Two truncating variants in FANCC and breast cancer risk.

Dörk, Thilo; Peterlongo, Paolo; Mannermaa, Arto; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Ahearn, Thomas; Andrulis, Irene LORCID logo; Anton-Culver, Hoda; Arndt, VolkerORCID logo; +162 more...Aronson, Kristan J; Augustinsson, Annelie; Freeman, Laura E Beane; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Behrens, Sabine; Bermisheva, Marina; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Brauch, HiltrudORCID logo; Brenner, Hermann; Burwinkel, Barbara; Canzian, Federico; Chan, Tsun L; Chang-Claude, Jenny; Chanock, Stephen J; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L; Couch, Fergus J; Czene, Kamila; Daly, Mary B; Dos-Santos-Silva, IsabelORCID logo; Dwek, MiriamORCID logo; Eccles, Diana M; Ekici, Arif BORCID logo; Eriksson, Mikael; Evans, D Gareth; Fasching, Peter AORCID logo; Figueroa, JonineORCID logo; Flyger, Henrik; Fritschi, Lin; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Chi; Gapstur, Susan M; García-Closas, Montserrat; García-Sáenz, José A; Gaudet, Mia M; Giles, Graham G; Goldberg, Mark S; Goldgar, David E; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Håkansson, Niclas; Hall, Per; Hamann, Ute; Hartman, Mikael; Hauke, Jan; Hein, AlexanderORCID logo; Hillemanns, Peter; Hogervorst, Frans BL; Hooning, Maartje J; Hopper, John L; Howell, Tony; Huo, Dezheng; Ito, HidemiORCID logo; Iwasaki, Motoki; Jakubowska, Anna; Janni, Wolfgang; John, Esther M; Jung, Audrey; Kaaks, Rudolf; Kang, Daehee; Kapoor, Pooja Middha; Khusnutdinova, Elza; Kim, Sung-Won; Kitahara, Cari M; Koutros, Stella; Kraft, Peter; Kristensen, Vessela N; Kwong, Ava; Lambrechts, Diether; Marchand, Loic Le; Li, Jingmei; Lindström, Sara; Linet, Martha; Lo, Wing-Yee; Long, Jirong; Lophatananon, Artitaya; Lubiński, Jan; Manoochehri, Mehdi; Manoukian, Siranoush; Margolin, Sara; Martinez, Elena; Matsuo, KeitaroORCID logo; Mavroudis, Dimitris; Meindl, Alfons; Menon, UshaORCID logo; Milne, Roger LORCID logo; Mohd Taib, Nur Aishah; Muir, KennethORCID logo; Mulligan, Anna Marie; Neuhausen, Susan L; Nevanlinna, HeliORCID logo; Neven, Patrick; Newman, William GORCID logo; Offit, Kenneth; Olopade, Olufunmilayo I; Olshan, Andrew F; Olson, Janet E; Olsson, Håkan; Park, Sue K; Park-Simon, Tjoung-Won; Peto, JulianORCID logo; Plaseska-Karanfilska, Dijana; Pohl-Rescigno, Esther; Presneau, Nadege; Rack, Brigitte; Radice, Paolo; Rashid, Muhammad U; Rennert, GadORCID logo; Rennert, Hedy S; Romero, AtochaORCID logo; Ruebner, Matthias; Saloustros, Emmanouil; Schmidt, Marjanka KORCID logo; Schmutzler, Rita K; Schneider, Michael O; Schoemaker, Minouk J; Scott, ChristopherORCID logo; Shen, Chen-Yang; Shu, Xiao-Ou; Simard, Jacques; Slager, Susan; Smichkoska, Snezhana; Southey, Melissa C; Spinelli, John J; Stone, JenniferORCID logo; Surowy, Harald; Swerdlow, Anthony J; Tamimi, Rulla M; Tapper, William J; Teo, Soo H; Terry, Mary Beth; Toland, Amanda E; Tollenaar, Rob AEM; Torres, Diana; Torres-Mejía, Gabriela; Troester, Melissa A; Truong, ThérèseORCID logo; Tsugane, ShoichiroORCID logo; Untch, Michael; Vachon, Celine M; Ouweland, Ans MW van den; Veen, Elke M van; Vijai, Joseph; Wendt, Camilla; Wolk, Alicja; Yu, Jyh-Cherng; Zheng, Wei; Ziogas, ArgyriosORCID logo; Ziv, Elad; ABCTB Investigators; NBCS Collaborators; Dunning, Alison MORCID logo; Pharoah, Paul DPORCID logo; Schindler, Detlev; Devilee, PeterORCID logo; and Easton, Douglas FORCID logo (2019) Two truncating variants in FANCC and breast cancer risk. SCIENTIFIC REPORTS, 9 (1). 12524-. ISSN 2045-2322 DOI: 10.1038/s41598-019-48804-y
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Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.


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