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 deFazio; 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; Ovarian Cancer Association Consortium

doi:http://dx.doi.org/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 deFazio, 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, Ovarian Cancer Association Consortium

Faculty of Health and Medical Sciences

42 Citations (Scopus)

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
Journal	P L o S Genetics
Volume	6
Issue number	7
Pages (from-to)	e1001016
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1001016
Publication status	Published - 1 Jul 2010

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Johnatty, S. E., Beesley, J., Chen, X., Macgregor, S., Duffy, D. L., Spurdle, A. B., deFazio, 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., ... Ovarian Cancer Association Consortium (2010). Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot". P L o S Genetics, 6(7), e1001016. https://doi.org/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". / Johnatty, Sharon E; Beesley, Jonathan; Chen, Xiaoqing et al.

In: P L o S Genetics, Vol. 6, No. 7, 01.07.2010, p. e1001016.

Research output: Contribution to journal › Journal article › Research › peer-review

Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, deFazio, 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 & Ovarian Cancer Association Consortium 2010, 'Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot"', P L o S Genetics, vol. 6, no. 7, pp. e1001016. https://doi.org/10.1371/journal.pgen.1001016

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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.",

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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 - deFazio, 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 - Ovarian Cancer Association Consortium

PY - 2010/7/1

Y1 - 2010/7/1

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.

U2 - http://dx.doi.org/10.1371/journal.pgen.1001016

DO - http://dx.doi.org/10.1371/journal.pgen.1001016

M3 - Journal article

SN - 1553-7390

VL - 6

SP - e1001016

JO - P L o S Genetics

JF - P L o S Genetics

IS - 7

ER -

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

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