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Dörk T , Peterlongo P , Mannermaa A , Bolla MK , Wang Q , Dennis J , Ahearn T , Andrulis IL , Anton-Culver H , Arndt V , Aronson KJ , Augustinsson A , Freeman LEB , Beckmann MW , Beeghly-Fadiel A , Behrens S , Bermisheva M , Blomqvist C , Bogdanova NV , Bojesen SE , Brauch H , Brenner H , Burwinkel B , Canzian F , Chan TL , Chang-Claude J , Chanock SJ , Choi JY , Christiansen H , Clarke CL , Couch FJ , Czene K , Daly MB , Dos-Santos-Silva I , Dwek M , Eccles DM , Ekici AB , Eriksson M , Evans DG , Fasching PA , Figueroa J , Flyger H , Fritschi L , Gabrielson M , Gago-Dominguez M , Gao C , Gapstur SM , García-Closas M , García-Sáenz JA , Gaudet MM , Giles GG , Goldberg MS , Goldgar DE , Guénel P , Haeberle L , Haiman CA , Håkansson N , Hall P , Hamann U , Hartman M , Hauke J , Hein A , Hillemanns P , Hogervorst FBL , Hooning MJ , Hopper JL , Howell T , Huo D , Ito H , Iwasaki M , Jakubowska A , Janni W , John EM , Jung A , Kaaks R , Kang D , Kapoor PM , Khusnutdinova E , Kim SW , Kitahara CM , Koutros S , Kraft P , Kristensen VN , Kwong A , Lambrechts D , Marchand LL , Li J , Lindström S , Linet M , Lo WY , Long J , Lophatananon A , Lubiński J , Manoochehri M , Manoukian S , Margolin S , Martinez E , Matsuo K , Mavroudis D , Meindl A , Menon U , Milne RL , Mohd Taib NA , Muir K , Mulligan AM , Neuhausen SL , Nevanlinna H , Neven P , Newman WG , Offit K , Olopade OI , Olshan AF , Olson JE , Olsson H , Park SK , Park-Simon TW , Peto J , Plaseska-Karanfilska D , Pohl-Rescigno E , Presneau N , Rack B , Radice P , Rashid MU , Rennert G , Rennert HS , Romero A , Ruebner M , Saloustros E , Schmidt MK , Schmutzler RK , Schneider MO , Schoemaker MJ , Scott C , Shen CY , Shu XO , Simard J , Slager S , Smichkoska S , Southey MC , Spinelli JJ , Stone J , Surowy H , Swerdlow AJ , Tamimi RM , Tapper WJ , Teo SH , Terry MB , Toland AE , Tollenaar Raem , Torres D , Torres-Mejía G , Troester MA , Truong T , Tsugane S , Untch M , Vachon CM , Ouweland Amwvd , Veen EMV , Vijai J , Wendt C , Wolk A , Yu JC , Zheng W , Ziogas A , Ziv E , Dunning AM , Pharoah PDP , Schindler D , Devilee P , Easton DF
Two truncating variants in FANCC and breast cancer risk
Sci Rep. 2019 Aug 29;9(1) :12524
PMID: 31467304    PMCID: PMC6715680   
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Abstract
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.
Notes
2045-2322 Dörk, Thilo Peterlongo, Paolo Mannermaa, Arto Bolla, Manjeet K Wang, Qin Dennis, Joe Ahearn, Thomas Andrulis, Irene L Orcid: 0000-0002-4226-6435 Anton-Culver, Hoda Arndt, Volker Orcid: 0000-0001-9320-8684 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, Hiltrud Orcid: 0000-0001-7531-2736 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, Isabel Dwek, Miriam Orcid: 0000-0001-7184-2932 Eccles, Diana M Ekici, Arif B Orcid: 0000-0001-6099-7066 Eriksson, Mikael Evans, D Gareth Fasching, Peter A Orcid: 0000-0003-4885-8471 Figueroa, Jonine Orcid: 0000-0002-5100-623x 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, Alexander Orcid: 0000-0003-2601-3398 Hillemanns, Peter Hogervorst, Frans B L Hooning, Maartje J Hopper, John L Howell, Tony Huo, Dezheng Ito, Hidemi Orcid: 0000-0002-8023-4581 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, Keitaro Orcid: 0000-0003-1761-6314 Mavroudis, Dimitris Meindl, Alfons Menon, Usha Orcid: 0000-0003-3708-1732 Milne, Roger L Orcid: 0000-0001-5764-7268 Mohd Taib, Nur Aishah Muir, Kenneth Orcid: 0000-0001-6429-988x Mulligan, Anna Marie Neuhausen, Susan L Nevanlinna, Heli Orcid: 0000-0002-0916-2976 Neven, Patrick Newman, William G Orcid: 0000-0002-6382-4678 Offit, Kenneth Olopade, Olufunmilayo I Olshan, Andrew F Olson, Janet E Olsson, Håkan Park, Sue K Park-Simon, Tjoung-Won Peto, Julian Orcid: 0000-0002-1685-8912 Plaseska-Karanfilska, Dijana Pohl-Rescigno, Esther Presneau, Nadege Rack, Brigitte Radice, Paolo Rashid, Muhammad U Rennert, Gad Orcid: 0000-0002-8512-068x Rennert, Hedy S Romero, Atocha Orcid: 0000-0002-1634-7397 Ruebner, Matthias Saloustros, Emmanouil Schmidt, Marjanka K Orcid: 0000-0002-2228-429x Schmutzler, Rita K Schneider, Michael O Schoemaker, Minouk J Scott, Christopher Orcid: 0000-0003-1340-0647 Shen, Chen-Yang Shu, Xiao-Ou Simard, Jacques Slager, Susan Smichkoska, Snezhana Southey, Melissa C Spinelli, John J Stone, Jennifer Orcid: 0000-0001-5077-0124 Surowy, Harald Swerdlow, Anthony J Tamimi, Rulla M Tapper, William J Teo, Soo H Terry, Mary Beth Toland, Amanda E Tollenaar, Rob A E M Torres, Diana Torres-Mejía, Gabriela Troester, Melissa A Truong, Thérèse Orcid: 0000-0002-2943-6786 Tsugane, Shoichiro Orcid: 0000-0003-4105-2774 Untch, Michael Vachon, Celine M Ouweland, Ans M W van den Veen, Elke M van Vijai, Joseph Wendt, Camilla Wolk, Alicja Yu, Jyh-Cherng Zheng, Wei Ziogas, Argyrios Orcid: 0000-0003-4529-3727 Ziv, Elad ABCTB Investigators NBCS Collaborators Dunning, Alison M Orcid: 0000-0001-6651-7166 Pharoah, Paul D P Orcid: 0000-0001-8494-732x Schindler, Detlev Devilee, Peter Orcid: 0000-0002-8023-2009 Easton, Douglas F Orcid: 0000-0003-2444-3247 R01 CA148667/CA/NCI NIH HHS/United States R01 CA120120/CA/NCI NIH HHS/United States GPH-129344/CIHR/Canada C8221/A19170/CRUK_/Cancer Research UK/United Kingdom C5047/A10692/CRUK_/Cancer Research UK/United Kingdom C5047/A15007/CRUK_/Cancer Research UK/United Kingdom 1000143/MRC_/Medical Research Council/United Kingdom R01 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Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Sci Rep. 2019 Aug 29;9(1):12524. doi: 10.1038/s41598-019-48804-y.