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

Sharon E Johnatty; Jonathan P Tyrer; Siddhartha Kar; Jonathan Beesley; Yi Lu; Bo Gao; Peter A Fasching; Alexander Hein; Arif B Ekici; Matthias W Beckmann; Diether Lambrechts; Els Van Nieuwenhuysen; Ignace Vergote; Sandrina Lambrechts; Mary Anne Rossing; Jennifer A Doherty; Jenny Chang-Claude; Francesmary Modugno; Roberta B Ness; Kirsten B Moysich; Douglas A Levine; Lambertus A Kiemeney; Leon F A G Massuger; Jacek Gronwald; Jan Lubiński; Anna Jakubowska; Cezary Cybulski; Louise Brinton; Jolanta Lissowska; Nicolas Wentzensen; Honglin Song; Valerie Rhenius; Ian Campbell; Diana Eccles; Weiva Sieh; Alice S Whittemore; Valerie McGuire; Joseph H Rothstein; Rebecca Sutphen; Hoda Anton-Culver; Argyrios Ziogas; Simon A Gayther; Aleksandra Gentry-Maharaj; Usha Menon; Susan J Ramus; Celeste L Pearce; Estrid Høgdall; Allan Jensen; Susanne Kruger Kjaer; Claus Høgdall; AGO Study Group

doi:10.1158/1078-0432.ccr-15-0632

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

Sharon E Johnatty, Jonathan P Tyrer, Siddhartha Kar, Jonathan Beesley, Yi Lu, Bo Gao, Peter A Fasching, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Diether Lambrechts, Els Van Nieuwenhuysen, Ignace Vergote, Sandrina Lambrechts, Mary Anne Rossing, Jennifer A Doherty, Jenny Chang-Claude, Francesmary Modugno, Roberta B Ness, Kirsten B MoysichDouglas A Levine, Lambertus A Kiemeney, Leon F A G Massuger, Jacek Gronwald, Jan Lubiński, Anna Jakubowska, Cezary Cybulski, Louise Brinton, Jolanta Lissowska, Nicolas Wentzensen, Honglin Song, Valerie Rhenius, Ian Campbell, Diana Eccles, Weiva Sieh, Alice S Whittemore, Valerie McGuire, Joseph H Rothstein, Rebecca Sutphen, Hoda Anton-Culver, Argyrios Ziogas, Simon A Gayther, Aleksandra Gentry-Maharaj, Usha Menon, Susan J Ramus, Celeste L Pearce, Estrid Høgdall, Allan Jensen, Susanne Kruger Kjaer, Claus Høgdall, AGO Study Group

20 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 novel EOC therapies.

Original language	English
Journal	Clinical Cancer Research
Volume	21
Issue number	23
Pages (from-to)	5264-76
Number of pages	13
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.ccr-15-0632
Publication status	Published - 1 Dec 2015

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Johnatty, S. E., Tyrer, J. P., Kar, S., Beesley, J., Lu, Y., Gao, B., Fasching, P. A., Hein, A., Ekici, A. B., Beckmann, M. W., Lambrechts, D., Van Nieuwenhuysen, E., Vergote, I., Lambrechts, S., Rossing, M. A., Doherty, J. A., Chang-Claude, J., Modugno, F., Ness, R. B., ... AGO Study Group (2015). Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium. Clinical Cancer Research, 21(23), 5264-76. https://doi.org/10.1158/1078-0432.ccr-15-0632

Johnatty, SE, Tyrer, JP, Kar, S, Beesley, J, Lu, Y, Gao, B, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Rossing, MA, Doherty, JA, Chang-Claude, J, Modugno, F, Ness, RB, Moysich, KB, Levine, DA, Kiemeney, LA, Massuger, LFAG, Gronwald, J, Lubiński, J, Jakubowska, A, Cybulski, C, Brinton, L, Lissowska, J, Wentzensen, N, Song, H, Rhenius, V, Campbell, I, Eccles, D, Sieh, W, Whittemore, AS, McGuire, V, Rothstein, JH, Sutphen, R, Anton-Culver, H, Ziogas, A, Gayther, SA, Gentry-Maharaj, A, Menon, U, Ramus, SJ, Pearce, CL, Høgdall, E, Jensen, A, Kjaer, SK , Høgdall, C & AGO Study Group 2015, 'Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium', Clinical Cancer Research, vol. 21, no. 23, pp. 5264-76. https://doi.org/10.1158/1078-0432.ccr-15-0632

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

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 novel EOC therapies.",

author = "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 Lubi{\'n}ski 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 Estrid H{\o}gdall and Allan Jensen and Kjaer, {Susanne Kruger} and Claus H{\o}gdall and {AGO Study Group}",

note = "{\textcopyright}2015 American Association for Cancer Research.",

year = "2015",

month = dec,

day = "1",

doi = "10.1158/1078-0432.ccr-15-0632",

language = "English",

volume = "21",

pages = "5264--76",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research (A A C R)",

number = "23",

}

TY - JOUR

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

T2 - Findings from the Ovarian Cancer Association Consortium

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 - Høgdall, Estrid

AU - Jensen, Allan

AU - Kjaer, Susanne Kruger

AU - Høgdall, Claus

AU - AGO Study Group

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 novel EOC therapies.

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 novel EOC therapies.

U2 - 10.1158/1078-0432.ccr-15-0632

DO - 10.1158/1078-0432.ccr-15-0632

M3 - Journal article

C2 - 26152742

SN - 1078-0432

VL - 21

SP - 5264

EP - 5276

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 23

ER -

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

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