Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Hui Shen; Brooke L. Fridley; Honglin Song; Kate Lawrenson; Julie M. Cunningham; Susan J. Ramus; Mine S. Cicek; Jonathan Tyrer; Douglas Stram; Melissa C. Larson; Martin Köbel; Argyrios Ziogas; Wei Zheng; Hannah P. Yang; Anna H. Wu; Eva L. Wozniak; Yin Ling Woo; Boris Winterhoff; Elisabeth Wik; Alice S. Whittemore; Nicolas Wentzensen; Rachel Palmieri Weber; Allison F. Vitonis; Daniel Vincent; Robert A. Vierkant; Ignace Vergote; David Van Den Berg; Anne M. Van Altena; Shelley S. Tworoger; Pamela J. Thompson; Daniel C. Tessier; Kathryn L. Terry; Soo Hwang Teo; Claire Templeman; Daniel O. Stram; Melissa C. Southey; Weiva Sieh; Nadeem Siddiqui; Yurii B. Shvetsov; Xiao Ou Shu; Viji Shridhar; Shan Wang-Gohrke; Gianluca Severi; Ira Schwaab; Helga B. Salvesen; Iwona K. Rzepecka; Ingo B. Runnebaum; Mary Anne Rossing; Lorna Rodriguez-Rodriguez; Harvey A. Risch; Stefan P. Renner; Elizabeth M. Poole; Malcolm C. Pike; Catherine M. Phelan; Liisa M. Pelttari; Tanja Pejovic; James Paul; Irene Orlow; Siti Zawiah Omar; Sara H. Olson; Kunle Odunsi; Stefan Nickels; Heli Nevanlinna; Roberta B. Ness; Steven A. Narod; Toru Nakanishi; Kirsten B. Moysich; Alvaro N.A. Monteiro; Joanna Moes-Sosnowska; Francesmary Modugno; Usha Menon; John R. McLaughlin; Valerie McGuire; Keitaro Matsuo; Noor Azmi Mat Adenan; Leon F.A.G. Massuger; Galina Lurie; Lene Lundvall; Jan Lubiński; Jolanta Lissowska; Douglas A. Levine; Arto Leminen; Alice W. Lee; Nhu D. Le; Sandrina Lambrechts; Diether Lambrechts; Jolanta Kupryjanczyk; Camilla Krakstad; Gottfried E. Konecny; Susanne Krüger Kjaer; Lambertus A. Kiemeney; Linda E. Kelemen; Gary L. Keeney; Beth Y. Karlan; Rod Karevan; Kimberly R. Kalli; Hiroaki Kajiyama; Bu Tian Ji; Allan Jensen; Anna Jakubowska; Edwin Iversen; Satoyo Hosono; Claus K. Høgdall; Estrid Høgdall; Maureen Hoatlin; Peter Hillemanns; Florian Heitz; Rebecca Hein; Philipp Harter; Mari K. Halle; Per Hall; Jacek Gronwald; Martin Gore; Marc T. Goodman; Graham G. Giles; Aleksandra Gentry-Maharaj; Montserrat Garcia-Closas; James M. Flanagan; Peter A. Fasching; Arif B. Ekici; Robert Edwards; Diana Eccles; Douglas F. Easton; Matthias Dürst; Andreas Du Bois; Thilo Dörk; Jennifer A. Doherty; Evelyn Despierre; Agnieszka Dansonka-Mieszkowska; Cezary Cybulski; Daniel W. Cramer; Linda S. Cook; Xiaoqing Chen; Bridget Charbonneau; Jenny Chang-Claude; Ian Campbell; Ralf Butzow; Clareann H. Bunker; Doerthe Brueggmann; Robert Brown; Angela Brooks-Wilson; Louise A. Brinton; Natalia Bogdanova; Matthew S. Block; Elizabeth Benjamin; Jonathan Beesley; Matthias W. Beckmann; Elisa V. Bandera; Laura Baglietto; François Bacot; Sebastian M. Armasu; Natalia Antonenkova; Hoda Anton-Culver; Katja K. Aben; Dong Liang; Xifeng Wu; Karen Lu; Michelle A.T. Hildebrandt; Joellen M. Schildkraut; Thomas A. Sellers; David Huntsman; Andrew Berchuck; Georgia Chenevix-Trench; Simon A. Gayther; Paul D.P. Pharoah; Peter W. Laird; Ellen L. Goode; Celeste Leigh Pearce

doi:10.1038/ncomms2629

Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Hui Shen, Brooke L. Fridley, Honglin Song, Kate Lawrenson, Julie M. Cunningham, Susan J. Ramus, Mine S. Cicek, Jonathan Tyrer, Douglas Stram, Melissa C. Larson, Martin Köbel, Argyrios Ziogas, Wei Zheng, Hannah P. Yang, Anna H. Wu, Eva L. Wozniak, Yin Ling Woo, Boris Winterhoff, Elisabeth Wik, Alice S. WhittemoreNicolas Wentzensen, Rachel Palmieri Weber, Allison F. Vitonis, Daniel Vincent, Robert A. Vierkant, Ignace Vergote, David Van Den Berg, Anne M. Van Altena, Shelley S. Tworoger, Pamela J. Thompson, Daniel C. Tessier, Kathryn L. Terry, Soo Hwang Teo, Claire Templeman, Daniel O. Stram, Melissa C. Southey, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao Ou Shu, Viji Shridhar, Shan Wang-Gohrke, Gianluca Severi, Ira Schwaab, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Mary Anne Rossing, Lorna Rodriguez-Rodriguez, Harvey A. Risch, Stefan P. Renner, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Liisa M. Pelttari, Tanja Pejovic, James Paul, Irene Orlow, Siti Zawiah Omar, Sara H. Olson, Kunle Odunsi, Stefan Nickels, Heli Nevanlinna, Roberta B. Ness, Steven A. Narod, Toru Nakanishi, Kirsten B. Moysich, Alvaro N.A. Monteiro, Joanna Moes-Sosnowska, Francesmary Modugno, Usha Menon, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Noor Azmi Mat Adenan, Leon F.A.G. Massuger, Galina Lurie, Lene Lundvall, Jan Lubiński, Jolanta Lissowska, Douglas A. Levine, Arto Leminen, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Gottfried E. Konecny, Susanne Krüger Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Gary L. Keeney, Beth Y. Karlan, Rod Karevan, Kimberly R. Kalli, Hiroaki Kajiyama, Bu Tian Ji, Allan Jensen, Anna Jakubowska, Edwin Iversen, Satoyo Hosono, Claus K. Høgdall, Estrid Høgdall, Maureen Hoatlin, Peter Hillemanns, Florian Heitz, Rebecca Hein, Philipp Harter, Mari K. Halle, Per Hall, Jacek Gronwald, Martin Gore, Marc T. Goodman, Graham G. Giles, Aleksandra Gentry-Maharaj, Montserrat Garcia-Closas, James M. Flanagan, Peter A. Fasching, Arif B. Ekici, Robert Edwards, Diana Eccles, Douglas F. Easton, Matthias Dürst, Andreas Du Bois, Thilo Dörk, Jennifer A. Doherty, Evelyn Despierre, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Daniel W. Cramer, Linda S. Cook, Xiaoqing Chen, Bridget Charbonneau, Jenny Chang-Claude, Ian Campbell, Ralf Butzow, Clareann H. Bunker, Doerthe Brueggmann, Robert Brown, Angela Brooks-Wilson, Louise A. Brinton, Natalia Bogdanova, Matthew S. Block, Elizabeth Benjamin, Jonathan Beesley, Matthias W. Beckmann, Elisa V. Bandera, Laura Baglietto, François Bacot, Sebastian M. Armasu, Natalia Antonenkova, Hoda Anton-Culver, Katja K. Aben, Dong Liang, Xifeng Wu, Karen Lu, Michelle A.T. Hildebrandt, Joellen M. Schildkraut, Thomas A. Sellers, David Huntsman, Andrew Berchuck, Georgia Chenevix-Trench, Simon A. Gayther, Paul D.P. Pharoah, Peter W. Laird, Ellen L. Goode, Celeste Leigh Pearce

Obstetrics and Gynecology

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

135 Scopus citations

Abstract

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10 ^-10) and clear cell (rs11651755 OR=0.77, P=1.6 × 10 ^-8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Original language	English (US)
Article number	1628
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms2629
State	Published - 2013

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms2629

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Shen, H., Fridley, B. L., Song, H., Lawrenson, K., Cunningham, J. M., Ramus, S. J., Cicek, M. S., Tyrer, J., Stram, D., Larson, M. C., Köbel, M., Ziogas, A., Zheng, W., Yang, H. P., Wu, A. H., Wozniak, E. L., Ling Woo, Y., Winterhoff, B., Wik, E., ... Leigh Pearce, C. (2013). Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nature communications, 4, Article 1628. https://doi.org/10.1038/ncomms2629

Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Köbel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Ling Woo, Y, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Palmieri Weber, R, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, SH, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, XO, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Anne Rossing, M, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Zawiah Omar, S, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Mat Adenan, NA, Massuger, LFAG, Lurie, G, Lundvall, L, Lubiński, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Krüger Kjaer, S, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, BT, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Høgdall, CK, Høgdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Dürst, M, Du Bois, A, Dörk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL & Leigh Pearce, C 2013, 'Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer', Nature communications, vol. 4, 1628. https://doi.org/10.1038/ncomms2629

@article{28e2be8fc1af40f9a0a1d71000b23df2,

title = "Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer",

abstract = "HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10 -10) and clear cell (rs11651755 OR=0.77, P=1.6 × 10 -8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.",

author = "Hui Shen and Fridley, {Brooke L.} and Honglin Song and Kate Lawrenson and Cunningham, {Julie M.} and Ramus, {Susan J.} and Cicek, {Mine S.} and Jonathan Tyrer and Douglas Stram and Larson, {Melissa C.} and Martin K{\"o}bel and Argyrios Ziogas and Wei Zheng and Yang, {Hannah P.} and Wu, {Anna H.} and Wozniak, {Eva L.} and {Ling Woo}, Yin and Boris Winterhoff and Elisabeth Wik and Whittemore, {Alice S.} and Nicolas Wentzensen and {Palmieri Weber}, Rachel and Vitonis, {Allison F.} and Daniel Vincent and Vierkant, {Robert A.} and Ignace Vergote and {Van Den Berg}, David and {Van Altena}, {Anne M.} and Tworoger, {Shelley S.} and Thompson, {Pamela J.} and Tessier, {Daniel C.} and Terry, {Kathryn L.} and Teo, {Soo Hwang} and Claire Templeman and Stram, {Daniel O.} and Southey, {Melissa C.} and Weiva Sieh and Nadeem Siddiqui and Shvetsov, {Yurii B.} and Shu, {Xiao Ou} and Viji Shridhar and Shan Wang-Gohrke and Gianluca Severi and Ira Schwaab and Salvesen, {Helga B.} and Rzepecka, {Iwona K.} and Runnebaum, {Ingo B.} and {Anne Rossing}, Mary and Lorna Rodriguez-Rodriguez and Risch, {Harvey A.} and Renner, {Stefan P.} and Poole, {Elizabeth M.} and Pike, {Malcolm C.} and Phelan, {Catherine M.} and Pelttari, {Liisa M.} and Tanja Pejovic and James Paul and Irene Orlow and {Zawiah Omar}, Siti and Olson, {Sara H.} and Kunle Odunsi and Stefan Nickels and Heli Nevanlinna and Ness, {Roberta B.} and Narod, {Steven A.} and Toru Nakanishi and Moysich, {Kirsten B.} and Monteiro, {Alvaro N.A.} and Joanna Moes-Sosnowska and Francesmary Modugno and Usha Menon and McLaughlin, {John R.} and Valerie McGuire and Keitaro Matsuo and {Mat Adenan}, {Noor Azmi} and Massuger, {Leon F.A.G.} and Galina Lurie and Lene Lundvall and Jan Lubi{\'n}ski and Jolanta Lissowska and Levine, {Douglas A.} and Arto Leminen and Lee, {Alice W.} and Le, {Nhu D.} and Sandrina Lambrechts and Diether Lambrechts and Jolanta Kupryjanczyk and Camilla Krakstad and Konecny, {Gottfried E.} and {Kr{\"u}ger Kjaer}, Susanne and Kiemeney, {Lambertus A.} and Kelemen, {Linda E.} and Keeney, {Gary L.} and Karlan, {Beth Y.} and Rod Karevan and Kalli, {Kimberly R.} and Hiroaki Kajiyama and Ji, {Bu Tian} and Allan Jensen and Anna Jakubowska and Edwin Iversen and Satoyo Hosono and H{\o}gdall, {Claus K.} and Estrid H{\o}gdall and Maureen Hoatlin and Peter Hillemanns and Florian Heitz and Rebecca Hein and Philipp Harter and Halle, {Mari K.} and Per Hall and Jacek Gronwald and Martin Gore and Goodman, {Marc T.} and Giles, {Graham G.} and Aleksandra Gentry-Maharaj and Montserrat Garcia-Closas and Flanagan, {James M.} and Fasching, {Peter A.} and Ekici, {Arif B.} and Robert Edwards and Diana Eccles and Easton, {Douglas F.} and Matthias D{\"u}rst and {Du Bois}, Andreas and Thilo D{\"o}rk and Doherty, {Jennifer A.} and Evelyn Despierre and Agnieszka Dansonka-Mieszkowska and Cezary Cybulski and Cramer, {Daniel W.} and Cook, {Linda S.} and Xiaoqing Chen and Bridget Charbonneau and Jenny Chang-Claude and Ian Campbell and Ralf Butzow and Bunker, {Clareann H.} and Doerthe Brueggmann and Robert Brown and Angela Brooks-Wilson and Brinton, {Louise A.} and Natalia Bogdanova and Block, {Matthew S.} and Elizabeth Benjamin and Jonathan Beesley and Beckmann, {Matthias W.} and Bandera, {Elisa V.} and Laura Baglietto and Fran{\c c}ois Bacot and Armasu, {Sebastian M.} and Natalia Antonenkova and Hoda Anton-Culver and Aben, {Katja K.} and Dong Liang and Xifeng Wu and Karen Lu and Hildebrandt, {Michelle A.T.} and Schildkraut, {Joellen M.} and Sellers, {Thomas A.} and David Huntsman and Andrew Berchuck and Georgia Chenevix-Trench and Gayther, {Simon A.} and Pharoah, {Paul D.P.} and Laird, {Peter W.} and Goode, {Ellen L.} and {Leigh Pearce}, Celeste",

year = "2013",

doi = "10.1038/ncomms2629",

language = "English (US)",

volume = "4",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

AU - Shen, Hui

AU - Fridley, Brooke L.

AU - Song, Honglin

AU - Lawrenson, Kate

AU - Cunningham, Julie M.

AU - Ramus, Susan J.

AU - Cicek, Mine S.

AU - Tyrer, Jonathan

AU - Stram, Douglas

AU - Larson, Melissa C.

AU - Köbel, Martin

AU - Ziogas, Argyrios

AU - Zheng, Wei

AU - Yang, Hannah P.

AU - Wu, Anna H.

AU - Wozniak, Eva L.

AU - Ling Woo, Yin

AU - Winterhoff, Boris

AU - Wik, Elisabeth

AU - Whittemore, Alice S.

AU - Wentzensen, Nicolas

AU - Palmieri Weber, Rachel

AU - Vitonis, Allison F.

AU - Vincent, Daniel

AU - Vierkant, Robert A.

AU - Vergote, Ignace

AU - Van Den Berg, David

AU - Van Altena, Anne M.

AU - Tworoger, Shelley S.

AU - Thompson, Pamela J.

AU - Tessier, Daniel C.

AU - Terry, Kathryn L.

AU - Teo, Soo Hwang

AU - Templeman, Claire

AU - Stram, Daniel O.

AU - Southey, Melissa C.

AU - Sieh, Weiva

AU - Siddiqui, Nadeem

AU - Shvetsov, Yurii B.

AU - Shu, Xiao Ou

AU - Shridhar, Viji

AU - Wang-Gohrke, Shan

AU - Severi, Gianluca

AU - Schwaab, Ira

AU - Salvesen, Helga B.

AU - Rzepecka, Iwona K.

AU - Runnebaum, Ingo B.

AU - Anne Rossing, Mary

AU - Rodriguez-Rodriguez, Lorna

AU - Risch, Harvey A.

AU - Renner, Stefan P.

AU - Poole, Elizabeth M.

AU - Pike, Malcolm C.

AU - Phelan, Catherine M.

AU - Pelttari, Liisa M.

AU - Pejovic, Tanja

AU - Paul, James

AU - Orlow, Irene

AU - Zawiah Omar, Siti

AU - Olson, Sara H.

AU - Odunsi, Kunle

AU - Nickels, Stefan

AU - Nevanlinna, Heli

AU - Ness, Roberta B.

AU - Narod, Steven A.

AU - Nakanishi, Toru

AU - Moysich, Kirsten B.

AU - Monteiro, Alvaro N.A.

AU - Moes-Sosnowska, Joanna

AU - Modugno, Francesmary

AU - Menon, Usha

AU - McLaughlin, John R.

AU - McGuire, Valerie

AU - Matsuo, Keitaro

AU - Mat Adenan, Noor Azmi

AU - Massuger, Leon F.A.G.

AU - Lurie, Galina

AU - Lundvall, Lene

AU - Lubiński, Jan

AU - Lissowska, Jolanta

AU - Levine, Douglas A.

AU - Leminen, Arto

AU - Lee, Alice W.

AU - Le, Nhu D.

AU - Lambrechts, Sandrina

AU - Lambrechts, Diether

AU - Kupryjanczyk, Jolanta

AU - Krakstad, Camilla

AU - Konecny, Gottfried E.

AU - Krüger Kjaer, Susanne

AU - Kiemeney, Lambertus A.

AU - Kelemen, Linda E.

AU - Keeney, Gary L.

AU - Karlan, Beth Y.

AU - Karevan, Rod

AU - Kalli, Kimberly R.

AU - Kajiyama, Hiroaki

AU - Ji, Bu Tian

AU - Jensen, Allan

AU - Jakubowska, Anna

AU - Iversen, Edwin

AU - Hosono, Satoyo

AU - Høgdall, Claus K.

AU - Høgdall, Estrid

AU - Hoatlin, Maureen

AU - Hillemanns, Peter

AU - Heitz, Florian

AU - Hein, Rebecca

AU - Harter, Philipp

AU - Halle, Mari K.

AU - Hall, Per

AU - Gronwald, Jacek

AU - Gore, Martin

AU - Goodman, Marc T.

AU - Giles, Graham G.

AU - Gentry-Maharaj, Aleksandra

AU - Garcia-Closas, Montserrat

AU - Flanagan, James M.

AU - Fasching, Peter A.

AU - Ekici, Arif B.

AU - Edwards, Robert

AU - Eccles, Diana

AU - Easton, Douglas F.

AU - Dürst, Matthias

AU - Du Bois, Andreas

AU - Dörk, Thilo

AU - Doherty, Jennifer A.

AU - Despierre, Evelyn

AU - Dansonka-Mieszkowska, Agnieszka

AU - Cybulski, Cezary

AU - Cramer, Daniel W.

AU - Cook, Linda S.

AU - Chen, Xiaoqing

AU - Charbonneau, Bridget

AU - Chang-Claude, Jenny

AU - Campbell, Ian

AU - Butzow, Ralf

AU - Bunker, Clareann H.

AU - Brueggmann, Doerthe

AU - Brown, Robert

AU - Brooks-Wilson, Angela

AU - Brinton, Louise A.

AU - Bogdanova, Natalia

AU - Block, Matthew S.

AU - Benjamin, Elizabeth

AU - Beesley, Jonathan

AU - Beckmann, Matthias W.

AU - Bandera, Elisa V.

AU - Baglietto, Laura

AU - Bacot, François

AU - Armasu, Sebastian M.

AU - Antonenkova, Natalia

AU - Anton-Culver, Hoda

AU - Aben, Katja K.

AU - Liang, Dong

AU - Wu, Xifeng

AU - Lu, Karen

AU - Hildebrandt, Michelle A.T.

AU - Schildkraut, Joellen M.

AU - Sellers, Thomas A.

AU - Huntsman, David

AU - Berchuck, Andrew

AU - Chenevix-Trench, Georgia

AU - Gayther, Simon A.

AU - Pharoah, Paul D.P.

AU - Laird, Peter W.

AU - Goode, Ellen L.

AU - Leigh Pearce, Celeste

PY - 2013

Y1 - 2013

N2 - HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10 -10) and clear cell (rs11651755 OR=0.77, P=1.6 × 10 -8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

AB - HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10 -10) and clear cell (rs11651755 OR=0.77, P=1.6 × 10 -8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

UR - http://www.scopus.com/inward/record.url?scp=84875904387&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875904387&partnerID=8YFLogxK

U2 - 10.1038/ncomms2629

DO - 10.1038/ncomms2629

M3 - Article

C2 - 23535649

AN - SCOPUS:84875904387

SN - 2041-1723

VL - 4

JO - Nature communications

JF - Nature communications

M1 - 1628

ER -

Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

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