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No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

2016; BMJ; Volume: 53; Issue: 5 Linguagem: Inglês

10.1136/jmedgenet-2015-103529

1468-6244

Douglas F. Easton, Fabienne Lesueur, Brennan Decker, Kyriaki Michailidou, Jun Li, Jamie Allen, Craig Luccarini, Karen A. Pooley, Mitul Shah, Manjeet K. Bolla, Sophia Wang, Joe Dennis, Jamil Ahmad, Ella R. Thompson, Francesca Damiola, Maroulio Pertesi, Catherine Voegele, Noura Mebirouk, Nivonirina Robinot, Geoffroy Durand, Nathalie Forey, Robert Luben, Shahana Ahmed, Kristiina Aittomäki, Hoda Anton‐Culver, Volker Arndt, Caroline Baynes, Matthias W. Beckman, Javier Benı́tez, David Van Den Berg, William J. Blot, Natalia Bogdanova, Stig E. Bojesen, Hermann Brenner, Jenny Chang‐Claude, Kee Seng Chia, Ji‐Yeob Choi, Don Conroy, Angela Cox, Simon S. Cross, Kamila Czene, Hatef Darabi, Peter Devilee, Mikael Eriksson, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Florentia Fostira, Montserrat García‐Closas, Graham G. Giles, Gord Glendon, Anna González‐Neira, Pascal Guénel, Christopher A. Haiman, Per Hall, Steven N. Hart, Mikael Hartman, Maartje J. Hooning, Chia‐Ni Hsiung, Hidemi Ito, Anna Jakubowska, Paul A. James, Esther M. John, Nichola Johnson, Michael E. Jones, Maria Kabisch, Daehee Kang, Veli‐Matti Kosma, Vessela Kristensen, Diether Lambrechts, Na Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jan Lubiński, Graham J. Mann, Siranoush Manoukian, Sara Margolin, Keitaro Matsuo, Alfons Meindl, Gillian Mitchell, Kenneth Muir, Ines Nevelsteen, Ans van den Ouweland, Paolo Peterlongo, Sze Yee Phuah, Katri Pylkäs, Simone M. Rowley, Suleeporn Sangrajrang, Rita K. Schmutzler, Chen‐Yang Shen, Xiao‐Ou Shu, Melissa C. Southey, Harald Surowy, Anthony J. Swerdlow, Soo‐Hwang Teo, Rob A.�E.�M. Tollenaar, Ian Tomlinson, Diana Torres, Thérèse Truong, Celine M. Vachon, Senno Verhoef, Michelle W. Wong‐Brown, Wei Zheng, Ying Zheng, Heli Nevanlinna, Rodney J. Scott, Irene L. Andrulis, Anna H. Wu, John L. Hopper, Fergus J. Couch, Robert Winqvist, Barbara Burwinkel, Elinor J. Sawyer, Marjanka K. Schmidt, Anja Rudolph, Thilo Dörk, Hiltrud Brauch, Ute Hamann, Susan L. Neuhausen, Roger L. Milne, Olivia Fletcher, Paul D.P. Pharoah, Ian Campbell, Alison M. Dunning, Florence Le Calvez‐Kelm, David E. Goldgar, Sean V. Tavtigian, Georgia Chenevix‐Trench,

Genomics and Rare Diseases

Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1 , and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.