Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer

作者：Amandine Billaud, Gisella Figlioli, Clémence Mooser, Irene Casamassima, Violette Azzoni, Jahnavi Srivatsa, Mara Colombo, Laura Caleca, Thomas U. Ahearn, Irene L. Andrulis, Antonis C. Antoniou, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Natalia Bogdanova, Manjeet K. Bolla, Bernardo Bonanni, Thomas Brüning, Nicola J. Camp, Archie Campbell, Jose E. Castelao, Melissa H. Cessna, Jenny Chang‐Claude, Kamila Czene, Joe Dennis, Peter Devilee, Thilo Dörk, Alison Dunning, Mikael Eriksson, Gareth Evans, Peter Fasching, Jonine Figueroa, Marike Gabrielson, Manuela Gago-Domínguez, Anna González‐Neira, Pascal Guénel, Andreas Hadjisavvas, E Hahnen, Ute Hamann, Peter Hillemanns, Antoinette Hollestelle, Maartje Hooning, Reiner Hoppe, A H Howell, Reiner Hoppe, A H Howell, Anna Jakubowska, Vessela N. Kristensen, Jan Lubiński, Michael Lush, Siranoush Manoukian, Dimitrios Mavroudis, Roger Milne, Anna Marie Mulligan, William Newman, Nadia Obi, Mihalis Panyiotidis, Guillermo Pita, Muhammad Usman Rashid, Valerie Rhenius, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Mitul Shah, Melissa C. Southey, Amanda Spurdle, Ian Tomlinson, Thérèse Truong, Qin Wang, Camilla Wendt, Paul L. Auer, Nicholas Boddicker, Clara Bodelón, Elizabeth S. Burnside, Fei Chen, Fergus Couch, Susan M. Domchek, Heather Eliassen, Christopher Haiman, James M. Hodge, Chunling Hu, Hongyan Huang, Sara Lindström, Maria Elena Martinez, Katherine L. Nathanson, Susan L. Neuhausen, Katie O´Brien, Janet E. Olson, Julie R. Palmer, Alpa V. Patel, Kathryn J. Ruddy, Dale P. Sandler, Lauren R. Teras, Clarice R. Weinberg, Jeffrey N. Weitzel, Stacey J. Winham, Siddhartha Yadav, Song Yao, Gary Zirpoli, Markéta Janatová, Zdeněk Kleibl, Petra Kleiblová, Jana Soukupová, Qihong Zhao, Lisa Devereux, Paul James, Ian Campbell, Tú Nguyen‐Dumont, James Dowty, Nadine Andrieu, Fabienne Lesueur, Dominique Stoppa-Lyonnet, M de la Hoya, Paolo Radice, Claus Storgaard Sorensen, Paolo Radice · 发表于：Apollo (University of Cambridge) · 年份：2026 · DOI：10.5281/zenodo.21452936 · 研究领域：BRCA gene mutations in cancer、Genetically Modified Organisms Research

The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing.