A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Alice W Lee; Ashley Bomkamp; Elisa V Bandera; Allan Jensen; Susan J Ramus; Marc T Goodman; Mary Anne Rossing; Francesmary Modugno; Kirsten B Moysich; Jenny Chang-Claude; Anja Rudolph; Aleksandra Gentry-Maharaj; Kathryn L Terry; Simon A Gayther; Daniel W Cramer; Jennifer A Doherty; Joellen M Schildkraut; Susanne K Kjaer; Roberta B Ness; Usha Menon; Andrew Berchuck; Bhramar Mukherjee; Lynda Roman; Paul D Pharoah; Georgia Chenevix-Trench; Sara Olson; Estrid Hogdall; Anna H Wu; Malcolm C Pike; Daniel O Stram; Celeste Leigh Pearce; Ovarian Cancer Association Consortium

doi:10.1002/ijc.30274

A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Alice W Lee, Ashley Bomkamp, Elisa V Bandera, Allan Jensen, Susan J Ramus, Marc T Goodman, Mary Anne Rossing, Francesmary Modugno, Kirsten B Moysich, Jenny Chang-Claude, Anja Rudolph, Aleksandra Gentry-Maharaj, Kathryn L Terry, Simon A Gayther, Daniel W Cramer, Jennifer A Doherty, Joellen M Schildkraut, Susanne K Kjaer, Roberta B Ness, Usha MenonAndrew Berchuck, Bhramar Mukherjee, Lynda Roman, Paul D Pharoah, Georgia Chenevix-Trench, Sara Olson, Estrid Hogdall, Anna H Wu, Malcolm C Pike, Daniel O Stram, Celeste Leigh Pearce, Ovarian Cancer Association Consortium

Department of Clinical Medicine

7 Citations (Scopus)

Abstract

Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.

Original language	English
Journal	International Journal of Cancer
Volume	139
Issue number	12
Pages (from-to)	2646-2654
Number of pages	9
ISSN	0020-7136
DOIs	https://doi.org/10.1002/ijc.30274
Publication status	Published - 15 Dec 2016

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Lee, A. W., Bomkamp, A., Bandera, E. V., Jensen, A., Ramus, S. J., Goodman, M. T., Rossing, M. A., Modugno, F., Moysich, K. B., Chang-Claude, J., Rudolph, A., Gentry-Maharaj, A., Terry, K. L., Gayther, S. A., Cramer, D. W., Doherty, J. A., Schildkraut, J. M., Kjaer, S. K., Ness, R. B., ... Ovarian Cancer Association Consortium (2016). A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer. International Journal of Cancer, 139(12), 2646-2654. https://doi.org/10.1002/ijc.30274

Lee, AW, Bomkamp, A, Bandera, EV, Jensen, A, Ramus, SJ, Goodman, MT, Rossing, MA, Modugno, F, Moysich, KB, Chang-Claude, J, Rudolph, A, Gentry-Maharaj, A, Terry, KL, Gayther, SA, Cramer, DW, Doherty, JA, Schildkraut, JM, Kjaer, SK, Ness, RB, Menon, U, Berchuck, A, Mukherjee, B, Roman, L, Pharoah, PD, Chenevix-Trench, G, Olson, S, Hogdall, E, Wu, AH, Pike, MC, Stram, DO, Pearce, CL & Ovarian Cancer Association Consortium 2016, 'A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer', International Journal of Cancer, vol. 139, no. 12, pp. 2646-2654. https://doi.org/10.1002/ijc.30274

@article{34eafb4d77ce43fea3ca3d6716460f26,

title = "A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer",

abstract = "Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.",

author = "Lee, {Alice W} and Ashley Bomkamp and Bandera, {Elisa V} and Allan Jensen and Ramus, {Susan J} and Goodman, {Marc T} and Rossing, {Mary Anne} and Francesmary Modugno and Moysich, {Kirsten B} and Jenny Chang-Claude and Anja Rudolph and Aleksandra Gentry-Maharaj and Terry, {Kathryn L} and Gayther, {Simon A} and Cramer, {Daniel W} and Doherty, {Jennifer A} and Schildkraut, {Joellen M} and Kjaer, {Susanne K} and Ness, {Roberta B} and Usha Menon and Andrew Berchuck and Bhramar Mukherjee and Lynda Roman and Pharoah, {Paul D} and Georgia Chenevix-Trench and Sara Olson and Estrid Hogdall and Wu, {Anna H} and Pike, {Malcolm C} and Stram, {Daniel O} and Pearce, {Celeste Leigh} and {Ovarian Cancer Association Consortium}",

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T1 - A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

AU - Lee, Alice W

AU - Bomkamp, Ashley

AU - Bandera, Elisa V

AU - Jensen, Allan

AU - Ramus, Susan J

AU - Goodman, Marc T

AU - Rossing, Mary Anne

AU - Modugno, Francesmary

AU - Moysich, Kirsten B

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Gentry-Maharaj, Aleksandra

AU - Terry, Kathryn L

AU - Gayther, Simon A

AU - Cramer, Daniel W

AU - Doherty, Jennifer A

AU - Schildkraut, Joellen M

AU - Kjaer, Susanne K

AU - Ness, Roberta B

AU - Menon, Usha

AU - Berchuck, Andrew

AU - Mukherjee, Bhramar

AU - Roman, Lynda

AU - Pharoah, Paul D

AU - Chenevix-Trench, Georgia

AU - Olson, Sara

AU - Hogdall, Estrid

AU - Wu, Anna H

AU - Pike, Malcolm C

AU - Stram, Daniel O

AU - Pearce, Celeste Leigh

AU - Ovarian Cancer Association Consortium

PY - 2016/12/15

Y1 - 2016/12/15

N2 - Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.

AB - Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.

U2 - 10.1002/ijc.30274

DO - 10.1002/ijc.30274

M3 - Journal article

C2 - 27420401

SN - 0020-7136

VL - 139

SP - 2646

EP - 2654

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 12

ER -

A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

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