| Title: |
Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk. |
| Authors: |
Barnes, Daniel R.; Tyrer, Jonathan P.; Dennis, Joe; Leslie, Goska; Bolla, Manjeet K.; Lush, Michael; Aeilts, Amber M.; Aittomäki, Kristiina; Andrieu, Nadine; Andrulis, Irene L.; Anton-Culver, Hoda; Arason, Adalgeir; Arun, Banu K.; Balmaña, Judith; Bandera, Elisa V.; Barkardottir, Rosa B.; Berger, Lieke P.V.; de Gonzalez, Amy Berrington; Berthet, Pascaline; Białkowska, Katarzyna; Bjørge, Line; Blanco, Amie M.; Blok, Marinus J.; Bobolis, Kristie A.; Bogdanova, Natalia V.; Brenton, James D.; Butz, Henriett; Buys, Saundra S.; Caligo, Maria A.; Campbell, Ian; Castillo, Carmen; Claes, Kathleen B.M.; GEMO Study Collaborators; EMBRACE Collaborators; Colonna, Sarah V.; Cook, Linda S.; Daly, Mary B.; Dansonka-Mieszkowska, Agnieszka; de la Hoya, Miguel; deFazio, Anna; DePersia, Allison; Ding, Yuan Chun; Domchek, Susan M.; Dörk, Thilo; Einbeigi, Zakaria; Engel, Christoph; Evans, D. Gareth; Foretova, Lenka; Fortner, Renée T.; Fostira, Florentia; Foti, Maria Cristina; Friedman, Eitan; Frone, Megan N.; Ganz, Patricia A.; Gentry-Maharaj, Aleksandra; Glendon, Gord; Godwin, Andrew K.; González-Neira, Anna; Greene, Mark H.; Gronwald, Jacek; Guerrieri-Gonzaga, Aliana; Hamann, Ute; Hansen, Thomas V.O.; Harris, Holly R.; Hauke, Jan; Heitz, Florian; Hogervorst, Frans B.L.; Hooning, Maartje J.; Hopper, John L.; Huff, Chad D.; Huntsman, David G.; Imyanitov, Evgeny N.; kConFab Investigators; Izatt, Louise; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; John, Esther M.; Kar, Siddhartha; Karlan, Beth Y.; Kennedy, Catherine J.; Kiemeney, Lambertus A.LM.; Konstantopoulou, Irene; Kupryjanczyk, Jolanta; Laitman, Yael; Lavie, Ofer; Lawrenson, Kate; Lester, Jenny; Lesueur, Fabienne; Lopez-Pleguezuelos, Carlos; Mai, Phuong L.; Manoukian, Siranoush; May, Taymaa; McNeish, Iain A.; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Mongiovi, Jennifer M.; Montagna, Marco; Moysich, Kirsten B.; Neuhausen, Susan L.; Nielsen, Finn C.; Noguès, Catherine; Oláh, Edit; Olopade, Olufunmilayo I.; Osorio, Ana; Papi, Laura; Pathak, Harsh; Pearce, Celeste L.; Pedersen, Inge S.; Peixoto, Ana; Pejovic, Tanja; Peng, Pei-Chen; Peshkin, Beth N.; Peterlongo, Paolo; Powell, C. Bethan; Prokofyeva, Darya; Pujana, Miquel Angel; Radice, Paolo; Rashid, Muhammad U.; Rennert, Gad; Richenberg, George; Sandler, Dale P.; Sasamoto, Naoko; Setiawan, Veronica W.; Sharma, Priyanka; Sieh, Weiva; Singer, Christian F.; Snape, Katie; Sokolenko, Anna P.; Soucy, Penny; Southey, Melissa C.; Stoppa-Lyonnet, Dominique; Sutphen, Rebecca; Sutter, Christian; Teixeira, Manuel R.; Terry, Kathryn L.; Thomsen, Liv Cecilie V.; Tischkowitz, Marc; Toland, Amanda E.; Van Gorp, Toon; Vega, Ana; Velez Edwards, Digna R.; Webb, Penelope M.; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Winham, Stacey J.; Wu, Anna H.; Yadav, Siddhartha; Yu, Yao; Ziogas, Argyrios; Berchuck, Andrew; Couch, Fergus J.; Goode, Ellen L.; Goodman, Marc T.; Monteiro, Alvaro N.; Offit, Kenneth; Ramus, Susan J.; Risch, Harvey A.; Schildkraut, Joellen M.; Thomassen, Mads; Simard, Jacques; Easton, Douglas F.; Jones, Michelle R.; Chenevix-Trench, Georgia; Gayther, Simon A.; Antoniou, Antonis C.; Pharoah, Paul D.P. |
| Publication Year: |
2024 |
| Description: |
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. ; sponsorship: NCI NIH HHS|R01 CA074850, NCI NIH HHS|P50 CA105009, NCI NIH HHS|P30 CA076292, NCI NIH HHS|P50 CA116201, NCI NIH HHS|R01 CA126841, Cancer Research UK|23382, NCI NIH HHS|U10 CA180868, NCI NIH HHS|U01 CA069417, NCI NIH HHS|R03 CA130065, NCI NIH HHS|R01 CA140323, NCI NIH HHS|UM1 CA164973, NCI NIH HHS|R01 CA260132, NCI NIH HHS|R01 CA176785, NCI NIH HHS|N01 PC067010, NCI NIH HHS|P50 CA159981, NCI NIH HHS|P30 CA016056, NCI NIH HHS|R01 CA087538, NCI NIH HHS|R01 CA142996, NCI NIH HHS|R00 CA256519, NCI NIH HHS|RC4 CA153828, NCI NIH HHS|P50 CA125183, Intramural NIH HHS|Z01 ES044005, NCI NIH HHS|P01 CA087969, NCI NIH ... |
| Document Type: |
report |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://lirias.kuleuven.be/handle/20.500.12942/742297; https://doi.org/10.1101/2024.02.29.24303243; https://pubmed.ncbi.nlm.nih.gov/38496424 |
| DOI: |
10.1101/2024.02.29.24303243 |
| Availability: |
https://lirias.kuleuven.be/handle/20.500.12942/742297; https://hdl.handle.net/20.500.12942/742297; https://lirias.kuleuven.be/retrieve/00e7f990-fa8b-45e3-8675-4f421b4c495f; https://doi.org/10.1101/2024.02.29.24303243; https://pubmed.ncbi.nlm.nih.gov/38496424 |
| Rights: |
info:eu-repo/semantics/openAccess ; public ; https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.CCA7EEB |
| Database: |
BASE |