Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot"

Sharon E. Johnatty; Jonathan Beesley; Xiaoqing Chen; Stuart Macgregor; David L. Duffy; Amanda B. Spurdle; Anna de Fazio; Natalie Gava; Penelope M. Webb; Mary Anne Rossing; Jennifer Anne Doherty; Marc T. Goodman; Galina Lurie; Pamela J. Thompson; Lynne R. Wilkens; Roberta B. Ness; Kirsten B. Moysich; Jenny Chang-Claude; Shan Wang-Gohrke; Daniel W. Cramer; Kathryn L. Terry; Susan E. Hankinson; Shelley S. Tworoger; Montserrat Garcia-Closas; Hannah Yang; Jolanta Lissowska; Stephen J. Chanock; Paul D. Pharoah; Honglin Song; Alice S. Whitemore; Celeste L. Pearce; Daniel O. Stram; Anna H. Wu; Malcolm C. Pike; Simon A. Gayther; Susan J. Ramus; Usha Menon; Aleksandra Gentry-Maharaj; Hoda Anton-Culver; Argyrios Ziogas; Estrid Hogdall; Susanne K. Kjaer; Claus Hogdall; Andrew Berchuck; Joellen M. Schildkraut; Edwin S. Iversen; Patricia G. Moorman; Catherine M. Phelan; Thomas A. Sellers; Julie M. Cunningham; Robert A. Vierkant; David N. Rider; Ellen L. Goode; Izhak Haviv; Georgia Chenevix-Trench

doi:10.1371/journal.pgen.1001016

Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot"

Sharon E. Johnatty, Jonathan Beesley, Xiaoqing Chen, Stuart Macgregor, David L. Duffy, Amanda B. Spurdle, Anna de Fazio, Natalie Gava, Penelope M. Webb, Mary Anne Rossing, Jennifer Anne Doherty, Marc T. Goodman, Galina Lurie, Pamela J. Thompson, Lynne R. Wilkens, Roberta B. Ness, Kirsten B. Moysich, Jenny Chang-Claude, Shan Wang-Gohrke, Daniel W. CramerKathryn L. Terry, Susan E. Hankinson, Shelley S. Tworoger, Montserrat Garcia-Closas, Hannah Yang, Jolanta Lissowska, Stephen J. Chanock, Paul D. Pharoah, Honglin Song, Alice S. Whitemore, Celeste L. Pearce, Daniel O. Stram, Anna H. Wu, Malcolm C. Pike, Simon A. Gayther, Susan J. Ramus, Usha Menon, Aleksandra Gentry-Maharaj, Hoda Anton-Culver, Argyrios Ziogas, Estrid Hogdall, Susanne K. Kjaer, Claus Hogdall, Andrew Berchuck, Joellen M. Schildkraut, Edwin S. Iversen, Patricia G. Moorman, Catherine M. Phelan, Thomas A. Sellers, Julie M. Cunningham, Robert A. Vierkant, David N. Rider, Ellen L. Goode, Izhak Haviv, Georgia Chenevix-Trench

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with P_per-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. P_per-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (P_per-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. OR_per-allele 1.14 (1.04-1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

Original language	English
Pages (from-to)	1-10
Number of pages	10
Journal	PLoS Genetics
Volume	6
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1001016
State	Published - 8 Jul 2010
Externally published	Yes

Bibliographical note

Funding Information:
We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of OCAC through their donations to the Ovarian Cancer Research Fund. The PBCS thanks Dr. Louise Brinton and Mark Sherman from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, USA, Drs. Neonila Szeszenia-Dabrowska and Beata Peplonska of the Nofer Institute of Occupational Medicine (Lodz, Poland), Witold Zatonski of the Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland), and Pei Chao and Michael Stagner from Information Management Services (Sliver Spring MD, USA), for their valuable contributions to the study. The GER study acknowledges Ursula Eilber and Tanja Koehler for competent technical assistance for German Ovarian Cancer study. The AOCS Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/ ). The AOCS and ACS Management Group (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all of the project staff and collaborating institutions. We also thank all the participants in all the participating studies.

Funding

We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of OCAC through their donations to the Ovarian Cancer Research Fund. The PBCS thanks Dr. Louise Brinton and Mark Sherman from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, USA, Drs. Neonila Szeszenia-Dabrowska and Beata Peplonska of the Nofer Institute of Occupational Medicine (Lodz, Poland), Witold Zatonski of the Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland), and Pei Chao and Michael Stagner from Information Management Services (Sliver Spring MD, USA), for their valuable contributions to the study. The GER study acknowledges Ursula Eilber and Tanja Koehler for competent technical assistance for German Ovarian Cancer study. The AOCS Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/ ). The AOCS and ACS Management Group (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all of the project staff and collaborating institutions. We also thank all the participants in all the participating studies.

Funders	Funder number
OCAC
National Cancer Institute	R01CA058598
Medical Research Council	G0801875

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1001016

Cite this

Johnatty, S. E., Beesley, J., Chen, X., Macgregor, S., Duffy, D. L., Spurdle, A. B., de Fazio, A., Gava, N., Webb, P. M., Rossing, M. A., Doherty, J. A., Goodman, M. T., Lurie, G., Thompson, P. J., Wilkens, L. R., Ness, R. B., Moysich, K. B., Chang-Claude, J., Wang-Gohrke, S., ... Chenevix-Trench, G. (2010). Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot". PLoS Genetics, 6(7), 1-10. https://doi.org/10.1371/journal.pgen.1001016

@article{70b1d68a7af3446980f089a48928ec73,

title = "Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility {"}Hot-Spot{"}",

abstract = "We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.",

author = "Johnatty, {Sharon E.} and Jonathan Beesley and Xiaoqing Chen and Stuart Macgregor and Duffy, {David L.} and Spurdle, {Amanda B.} and {de Fazio}, Anna and Natalie Gava and Webb, {Penelope M.} and Rossing, {Mary Anne} and Doherty, {Jennifer Anne} and Goodman, {Marc T.} and Galina Lurie and Thompson, {Pamela J.} and Wilkens, {Lynne R.} and Ness, {Roberta B.} and Moysich, {Kirsten B.} and Jenny Chang-Claude and Shan Wang-Gohrke and Cramer, {Daniel W.} and Terry, {Kathryn L.} and Hankinson, {Susan E.} and Tworoger, {Shelley S.} and Montserrat Garcia-Closas and Hannah Yang and Jolanta Lissowska and Chanock, {Stephen J.} and Pharoah, {Paul D.} and Honglin Song and Whitemore, {Alice S.} and Pearce, {Celeste L.} and Stram, {Daniel O.} and Wu, {Anna H.} and Pike, {Malcolm C.} and Gayther, {Simon A.} and Ramus, {Susan J.} and Usha Menon and Aleksandra Gentry-Maharaj and Hoda Anton-Culver and Argyrios Ziogas and Estrid Hogdall and Kjaer, {Susanne K.} and Claus Hogdall and Andrew Berchuck and Schildkraut, {Joellen M.} and Iversen, {Edwin S.} and Moorman, {Patricia G.} and Phelan, {Catherine M.} and Sellers, {Thomas A.} and Cunningham, {Julie M.} and Vierkant, {Robert A.} and Rider, {David N.} and Goode, {Ellen L.} and Izhak Haviv and Georgia Chenevix-Trench",

note = "Funding Information: We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of OCAC through their donations to the Ovarian Cancer Research Fund. The PBCS thanks Dr. Louise Brinton and Mark Sherman from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, USA, Drs. Neonila Szeszenia-Dabrowska and Beata Peplonska of the Nofer Institute of Occupational Medicine (Lodz, Poland), Witold Zatonski of the Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland), and Pei Chao and Michael Stagner from Information Management Services (Sliver Spring MD, USA), for their valuable contributions to the study. The GER study acknowledges Ursula Eilber and Tanja Koehler for competent technical assistance for German Ovarian Cancer study. The AOCS Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/ ). The AOCS and ACS Management Group (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all of the project staff and collaborating institutions. We also thank all the participants in all the participating studies. ",

year = "2010",

month = jul,

day = "8",

doi = "10.1371/journal.pgen.1001016",

language = "אנגלית",

volume = "6",

pages = "1--10",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

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Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, de Fazio, A, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, Ziogas, A, Hogdall, E, Kjaer, SK, Hogdall, C, Berchuck, A, Schildkraut, JM, Iversen, ES, Moorman, PG, Phelan, CM, Sellers, TA, Cunningham, JM, Vierkant, RA, Rider, DN, Goode, EL, Haviv, I & Chenevix-Trench, G 2010, 'Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot"', PLoS Genetics, vol. 6, no. 7, pp. 1-10. https://doi.org/10.1371/journal.pgen.1001016

TY - JOUR

T1 - Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot"

AU - Johnatty, Sharon E.

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Macgregor, Stuart

AU - Duffy, David L.

AU - Spurdle, Amanda B.

AU - de Fazio, Anna

AU - Gava, Natalie

AU - Webb, Penelope M.

AU - Rossing, Mary Anne

AU - Doherty, Jennifer Anne

AU - Goodman, Marc T.

AU - Lurie, Galina

AU - Thompson, Pamela J.

AU - Wilkens, Lynne R.

AU - Ness, Roberta B.

AU - Moysich, Kirsten B.

AU - Chang-Claude, Jenny

AU - Wang-Gohrke, Shan

AU - Cramer, Daniel W.

AU - Terry, Kathryn L.

AU - Hankinson, Susan E.

AU - Tworoger, Shelley S.

AU - Garcia-Closas, Montserrat

AU - Yang, Hannah

AU - Lissowska, Jolanta

AU - Chanock, Stephen J.

AU - Pharoah, Paul D.

AU - Song, Honglin

AU - Whitemore, Alice S.

AU - Pearce, Celeste L.

AU - Stram, Daniel O.

AU - Wu, Anna H.

AU - Pike, Malcolm C.

AU - Gayther, Simon A.

AU - Ramus, Susan J.

AU - Menon, Usha

AU - Gentry-Maharaj, Aleksandra

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Hogdall, Estrid

AU - Kjaer, Susanne K.

AU - Hogdall, Claus

AU - Berchuck, Andrew

AU - Schildkraut, Joellen M.

AU - Iversen, Edwin S.

AU - Moorman, Patricia G.

AU - Phelan, Catherine M.

AU - Sellers, Thomas A.

AU - Cunningham, Julie M.

AU - Vierkant, Robert A.

AU - Rider, David N.

AU - Goode, Ellen L.

AU - Haviv, Izhak

AU - Chenevix-Trench, Georgia

N1 - Funding Information: We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of OCAC through their donations to the Ovarian Cancer Research Fund. The PBCS thanks Dr. Louise Brinton and Mark Sherman from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, USA, Drs. Neonila Szeszenia-Dabrowska and Beata Peplonska of the Nofer Institute of Occupational Medicine (Lodz, Poland), Witold Zatonski of the Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland), and Pei Chao and Michael Stagner from Information Management Services (Sliver Spring MD, USA), for their valuable contributions to the study. The GER study acknowledges Ursula Eilber and Tanja Koehler for competent technical assistance for German Ovarian Cancer study. The AOCS Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/ ). The AOCS and ACS Management Group (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) thank all of the project staff and collaborating institutions. We also thank all the participants in all the participating studies.

PY - 2010/7/8

Y1 - 2010/7/8

N2 - We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

AB - We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

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Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot"

Abstract

Bibliographical note

Funding

UN SDGs

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