Two truncating variants in FANCC and breast cancer risk.

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.

• Authors: Thilo Dörk, Paolo Peterlongo, Arto Mannermaa, Manjeet K Bolla, Qin Wang, Joe Dennis, Thomas Ahearn, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J Aronson, Annelie Augustinsson, Laura E Beane Freeman, Matthias W Beckmann, Alicia Beeghly-Fadiel, Sabine Behrens, Marina Bermisheva, Carl Blomqvist, Natalia V Bogdanova, Stig E Bojesen, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Federico Canzian, Tsun L Chan, Jenny Chang-Claude, Stephen J Chanock, Ji-Yeob Choi, Hans Christiansen, Christine L Clarke, Fergus J Couch, Kamila Czene, Mary B Daly, Isabel Dos-Santos-Silva, Miriam Dwek, Diana M Eccles, Arif B Ekici, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Jonine Figueroa, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Chi Gao, Susan M Gapstur, Montserrat García-Closas, José A García-Sáenz, Mia M Gaudet, Graham G Giles, Mark S Goldberg, David E Goldgar, Pascal Guénel, Lothar Haeberle, Christopher A Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Mikael Hartman, Jan Hauke, Alexander Hein, Peter Hillemanns, Frans B L Hogervorst, Maartje J Hooning, John L Hopper, Tony Howell, Dezheng Huo, Hidemi Ito, Motoki Iwasaki, Anna Jakubowska, Wolfgang Janni, Esther M John, Audrey Jung, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Elza Khusnutdinova, Sung-Won Kim, Cari M Kitahara, Stella Koutros, Peter Kraft, Vessela N Kristensen, Ava Kwong, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Sara Lindström, Martha Linet, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Jan Lubiński, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Elena Martinez, Keitaro Matsuo, Dimitris Mavroudis, Alfons Meindl, Usha Menon, Roger L Milne, Nur Aishah Mohd Taib, Kenneth Muir, Anna Marie Mulligan, Susan L Neuhausen, Heli Nevanlinna, Patrick Neven, William G Newman, Kenneth Offit, Olufunmilayo I Olopade, Andrew F Olshan, Janet E Olson, Håkan Olsson, Sue K Park, Tjoung-Won Park-Simon, Julian Peto, Dijana Plaseska-Karanfilska, Esther Pohl-Rescigno, Nadege Presneau, Brigitte Rack, Paolo Radice, Muhammad U Rashid, Gad Rennert, Hedy S Rennert, Atocha Romero, Matthias Ruebner, Emmanouil Saloustros, Marjanka K Schmidt, Rita K Schmutzler, Michael O Schneider, Minouk J Schoemaker, Christopher Scott, Chen-Yang Shen, Xiao-Ou Shu, Jacques Simard, Susan Slager, Snezhana Smichkoska, Melissa C Southey, John J Spinelli, Jennifer Stone, Harald Surowy, Anthony J Swerdlow, Rulla M Tamimi, William J Tapper, Soo H Teo, Mary Beth Terry, Amanda E Toland, Rob A E M Tollenaar, Diana Torres, Gabriela Torres-Mejía, Melissa A Troester, Thérèse Truong, Shoichiro Tsugane, Michael Untch, Celine M Vachon, Ans M W van den Ouweland, Elke M van Veen, Joseph Vijai, Camilla Wendt, Alicja Wolk, Jyh-Cherng Yu, Wei Zheng, Argyrios Ziogas, Elad Ziv, ABCTB Investigators, NBCS Collaborators, Alison M Dunning, Paul D P Pharoah, Detlev Schindler, Peter Devilee, Douglas F Easton
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 12524 (08 29 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31467304 (Publication Type: Journal Article, 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.)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• FANCC protein, human
• Fanconi Anemia Complementation Group C Protein

Topics

• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Breast Neoplasms (genetics, metabolism)
• Case-Control Studies
• Fanconi Anemia (genetics)
• Fanconi Anemia Complementation Group C Protein (genetics, metabolism)
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Humans
• Sequence Deletion