Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

Dylan M Glubb; Deborah J Thompson; Katja Kh Aben; Ahmad Alsulimani; Frédéric Amant; Daniela Annibali; John Attia; Aurelio Barricarte; Matthias W Beckmann; Andrew Berchuck; Marina Bermisheva; Marcus Q Bernardini; Katharina Bischof; Line Bjørge; Clara Bodelon; Alison H Brand; James D Brenton; Louise A Brinton; Fiona Bruinsma; Daniel D Buchanan; Stefanie Burghaus; Ralf Bützow; Hui Cai; Michael E Carney; Stephen J Chanock; Chu Chen; Xiaoqing Chen; Zhihua Chen; Linda S Cook; Julie M Cunningham; Immaculata De Vivo; Anna DeFazio; Jennifer A Doherty; Thilo Dork; Andreas du Bois; Alison M Dunning; Matthias Durst; Todd Edwards; Robert P Edwards; Arif B Ekici; Ailith Ewing; Peter A Fasching; Sarah Ferguson; James M Flanagan; Florentia Fostira; George Fountzilas; Christine M Friedenreich; Bo Gao; Mia M Gaudet; Jan Gawełko; Aleksandra Gentry-Maharaj; Graham G Giles; Rosalind Glasspool; Marc T Goodman; Jacek Gronwald; Holly R Harris; Philipp Harter; Alexander Hein; Florian Heitz; Michelle A T Hildebrandt; Peter Hillemanns; Estrid Høgdall; Claus K Høgdall; Elizabeth G Holliday; David G Huntsman; Tomasz Huzarski; Anna Jakubowska; Michael E Jones; Beth Y Karlan; Anthony Karnezis; Joseph L Kelley; Elza Khusnutdinova; Jeffrey L Killeen; Susanne K Kjaer; Rüdiger Klapdor; Martin Köbel; Bozena Konopka; Irene Konstantopoulou; Reidun K Kopperud; Madhuri Koti; Peter Kraft; Jolanta Kupryjanczyk; Diether Lambrechts; Melissa C Larson; Loic Le Marchand; Shashikant Lele; Jenny Lester; Andrew J Li; Dong Liang; Clemens Liebrich; Loren Lipworth; Jolanta Lissowska; Lingeng Lu; Karen H Lu; Alessandra Macciotta; Amalia Mattiello; Taymaa May; Jessica N McAlpine; Valerie McGuire; Iain A McNeish; Usha Menon; Francesmary Modugno; Kirsten B Moysich; Heli Nevanlinna; Kunle Odunsi; Håkan Olsson; Sandra Orsulic; Ana Osorio; Domenico Palli; Tjoung-Won Park-Simon; Celeste L Pearce; Tanja Pejovic; Jennifer B Permuth; Agnieszka Podgorska; Susan J Ramus; Timothy R Rebbeck; Marjorie J Riggan; Harvey A Risch; Joseph H Rothstein; Ingo B Runnebaum; Rodney J Scott; Thomas A Sellers; Janine Senz; Veronica Wendy Setiawan; Nadeem Siddiqui; Weiva Sieh; Beata Spiewankiewicz; Rebecca Sutphen; Anthony J Swerdlow; Lukasz Michal Szafron; Soo Hwang Teo; Pamela J Thompson; Liv Cecilie Vestrheim Thomsen; Linda Titus; Alicia Tone; Rosario Tumino; Constance Turman; Adriaan Vanderstichele; Digna Velez Edwards; Ignace Vergote; Robert A Vierkant; Zhaoming Wang; Shan Wang-Gohrke; Penelope M Webb; Emily White; Alice S Whittemore; Stacey J Winham; Xifeng Wu; Anna H Wu; Drakoulis Yannoukakos; Amanda B Spurdle; Tracy A O'Mara

doi:10.1158/1055-9965.EPI-20-0739

Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

Dylan M Glubb, Deborah J Thompson, Katja Kh Aben, Ahmad Alsulimani, Frédéric Amant, Daniela Annibali, John Attia, Aurelio Barricarte, Matthias W Beckmann, Andrew Berchuck, Marina Bermisheva, Marcus Q Bernardini, Katharina Bischof, Line Bjørge, Clara Bodelon, Alison H Brand, James D Brenton, Louise A Brinton, Fiona Bruinsma, Daniel D BuchananStefanie Burghaus, Ralf Bützow, Hui Cai, Michael E Carney, Stephen J Chanock, Chu Chen, Xiaoqing Chen, Zhihua Chen, Linda S Cook, Julie M Cunningham, Immaculata De Vivo, Anna DeFazio, Jennifer A Doherty, Thilo Dork, Andreas du Bois, Alison M Dunning, Matthias Durst, Todd Edwards, Robert P Edwards, Arif B Ekici, Ailith Ewing, Peter A Fasching, Sarah Ferguson, James M Flanagan, Florentia Fostira, George Fountzilas, Christine M Friedenreich, Bo Gao, Mia M Gaudet, Jan Gawełko, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Holly R Harris, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Estrid Høgdall, Claus K Høgdall, Elizabeth G Holliday, David G Huntsman, Tomasz Huzarski, Anna Jakubowska, Michael E Jones, Beth Y Karlan, Anthony Karnezis, Joseph L Kelley, Elza Khusnutdinova, Jeffrey L Killeen, Susanne K Kjaer, Rüdiger Klapdor, Martin Köbel, Bozena Konopka, Irene Konstantopoulou, Reidun K Kopperud, Madhuri Koti, Peter Kraft, Jolanta Kupryjanczyk, Diether Lambrechts, Melissa C Larson, Loic Le Marchand, Shashikant Lele, Jenny Lester, Andrew J Li, Dong Liang, Clemens Liebrich, Loren Lipworth, Jolanta Lissowska, Lingeng Lu, Karen H Lu, Alessandra Macciotta, Amalia Mattiello, Taymaa May, Jessica N McAlpine, Valerie McGuire, Iain A McNeish, Usha Menon, Francesmary Modugno, Kirsten B Moysich, Heli Nevanlinna, Kunle Odunsi, Håkan Olsson, Sandra Orsulic, Ana Osorio, Domenico Palli, Tjoung-Won Park-Simon, Celeste L Pearce, Tanja Pejovic, Jennifer B Permuth, Agnieszka Podgorska, Susan J Ramus, Timothy R Rebbeck, Marjorie J Riggan, Harvey A Risch, Joseph H Rothstein, Ingo B Runnebaum, Rodney J Scott, Thomas A Sellers, Janine Senz, Veronica Wendy Setiawan, Nadeem Siddiqui, Weiva Sieh, Beata Spiewankiewicz, Rebecca Sutphen, Anthony J Swerdlow, Lukasz Michal Szafron, Soo Hwang Teo, Pamela J Thompson, Liv Cecilie Vestrheim Thomsen, Linda Titus, Alicia Tone, Rosario Tumino, Constance Turman, Adriaan Vanderstichele, Digna Velez Edwards, Ignace Vergote, Robert A Vierkant, Zhaoming Wang, Shan Wang-Gohrke, Penelope M Webb, Emily White, Alice S Whittemore, Stacey J Winham, Xifeng Wu, Anna H Wu, Drakoulis Yannoukakos, Amanda B Spurdle, Tracy A O'Mara

Patologi

13 Citationer (Scopus)

Abstract

BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( r G = 0.43, P = 2.66 × 10 -5). We found seven loci associated with risk for both cancers ( P Bonferroni < 2.4 × 10 -9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( P < 5 × 10 -7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

CONCLUSIONS: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Originalsprog	Engelsk
Tidsskrift	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Vol/bind	30
Udgave nummer	1
Sider (fra-til)	217-228
Antal sider	12
ISSN	1055-9965
DOI	https://doi.org/10.1158/1055-9965.EPI-20-0739
Status	Udgivet - jan. 2021

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10.1158/1055-9965.EPI-20-0739

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Citationsformater

Glubb, D. M., Thompson, D. J., Aben, K. K., Alsulimani, A., Amant, F., Annibali, D., Attia, J., Barricarte, A., Beckmann, M. W., Berchuck, A., Bermisheva, M., Bernardini, M. Q., Bischof, K., Bjørge, L., Bodelon, C., Brand, A. H., Brenton, J. D., Brinton, L. A., Bruinsma, F., ... O'Mara, T. A. (2021). Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 30(1), 217-228. https://doi.org/10.1158/1055-9965.EPI-20-0739

Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers. / Glubb, Dylan M; Thompson, Deborah J; Aben, Katja Kh et al.
I: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Bind 30, Nr. 1, 01.2021, s. 217-228.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Glubb, DM, Thompson, DJ, Aben, KK, Alsulimani, A, Amant, F, Annibali, D, Attia, J, Barricarte, A, Beckmann, MW, Berchuck, A, Bermisheva, M, Bernardini, MQ, Bischof, K, Bjørge, L, Bodelon, C, Brand, AH, Brenton, JD, Brinton, LA, Bruinsma, F, Buchanan, DD, Burghaus, S, Bützow, R, Cai, H, Carney, ME, Chanock, SJ, Chen, C, Chen, X, Chen, Z, Cook, LS, Cunningham, JM, De Vivo, I, DeFazio, A, Doherty, JA, Dork, T, du Bois, A, Dunning, AM, Durst, M, Edwards, T, Edwards, RP, Ekici, AB, Ewing, A, Fasching, PA, Ferguson, S, Flanagan, JM, Fostira, F, Fountzilas, G, Friedenreich, CM, Gao, B, Gaudet, MM, Gawełko, J, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harris, HR, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Høgdall, E , Høgdall, CK, Holliday, EG, Huntsman, DG, Huzarski, T, Jakubowska, A, Jones, ME, Karlan, BY, Karnezis, A, Kelley, JL, Khusnutdinova, E, Killeen, JL, Kjaer, SK, Klapdor, R, Köbel, M, Konopka, B, Konstantopoulou, I, Kopperud, RK, Koti, M, Kraft, P, Kupryjanczyk, J, Lambrechts, D, Larson, MC, Le Marchand, L, Lele, S, Lester, J, Li, AJ, Liang, D, Liebrich, C, Lipworth, L, Lissowska, J, Lu, L, Lu, KH, Macciotta, A, Mattiello, A, May, T, McAlpine, JN, McGuire, V, McNeish, IA, Menon, U, Modugno, F, Moysich, KB, Nevanlinna, H, Odunsi, K, Olsson, H, Orsulic, S, Osorio, A, Palli, D, Park-Simon, T-W, Pearce, CL, Pejovic, T, Permuth, JB, Podgorska, A, Ramus, SJ, Rebbeck, TR, Riggan, MJ, Risch, HA, Rothstein, JH, Runnebaum, IB, Scott, RJ, Sellers, TA, Senz, J, Setiawan, VW, Siddiqui, N, Sieh, W, Spiewankiewicz, B, Sutphen, R, Swerdlow, AJ, Szafron, LM, Teo, SH, Thompson, PJ, Thomsen, LCV, Titus, L, Tone, A, Tumino, R, Turman, C, Vanderstichele, A, Velez Edwards, D, Vergote, I, Vierkant, RA, Wang, Z, Wang-Gohrke, S, Webb, PM, White, E, Whittemore, AS, Winham, SJ, Wu, X, Wu, AH, Yannoukakos, D, Spurdle, AB & O'Mara, TA 2021, 'Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers', Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, bind 30, nr. 1, s. 217-228. https://doi.org/10.1158/1055-9965.EPI-20-0739

Glubb DM, Thompson DJ, Aben KK, Alsulimani A, Amant F, Annibali D et al. Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2021 jan.;30(1):217-228. doi: 10.1158/1055-9965.EPI-20-0739

Glubb, Dylan M ; Thompson, Deborah J ; Aben, Katja Kh et al. / Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers. I: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2021 ; Bind 30, Nr. 1. s. 217-228.

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title = "Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers",

abstract = "BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( r G = 0.43, P = 2.66 × 10 -5). We found seven loci associated with risk for both cancers ( P Bonferroni < 2.4 × 10 -9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( P < 5 × 10 -7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. CONCLUSIONS: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.",

author = "Glubb, {Dylan M} and Thompson, {Deborah J} and Aben, {Katja Kh} and Ahmad Alsulimani and Fr{\'e}d{\'e}ric Amant and Daniela Annibali and John Attia and Aurelio Barricarte and Beckmann, {Matthias W} and Andrew Berchuck and Marina Bermisheva and Bernardini, {Marcus Q} and Katharina Bischof and Line Bj{\o}rge and Clara Bodelon and Brand, {Alison H} and Brenton, {James D} and Brinton, {Louise A} and Fiona Bruinsma and Buchanan, {Daniel D} and Stefanie Burghaus and Ralf B{\"u}tzow and Hui Cai and Carney, {Michael E} and Chanock, {Stephen J} and Chu Chen and Xiaoqing Chen and Zhihua Chen and Cook, {Linda S} and Cunningham, {Julie M} and {De Vivo}, Immaculata and Anna DeFazio and Doherty, {Jennifer A} and Thilo Dork and {du Bois}, Andreas and Dunning, {Alison M} and Matthias Durst and Todd Edwards and Edwards, {Robert P} and Ekici, {Arif B} and Ailith Ewing and Fasching, {Peter A} and Sarah Ferguson and Flanagan, {James M} and Florentia Fostira and George Fountzilas and Friedenreich, {Christine M} and Bo Gao and Gaudet, {Mia M} and Jan Gawe{\l}ko and Aleksandra Gentry-Maharaj and Giles, {Graham G} and Rosalind Glasspool and Goodman, {Marc T} and Jacek Gronwald and Harris, {Holly R} and Philipp Harter and Alexander Hein and Florian Heitz and Hildebrandt, {Michelle A T} and Peter Hillemanns and Estrid H{\o}gdall and H{\o}gdall, {Claus K} and Holliday, {Elizabeth G} and Huntsman, {David G} and Tomasz Huzarski and Anna Jakubowska and Jones, {Michael E} and Karlan, {Beth Y} and Anthony Karnezis and Kelley, {Joseph L} and Elza Khusnutdinova and Killeen, {Jeffrey L} and Kjaer, {Susanne K} and R{\"u}diger Klapdor and Martin K{\"o}bel and Bozena Konopka and Irene Konstantopoulou and Kopperud, {Reidun K} and Madhuri Koti and Peter Kraft and Jolanta Kupryjanczyk and Diether Lambrechts and Larson, {Melissa C} and {Le Marchand}, Loic and Shashikant Lele and Jenny Lester and Li, {Andrew J} and Dong Liang and Clemens Liebrich and Loren Lipworth and Jolanta Lissowska and Lingeng Lu and Lu, {Karen H} and Alessandra Macciotta and Amalia Mattiello and Taymaa May and McAlpine, {Jessica N} and Valerie McGuire and McNeish, {Iain A} and Usha Menon and Francesmary Modugno and Moysich, {Kirsten B} and Heli Nevanlinna and Kunle Odunsi and H{\aa}kan Olsson and Sandra Orsulic and Ana Osorio and Domenico Palli and Tjoung-Won Park-Simon and Pearce, {Celeste L} and Tanja Pejovic and Permuth, {Jennifer B} and Agnieszka Podgorska and Ramus, {Susan J} and Rebbeck, {Timothy R} and Riggan, {Marjorie J} and Risch, {Harvey A} and Rothstein, {Joseph H} and Runnebaum, {Ingo B} and Scott, {Rodney J} and Sellers, {Thomas A} and Janine Senz and Setiawan, {Veronica Wendy} and Nadeem Siddiqui and Weiva Sieh and Beata Spiewankiewicz and Rebecca Sutphen and Swerdlow, {Anthony J} and Szafron, {Lukasz Michal} and Teo, {Soo Hwang} and Thompson, {Pamela J} and Thomsen, {Liv Cecilie Vestrheim} and Linda Titus and Alicia Tone and Rosario Tumino and Constance Turman and Adriaan Vanderstichele and {Velez Edwards}, Digna and Ignace Vergote and Vierkant, {Robert A} and Zhaoming Wang and Shan Wang-Gohrke and Webb, {Penelope M} and Emily White and Whittemore, {Alice S} and Winham, {Stacey J} and Xifeng Wu and Wu, {Anna H} and Drakoulis Yannoukakos and Spurdle, {Amanda B} and O'Mara, {Tracy A}",

note = "{\textcopyright}2020 American Association for Cancer Research.",

year = "2021",

month = jan,

doi = "10.1158/1055-9965.EPI-20-0739",

language = "English",

volume = "30",

pages = "217--228",

journal = "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "1",

}

TY - JOUR

T1 - Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

AU - Glubb, Dylan M

AU - Thompson, Deborah J

AU - Aben, Katja Kh

AU - Alsulimani, Ahmad

AU - Amant, Frédéric

AU - Annibali, Daniela

AU - Attia, John

AU - Barricarte, Aurelio

AU - Beckmann, Matthias W

AU - Berchuck, Andrew

AU - Bermisheva, Marina

AU - Bernardini, Marcus Q

AU - Bischof, Katharina

AU - Bjørge, Line

AU - Bodelon, Clara

AU - Brand, Alison H

AU - Brenton, James D

AU - Brinton, Louise A

AU - Bruinsma, Fiona

AU - Buchanan, Daniel D

AU - Burghaus, Stefanie

AU - Bützow, Ralf

AU - Cai, Hui

AU - Carney, Michael E

AU - Chanock, Stephen J

AU - Chen, Chu

AU - Chen, Xiaoqing

AU - Chen, Zhihua

AU - Cook, Linda S

AU - Cunningham, Julie M

AU - De Vivo, Immaculata

AU - DeFazio, Anna

AU - Doherty, Jennifer A

AU - Dork, Thilo

AU - du Bois, Andreas

AU - Dunning, Alison M

AU - Durst, Matthias

AU - Edwards, Todd

AU - Edwards, Robert P

AU - Ekici, Arif B

AU - Ewing, Ailith

AU - Fasching, Peter A

AU - Ferguson, Sarah

AU - Flanagan, James M

AU - Fostira, Florentia

AU - Fountzilas, George

AU - Friedenreich, Christine M

AU - Gao, Bo

AU - Gaudet, Mia M

AU - Gawełko, Jan

AU - Gentry-Maharaj, Aleksandra

AU - Giles, Graham G

AU - Glasspool, Rosalind

AU - Goodman, Marc T

AU - Gronwald, Jacek

AU - Harris, Holly R

AU - Harter, Philipp

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hildebrandt, Michelle A T

AU - Hillemanns, Peter

AU - Høgdall, Estrid

AU - Høgdall, Claus K

AU - Holliday, Elizabeth G

AU - Huntsman, David G

AU - Huzarski, Tomasz

AU - Jakubowska, Anna

AU - Jones, Michael E

AU - Karlan, Beth Y

AU - Karnezis, Anthony

AU - Kelley, Joseph L

AU - Khusnutdinova, Elza

AU - Killeen, Jeffrey L

AU - Kjaer, Susanne K

AU - Klapdor, Rüdiger

AU - Köbel, Martin

AU - Konopka, Bozena

AU - Konstantopoulou, Irene

AU - Kopperud, Reidun K

AU - Koti, Madhuri

AU - Kraft, Peter

AU - Kupryjanczyk, Jolanta

AU - Lambrechts, Diether

AU - Larson, Melissa C

AU - Le Marchand, Loic

AU - Lele, Shashikant

AU - Lester, Jenny

AU - Li, Andrew J

AU - Liang, Dong

AU - Liebrich, Clemens

AU - Lipworth, Loren

AU - Lissowska, Jolanta

AU - Lu, Lingeng

AU - Lu, Karen H

AU - Macciotta, Alessandra

AU - Mattiello, Amalia

AU - May, Taymaa

AU - McAlpine, Jessica N

AU - McGuire, Valerie

AU - McNeish, Iain A

AU - Menon, Usha

AU - Modugno, Francesmary

AU - Moysich, Kirsten B

AU - Nevanlinna, Heli

AU - Odunsi, Kunle

AU - Olsson, Håkan

AU - Orsulic, Sandra

AU - Osorio, Ana

AU - Palli, Domenico

AU - Park-Simon, Tjoung-Won

AU - Pearce, Celeste L

AU - Pejovic, Tanja

AU - Permuth, Jennifer B

AU - Podgorska, Agnieszka

AU - Ramus, Susan J

AU - Rebbeck, Timothy R

AU - Riggan, Marjorie J

AU - Risch, Harvey A

AU - Rothstein, Joseph H

AU - Runnebaum, Ingo B

AU - Scott, Rodney J

AU - Sellers, Thomas A

AU - Senz, Janine

AU - Setiawan, Veronica Wendy

AU - Siddiqui, Nadeem

AU - Sieh, Weiva

AU - Spiewankiewicz, Beata

AU - Sutphen, Rebecca

AU - Swerdlow, Anthony J

AU - Szafron, Lukasz Michal

AU - Teo, Soo Hwang

AU - Thompson, Pamela J

AU - Thomsen, Liv Cecilie Vestrheim

AU - Titus, Linda

AU - Tone, Alicia

AU - Tumino, Rosario

AU - Turman, Constance

AU - Vanderstichele, Adriaan

AU - Velez Edwards, Digna

AU - Vergote, Ignace

AU - Vierkant, Robert A

AU - Wang, Zhaoming

AU - Wang-Gohrke, Shan

AU - Webb, Penelope M

AU - White, Emily

AU - Whittemore, Alice S

AU - Winham, Stacey J

AU - Wu, Xifeng

AU - Wu, Anna H

AU - Yannoukakos, Drakoulis

AU - Spurdle, Amanda B

AU - O'Mara, Tracy A

PY - 2021/1

Y1 - 2021/1

N2 - BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( r G = 0.43, P = 2.66 × 10 -5). We found seven loci associated with risk for both cancers ( P Bonferroni < 2.4 × 10 -9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( P < 5 × 10 -7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. CONCLUSIONS: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

AB - BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( r G = 0.43, P = 2.66 × 10 -5). We found seven loci associated with risk for both cancers ( P Bonferroni < 2.4 × 10 -9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( P < 5 × 10 -7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. CONCLUSIONS: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

UR - http://www.scopus.com/inward/record.url?scp=85122168882&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-20-0739

DO - 10.1158/1055-9965.EPI-20-0739

M3 - Journal article

C2 - 33144283

SN - 1055-9965

VL - 30

SP - 217

EP - 228

JO - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

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Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers

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