSION; ACTIVATION;

D O I：

10.1158/1078-0432.CCR-15-0632

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 x 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 x 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 x 10(-3)). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264-76. 2015 AACR.

引用

页码：5264 / 5276

页数：13

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