Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

Daniel R. Barnes; Jonathan P. Tyrer; Joe Dennis; Goska Leslie; Manjeet K. Bolla; Michael Lush; Amber M. Aeilts; Kristiina Aittomäki; Nadine Andrieu; Irene L. Andrulis; Hoda Anton-Culver; Adalgeir Arason; Banu K. Arun; Judith Balmaña; Elisa V. Bandera; Rosa B. Barkardottir; Lieke P.V. Berger; Amy Berrington de Gonzalez; Pascaline Berthet; Katarzyna Białkowska; Line Bjørge; Amie M. Blanco; Marinus J. Blok; Kristie A. Bobolis; Natalia V. Bogdanova; James D. Brenton; Henriett Butz; Saundra S. Buys; Maria A. Caligo; Ian Campbell; Carmen Castillo; Kathleen B.M. Claes; Sarah V. Colonna; Linda S. Cook; Mary B. Daly; Agnieszka Dansonka-Mieszkowska; Miguel de la Hoya; Anna DeFazio; Allison DePersia; Yuan Chun Ding; Susan M. Domchek; Thilo Dörk; Zakaria Einbeigi; Christoph Engel; D. Gareth Evans; Lenka Foretova; Renée T. Fortner; Florentia Fostira; Maria Cristina Foti; Eitan Friedman; Megan N. Frone; Patricia A. Ganz; Aleksandra Gentry-Maharaj; Gord Glendon; Andrew K. Godwin; Anna González-Neira; Mark H. Greene; Jacek Gronwald; Aliana Guerrieri-Gonzaga; Ute Hamann; Thomas v.O. Hansen; Holly R. Harris; Jan Hauke; Florian Heitz; Frans B.L. Hogervorst; Maartje J. Hooning; John L. Hopper; Chad D Huff; David G. Huntsman; Evgeny N. Imyanitov; Louise Izatt; Anna Jakubowska; Paul A. James; Ramunas Janavicius; Esther M. John; Siddhartha Kar; Beth Y. Karlan; Catherine J. Kennedy; Lambertus A.L.M. Kiemeney; Irene Konstantopoulou; Jolanta Kupryjanczyk; Yael Laitman; Ofer Lavie; Kate Lawrenson; Jenny Lester; Fabienne Lesueur; Carlos Lopez-Pleguezuelos; Phuong L. Mai; Siranoush Manoukian; Taymaa May; Iain A. McNeish; Usha Menon; Roger L. Milne; Francesmary Modugno; Jennifer M. Mongiovi; Marco Montagna; Kirsten B. Moysich; Susan L. Neuhausen; Finn C. Nielsen; Catherine Noguès; Edit Oláh; Olufunmilayo I. Olopade; Ana Osorio; Laura Papi; Harsh Pathak; Celeste L. Pearce; Inge S. Pedersen; Ana Peixoto; Tanja Pejovic; Pei-Chen Peng; Beth N. Peshkin; Paolo Peterlongo; C. Bethan Powell; Darya Prokofyeva; Miquel Angel Pujana; Paolo Radice; Muhammad U. Rashid; Gad Rennert; George Richenberg; Dale P. Sandler; Naoko Sasamoto; Veronica W. Setiawan; Priyanka Sharma; Weiva Sieh; Christian F. Singer; Katie Snape; Anna P. Sokolenko; Penny Soucy; Melissa C. Southey; Dominique Stoppa-Lyonnet; Rebecca Sutphen; Christian Sutter; Manuel R. Teixeira; Kathryn L. Terry; Liv Cecilie V. Thomsen; Marc Tischkowitz; Amanda E. Toland; Toon Van Gorp; Ana Vega; Digna R. Velez Edwards; Penelope M. Webb; Jeffrey N. Weitzel; Nicolas Wentzensen; Alice S. Whittemore; Stacey J. Winham; Anna H. Wu; Siddhartha Yadav; Yao Yu; Argyrios Ziogas; Andrew Berchuck; Fergus J. Couch; Ellen L. Goode; Marc T. Goodman; Alvaro N. Monteiro; Kenneth Offit; Susan J. Ramus; Harvey A. Risch; Joellen M. Schildkraut; Mads Thomassen; Jacques Simard; Douglas F. Easton; Michelle R. Jones; Georgia Chenevix-Trench; Simon A. Gayther; Antonis C. Antoniou; Paul D.P. Pharoah; GEMO Study Collaborators; EMBRACE Collaborators; kConFab Investigators; Ovarian Cancer Association Consortium; Consortium of Investigators of Modifiers of BRCA1 and BRCA2

doi:10.1101/2024.02.29.24303243

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

Daniel R. Barnes, Jonathan P. Tyrer, Joe Dennis, Goska Leslie, Manjeet K. Bolla, Michael Lush, Amber M. Aeilts, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Banu K. Arun, Judith Balmaña, Elisa V. Bandera, Rosa B. Barkardottir, Lieke P.V. Berger, Amy Berrington de Gonzalez, Pascaline Berthet, Katarzyna BiałkowskaLine Bjørge, Amie M. Blanco, Marinus J. Blok, Kristie A. Bobolis, Natalia V. Bogdanova, James D. Brenton, Henriett Butz, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Carmen Castillo, Kathleen B.M. Claes, Sarah V. Colonna, Linda S. Cook, Mary B. Daly, Agnieszka Dansonka-Mieszkowska, Miguel de la Hoya, Anna DeFazio, Allison DePersia, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Zakaria Einbeigi, Christoph Engel, D. Gareth Evans, Lenka Foretova, Renée T. Fortner, Florentia Fostira, Maria Cristina Foti, Eitan Friedman, Megan N. Frone, Patricia A. Ganz, Aleksandra Gentry-Maharaj, Gord Glendon, Andrew K. Godwin, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Aliana Guerrieri-Gonzaga, Ute Hamann, Thomas v.O. Hansen, Holly R. Harris, Jan Hauke, Florian Heitz, Frans B.L. Hogervorst, Maartje J. Hooning, John L. Hopper, Chad D Huff, David G. Huntsman, Evgeny N. Imyanitov, Louise Izatt, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Siddhartha Kar, Beth Y. Karlan, Catherine J. Kennedy, Lambertus A.L.M. Kiemeney, Irene Konstantopoulou, Jolanta Kupryjanczyk, Yael Laitman, Ofer Lavie, Kate Lawrenson, Jenny Lester, Fabienne Lesueur, Carlos Lopez-Pleguezuelos, Phuong L. Mai, Siranoush Manoukian, Taymaa May, Iain A. McNeish, Usha Menon, Roger L. Milne, Francesmary Modugno, Jennifer M. Mongiovi, Marco Montagna, Kirsten B. Moysich, Susan L. Neuhausen, Finn C. Nielsen, Catherine Noguès, Edit Oláh, Olufunmilayo I. Olopade, Ana Osorio, Laura Papi, Harsh Pathak, Celeste L. Pearce, Inge S. Pedersen, Ana Peixoto, Tanja Pejovic, Pei-Chen Peng, Beth N. Peshkin, Paolo Peterlongo, C. Bethan Powell, Darya Prokofyeva, Miquel Angel Pujana, Paolo Radice, Muhammad U. Rashid, Gad Rennert, George Richenberg, Dale P. Sandler, Naoko Sasamoto, Veronica W. Setiawan, Priyanka Sharma, Weiva Sieh, Christian F. Singer, Katie Snape, Anna P. Sokolenko, Penny Soucy, Melissa C. Southey, Dominique Stoppa-Lyonnet, Rebecca Sutphen, Christian Sutter, Manuel R. Teixeira, Kathryn L. Terry, Liv Cecilie V. Thomsen, Marc Tischkowitz, Amanda E. Toland, Toon Van Gorp, Ana Vega, Digna R. Velez Edwards, Penelope M. Webb, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Stacey J. Winham, Anna H. Wu, Siddhartha Yadav, Yao Yu, Argyrios Ziogas, Andrew Berchuck, Fergus J. Couch, Ellen L. Goode, Marc T. Goodman, Alvaro N. Monteiro, Kenneth Offit, Susan J. Ramus, Harvey A. Risch, Joellen M. Schildkraut, Mads Thomassen, Jacques Simard, Douglas F. Easton, Michelle R. Jones, Georgia Chenevix-Trench, Simon A. Gayther, Antonis C. Antoniou, Paul D.P. Pharoah, GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, Ovarian Cancer Association Consortium, Consortium of Investigators of Modifiers of BRCA1 and BRCA2

Publikation: Working paper/Preprint › Preprint

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Abstract

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan.

Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62).

Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Originalsprog	Engelsk
Udgiver	medRxiv
Antal sider	90
DOI	https://doi.org/10.1101/2024.02.29.24303243
Status	Udgivet - 4 mar. 2024

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10.1101/2024.02.29.24303243Licens: CC BY-NC-ND 4.0

Barnes et al. (2024). Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer riskForlagets udgivne version, 2,45 MBLicens: CC BY-NC-ND 4.0

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Barnes, D. R., Tyrer, J. P., Dennis, J., Leslie, G., Bolla, M. K., Lush, M., Aeilts, A. M., Aittomäki, K., Andrieu, N., Andrulis, I. L., Anton-Culver, H., Arason, A., Arun, B. K., Balmaña, J., Bandera, E. V., Barkardottir, R. B., Berger, L. P. V., Berrington de Gonzalez, A., Berthet, P., ... Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (2024). Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk. medRxiv. https://doi.org/10.1101/2024.02.29.24303243

@misc{0cea0f27a24c43e587de102a88556a9e,

title = "Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk",

abstract = "Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan.Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62).Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.",

author = "Barnes, {Daniel R.} and Tyrer, {Jonathan P.} and Joe Dennis and Goska Leslie and Bolla, {Manjeet K.} and Michael Lush and Aeilts, {Amber M.} and Kristiina Aittom{\"a}ki and Nadine Andrieu and Andrulis, {Irene L.} and Hoda Anton-Culver and Adalgeir Arason and Arun, {Banu K.} and Judith Balma{\~n}a and Bandera, {Elisa V.} and Barkardottir, {Rosa B.} and Berger, {Lieke P.V.} and {Berrington de Gonzalez}, Amy and Pascaline Berthet and Katarzyna Bia{\l}kowska and Line Bj{\o}rge and Blanco, {Amie M.} and Blok, {Marinus J.} and Bobolis, {Kristie A.} and Bogdanova, {Natalia V.} and Brenton, {James D.} and Henriett Butz and Buys, {Saundra S.} and Caligo, {Maria A.} and Ian Campbell and Carmen Castillo and Claes, {Kathleen B.M.} and Colonna, {Sarah V.} and Cook, {Linda S.} and Daly, {Mary B.} and Agnieszka Dansonka-Mieszkowska and {de la Hoya}, Miguel and Anna DeFazio and Allison DePersia and Ding, {Yuan Chun} and Domchek, {Susan M.} and Thilo D{\"o}rk and Zakaria Einbeigi and Christoph Engel and Evans, {D. Gareth} and Lenka Foretova and Fortner, {Ren{\'e}e T.} and Florentia Fostira and Foti, {Maria Cristina} and Eitan Friedman and Frone, {Megan N.} and Ganz, {Patricia A.} and Aleksandra Gentry-Maharaj and Gord Glendon and Godwin, {Andrew K.} and Anna Gonz{\'a}lez-Neira and Greene, {Mark H.} and Jacek Gronwald and Aliana Guerrieri-Gonzaga and Ute Hamann and Hansen, {Thomas v.O.} and Harris, {Holly R.} and Jan Hauke and Florian Heitz and Hogervorst, {Frans B.L.} and Hooning, {Maartje J.} and Hopper, {John L.} and Huff, {Chad D} and Huntsman, {David G.} and Imyanitov, {Evgeny N.} and Louise Izatt and Anna Jakubowska and James, {Paul A.} and Ramunas Janavicius and John, {Esther M.} and Siddhartha Kar and Karlan, {Beth Y.} and Kennedy, {Catherine J.} and Kiemeney, {Lambertus A.L.M.} and Irene Konstantopoulou and Jolanta Kupryjanczyk and Yael Laitman and Ofer Lavie and Kate Lawrenson and Jenny Lester and Fabienne Lesueur and Carlos Lopez-Pleguezuelos and Mai, {Phuong L.} and Siranoush Manoukian and Taymaa May and McNeish, {Iain A.} and Usha Menon and Milne, {Roger L.} and Francesmary Modugno and Mongiovi, {Jennifer M.} and Marco Montagna and Moysich, {Kirsten B.} and Neuhausen, {Susan L.} and Nielsen, {Finn C.} and Catherine Nogu{\`e}s and Edit Ol{\'a}h and Olopade, {Olufunmilayo I.} and Ana Osorio and Laura Papi and Harsh Pathak and Pearce, {Celeste L.} and Pedersen, {Inge S.} and Ana Peixoto and Tanja Pejovic and Pei-Chen Peng and Peshkin, {Beth N.} and Paolo Peterlongo and Powell, {C. Bethan} and Darya Prokofyeva and Pujana, {Miquel Angel} and Paolo Radice and Rashid, {Muhammad U.} and Gad Rennert and George Richenberg and Sandler, {Dale P.} and Naoko Sasamoto and Setiawan, {Veronica W.} and Priyanka Sharma and Weiva Sieh and Singer, {Christian F.} and Katie Snape and Sokolenko, {Anna P.} and Penny Soucy and Southey, {Melissa C.} and Dominique Stoppa-Lyonnet and Rebecca Sutphen and Christian Sutter and Teixeira, {Manuel R.} and Terry, {Kathryn L.} and Thomsen, {Liv Cecilie V.} and Marc Tischkowitz and Toland, {Amanda E.} and {Van Gorp}, Toon and Ana Vega and {Velez Edwards}, {Digna R.} and Webb, {Penelope M.} and Weitzel, {Jeffrey N.} and Nicolas Wentzensen and Whittemore, {Alice S.} and Winham, {Stacey J.} and Wu, {Anna H.} and Siddhartha Yadav and Yao Yu and Argyrios Ziogas and Andrew Berchuck and Couch, {Fergus J.} and Goode, {Ellen L.} and Goodman, {Marc T.} and Monteiro, {Alvaro N.} and Kenneth Offit and Ramus, {Susan J.} and Risch, {Harvey A.} and Schildkraut, {Joellen M.} and Mads Thomassen and Jacques Simard and Easton, {Douglas F.} and Jones, {Michelle R.} and Georgia Chenevix-Trench and Gayther, {Simon A.} and Antoniou, {Antonis C.} and Pharoah, {Paul D.P.} and {GEMO Study Collaborators} and {EMBRACE Collaborators} and {kConFab Investigators} and {Ovarian Cancer Association Consortium} and {Consortium of Investigators of Modifiers of BRCA1 and BRCA2}",

year = "2024",

month = mar,

day = "4",

doi = "10.1101/2024.02.29.24303243",

language = "English",

publisher = "medRxiv",

type = "WorkingPaper",

institution = "medRxiv",

}

Barnes, DR, Tyrer, JP, Dennis, J, Leslie, G, Bolla, MK, Lush, M, Aeilts, AM, Aittomäki, K, Andrieu, N, Andrulis, IL, Anton-Culver, H, Arason, A, Arun, BK, Balmaña, J, Bandera, EV, Barkardottir, RB, Berger, LPV, Berrington de Gonzalez, A, Berthet, P, Białkowska, K, Bjørge, L, Blanco, AM, Blok, MJ, Bobolis, KA, Bogdanova, NV, Brenton, JD, Butz, H, Buys, SS, Caligo, MA, Campbell, I, Castillo, C, Claes, KBM, Colonna, SV, Cook, LS, Daly, MB, Dansonka-Mieszkowska, A, de la Hoya, M, DeFazio, A, DePersia, A, Ding, YC, Domchek, SM, Dörk, T, Einbeigi, Z, Engel, C, Evans, DG, Foretova, L, Fortner, RT, Fostira, F, Foti, MC, Friedman, E, Frone, MN, Ganz, PA, Gentry-Maharaj, A, Glendon, G, Godwin, AK, González-Neira, A, Greene, MH, Gronwald, J, Guerrieri-Gonzaga, A, Hamann, U, Hansen, TVO, Harris, HR, Hauke, J, Heitz, F, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Huff, CD, Huntsman, DG, Imyanitov, EN, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, John, EM, Kar, S, Karlan, BY, Kennedy, CJ, Kiemeney, LALM, Konstantopoulou, I, Kupryjanczyk, J, Laitman, Y, Lavie, O, Lawrenson, K, Lester, J, Lesueur, F, Lopez-Pleguezuelos, C, Mai, PL, Manoukian, S, May, T, McNeish, IA, Menon, U, Milne, RL, Modugno, F, Mongiovi, JM, Montagna, M, Moysich, KB, Neuhausen, SL, Nielsen, FC, Noguès, C, Oláh, E, Olopade, OI, Osorio, A, Papi, L, Pathak, H, Pearce, CL, Pedersen, IS, Peixoto, A, Pejovic, T, Peng, P-C, Peshkin, BN, Peterlongo, P, Powell, CB, Prokofyeva, D, Pujana, MA, Radice, P, Rashid, MU, Rennert, G, Richenberg, G, Sandler, DP, Sasamoto, N, Setiawan, VW, Sharma, P, Sieh, W, Singer, CF, Snape, K, Sokolenko, AP, Soucy, P, Southey, MC, Stoppa-Lyonnet, D, Sutphen, R, Sutter, C, Teixeira, MR, Terry, KL, Thomsen, LCV, Tischkowitz, M, Toland, AE, Van Gorp, T, Vega, A, Velez Edwards, DR, Webb, PM, Weitzel, JN, Wentzensen, N, Whittemore, AS, Winham, SJ, Wu, AH, Yadav, S, Yu, Y, Ziogas, A, Berchuck, A, Couch, FJ, Goode, EL, Goodman, MT, Monteiro, AN, Offit, K, Ramus, SJ, Risch, HA, Schildkraut, JM, Thomassen, M, Simard, J, Easton, DF, Jones, MR, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, GEMO Study Collaborators, EMBRACE Collaborators, kConFab Investigators, Ovarian Cancer Association Consortium & Consortium of Investigators of Modifiers of BRCA1 and BRCA2 2024 'Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk' medRxiv. https://doi.org/10.1101/2024.02.29.24303243

TY - UNPB

T1 - Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

AU - Barnes, Daniel R.

AU - Tyrer, Jonathan P.

AU - Dennis, Joe

AU - Leslie, Goska

AU - Bolla, Manjeet K.

AU - Lush, Michael

AU - Aeilts, Amber M.

AU - Aittomäki, Kristiina

AU - Andrieu, Nadine

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arason, Adalgeir

AU - Arun, Banu K.

AU - Balmaña, Judith

AU - Bandera, Elisa V.

AU - Barkardottir, Rosa B.

AU - Berger, Lieke P.V.

AU - Berrington de Gonzalez, Amy

AU - Berthet, Pascaline

AU - Białkowska, Katarzyna

AU - Bjørge, Line

AU - Blanco, Amie M.

AU - Blok, Marinus J.

AU - Bobolis, Kristie A.

AU - Bogdanova, Natalia V.

AU - Brenton, James D.

AU - Butz, Henriett

AU - Buys, Saundra S.

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Castillo, Carmen

AU - Claes, Kathleen B.M.

AU - Colonna, Sarah V.

AU - Cook, Linda S.

AU - Daly, Mary B.

AU - Dansonka-Mieszkowska, Agnieszka

AU - de la Hoya, Miguel

AU - DeFazio, Anna

AU - DePersia, Allison

AU - Ding, Yuan Chun

AU - Domchek, Susan M.

AU - Dörk, Thilo

AU - Einbeigi, Zakaria

AU - Engel, Christoph

AU - Evans, D. Gareth

AU - Foretova, Lenka

AU - Fortner, Renée T.

AU - Fostira, Florentia

AU - Foti, Maria Cristina

AU - Friedman, Eitan

AU - Frone, Megan N.

AU - Ganz, Patricia A.

AU - Gentry-Maharaj, Aleksandra

AU - Glendon, Gord

AU - Godwin, Andrew K.

AU - González-Neira, Anna

AU - Greene, Mark H.

AU - Gronwald, Jacek

AU - Guerrieri-Gonzaga, Aliana

AU - Hamann, Ute

AU - Hansen, Thomas v.O.

AU - Harris, Holly R.

AU - Hauke, Jan

AU - Heitz, Florian

AU - Hogervorst, Frans B.L.

AU - Hooning, Maartje J.

AU - Hopper, John L.

AU - Huff, Chad D

AU - Huntsman, David G.

AU - Imyanitov, Evgeny N.

AU - Izatt, Louise

AU - Jakubowska, Anna

AU - James, Paul A.

AU - Janavicius, Ramunas

AU - John, Esther M.

AU - Kar, Siddhartha

AU - Karlan, Beth Y.

AU - Kennedy, Catherine J.

AU - Kiemeney, Lambertus A.L.M.

AU - Konstantopoulou, Irene

AU - Kupryjanczyk, Jolanta

AU - Laitman, Yael

AU - Lavie, Ofer

AU - Lawrenson, Kate

AU - Lester, Jenny

AU - Lesueur, Fabienne

AU - Lopez-Pleguezuelos, Carlos

AU - Mai, Phuong L.

AU - Manoukian, Siranoush

AU - May, Taymaa

AU - McNeish, Iain A.

AU - Menon, Usha

AU - Milne, Roger L.

AU - Modugno, Francesmary

AU - Mongiovi, Jennifer M.

AU - Montagna, Marco

AU - Moysich, Kirsten B.

AU - Neuhausen, Susan L.

AU - Nielsen, Finn C.

AU - Noguès, Catherine

AU - Oláh, Edit

AU - Olopade, Olufunmilayo I.

AU - Osorio, Ana

AU - Papi, Laura

AU - Pathak, Harsh

AU - Pearce, Celeste L.

AU - Pedersen, Inge S.

AU - Peixoto, Ana

AU - Pejovic, Tanja

AU - Peng, Pei-Chen

AU - Peshkin, Beth N.

AU - Peterlongo, Paolo

AU - Powell, C. Bethan

AU - Prokofyeva, Darya

AU - Pujana, Miquel Angel

AU - Radice, Paolo

AU - Rashid, Muhammad U.

AU - Rennert, Gad

AU - Richenberg, George

AU - Sandler, Dale P.

AU - Sasamoto, Naoko

AU - Setiawan, Veronica W.

AU - Sharma, Priyanka

AU - Sieh, Weiva

AU - Singer, Christian F.

AU - Snape, Katie

AU - Sokolenko, Anna P.

AU - Soucy, Penny

AU - Southey, Melissa C.

AU - Stoppa-Lyonnet, Dominique

AU - Sutphen, Rebecca

AU - Sutter, Christian

AU - Teixeira, Manuel R.

AU - Terry, Kathryn L.

AU - Thomsen, Liv Cecilie V.

AU - Tischkowitz, Marc

AU - Toland, Amanda E.

AU - Van Gorp, Toon

AU - Vega, Ana

AU - Velez Edwards, Digna R.

AU - Webb, Penelope M.

AU - Weitzel, Jeffrey N.

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S.

AU - Winham, Stacey J.

AU - Wu, Anna H.

AU - Yadav, Siddhartha

AU - Yu, Yao

AU - Ziogas, Argyrios

AU - Berchuck, Andrew

AU - Couch, Fergus J.

AU - Goode, Ellen L.

AU - Goodman, Marc T.

AU - Monteiro, Alvaro N.

AU - Offit, Kenneth

AU - Ramus, Susan J.

AU - Risch, Harvey A.

AU - Schildkraut, Joellen M.

AU - Thomassen, Mads

AU - Simard, Jacques

AU - Easton, Douglas F.

AU - Jones, Michelle R.

AU - Chenevix-Trench, Georgia

AU - Gayther, Simon A.

AU - Antoniou, Antonis C.

AU - Pharoah, Paul D.P.

AU - GEMO Study Collaborators

AU - EMBRACE Collaborators

AU - kConFab Investigators

AU - Ovarian Cancer Association Consortium

AU - Consortium of Investigators of Modifiers of BRCA1 and BRCA2

PY - 2024/3/4

Y1 - 2024/3/4

N2 - Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan.Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62).Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

AB - Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan.Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62).Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

U2 - 10.1101/2024.02.29.24303243

DO - 10.1101/2024.02.29.24303243

M3 - Preprint

BT - Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

PB - medRxiv

ER -

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

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