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 K.H. Aben; Ahmad Alsulimani; Frederic Amant; Daniela Annibali; John Attia; Aurelio Barricarte; Matthias W. Beckmann; Andrew Berchuck; Marina Bermisheva; Marcus Q. Bernardini; Katharina Bischof; Line Bjorge; Clara Bodelon; Alison H. Brand; James D. Brenton; Louise A. Brinton; Fiona Bruinsma; Daniel D. Buchanan; Stefanie Burghaus; Ralf Butzow; Hui Cai; Michael E. Carney; Stephen J. Chanock; Chu Chen; Xiao Qing Chen; Zhihua Chen; Linda S. Cook; Julie M. Cunningham; Immaculata De Vivo; Anna deFazio; Jennifer A. Doherty; Thilo Dörk; Andreas du Bois; Alison M. Dunning; Matthias Dürst; 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; Allan Jensen; 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 Michael 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; for the OPAL study group and for the AOCS Group; 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 K.H. Aben, Ahmad Alsulimani, Frederic Amant, Daniela Annibali, John Attia, Aurelio Barricarte, Matthias W. Beckmann, Andrew Berchuck, Marina Bermisheva, Marcus Q. Bernardini, Katharina Bischof, Line Bjorge, Clara Bodelon, Alison H. Brand, James D. Brenton, Louise A. Brinton, Fiona Bruinsma, Daniel D. BuchananStefanie Burghaus, Ralf Butzow, Hui Cai, Michael E. Carney, Stephen J. Chanock, Chu Chen, Xiao Qing Chen, Zhihua Chen, Linda S. Cook, Julie M. Cunningham, Immaculata De Vivo, Anna deFazio, Jennifer A. Doherty, Thilo Dörk, Andreas du Bois, Alison M. Dunning, Matthias Dürst, 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, Allan Jensen, 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 Michael 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, for the OPAL study group and for the AOCS Group, Emily White, Alice S. Whittemore, Stacey J. Winham, Xifeng Wu, Anna H. Wu, Drakoulis Yannoukakos, Amanda B. Spurdle, Tracy A. O'Mara

Medicine Monash Health

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

12 Citations (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 (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 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.

Original language	English
Pages (from-to)	217-228
Number of pages	12
Journal	Cancer Epidemiology, Biomarkers and Prevention
Volume	30
Issue number	1
DOIs	https://doi.org/10.1158/1055-9965.EPI-20-0739
Publication status	Published - Jan 2021

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10.1158/1055-9965.EPI-20-0739

Cite this

Glubb, D. M., Thompson, D. J., Aben, K. K. H., Alsulimani, A., Amant, F., Annibali, D., Attia, J., Barricarte, A., Beckmann, M. W., Berchuck, A., Bermisheva, M., Bernardini, M. Q., Bischof, K., Bjorge, 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 and Prevention, 30(1), 217-228. https://doi.org/10.1158/1055-9965.EPI-20-0739

@article{101d752ec959490a9e27c7a884ef0487,

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 (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 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 K.H.} and Ahmad Alsulimani and Frederic 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 Bjorge 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 Butzow and Hui Cai and Carney, {Michael E.} and Chanock, {Stephen J.} and Chu Chen and Chen, {Xiao Qing} and Zhihua Chen and Cook, {Linda S.} and Cunningham, {Julie M.} and {De Vivo}, Immaculata and Anna deFazio and Doherty, {Jennifer A.} and Thilo D{\"o}rk and {du Bois}, Andreas and Dunning, {Alison M.} and Matthias D{\"u}rst 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 Allan Jensen 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 Park-Simon, {Tjoung Won} 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 Michael} 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 Edwards, {Digna Velez} and Ignace Vergote and Vierkant, {Robert A.} and Zhaoming Wang and Shan Wang-Gohrke and Webb, {Penelope M.} and {for the OPAL study group and for the AOCS Group} 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 = "Publisher Copyright: {\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 and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research (AACR)",

number = "1",

}

Glubb, DM, Thompson, DJ, Aben, KKH, Alsulimani, A, Amant, F, Annibali, D, Attia, J, Barricarte, A, Beckmann, MW, Berchuck, A, Bermisheva, M, Bernardini, MQ, Bischof, K, Bjorge, L, Bodelon, C, Brand, AH, Brenton, JD, Brinton, LA, Bruinsma, F, Buchanan, DD, Burghaus, S, Butzow, R, Cai, H, Carney, ME, Chanock, SJ, Chen, C, Chen, XQ, Chen, Z, Cook, LS, Cunningham, JM, De Vivo, I, deFazio, A, Doherty, JA, Dörk, T, du Bois, A, Dunning, AM, Dürst, 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, Jensen, 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, TW, 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, Edwards, DV, Vergote, I, Vierkant, RA, Wang, Z, Wang-Gohrke, S, Webb, PM, for the OPAL study group and for the AOCS Group, 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 and Prevention, vol. 30, no. 1, pp. 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 K.H. et al.
In: Cancer Epidemiology, Biomarkers and Prevention, Vol. 30, No. 1, 01.2021, p. 217-228.

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

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 K.H.

AU - Alsulimani, Ahmad

AU - Amant, Frederic

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 - Bjorge, 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 - Butzow, Ralf

AU - Cai, Hui

AU - Carney, Michael E.

AU - Chanock, Stephen J.

AU - Chen, Chu

AU - Chen, Xiao Qing

AU - Chen, Zhihua

AU - Cook, Linda S.

AU - Cunningham, Julie M.

AU - De Vivo, Immaculata

AU - deFazio, Anna

AU - Doherty, Jennifer A.

AU - Dörk, Thilo

AU - du Bois, Andreas

AU - Dunning, Alison M.

AU - Dürst, 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 - Jensen, Allan

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 Michael

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 - Edwards, Digna Velez

AU - Vergote, Ignace

AU - Vierkant, Robert A.

AU - Wang, Zhaoming

AU - Wang-Gohrke, Shan

AU - Webb, Penelope M.

AU - for the OPAL study group and for the AOCS Group

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 (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 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 (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 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 - Article

C2 - 33144283

AN - SCOPUS:85122168882

SN - 1055-9965

VL - 30

SP - 217

EP - 228

JO - Cancer Epidemiology, Biomarkers and Prevention

JF - Cancer Epidemiology, Biomarkers and Prevention

IS - 1

ER -

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers

Abstract

UN SDGs

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