Homologous recombination DNA repair defects in PALB2-associated breast cancers

作者：Anqi Li, Felipe Correa Geyer, Pedro Blecua, Ju Youn Lee, Pier Selenica, David N. Brown, Fresia G. Pareja, Simon Lee, Rahul Kumar, Bárbara Rivera, Rui Bi, Salvatore Piscuoglio, Hannah Yong Wen, John R. Lozada, Rodrigo Gularte‐Mérida, Luca Cavallone, Zoulikha Rezoug, Tú Nguyen‐Dumont, Paolo Peterlongo, Carlo Alberto Tondini, Thorkild Terkelsen, Karina Rønlund, Susanne E. Boonen, Arto Mannerma, Robert Winqvist, Markéta Janatová, Pathmanathan Rajadurai, Bing Xia, Larry Norton, Mark E. Robson, Pei-Sze Ng, Lai‐Meng Looi, Melissa C. Southey, Britta Weigelt, Teo Soo-Hwang, Marc D. Tischkowitz, William David Foulkes, Jorge Sergio Reis-Filho, kConFab Investigators, Morteza Aghmesheh, David J. Amor, Leslie R. Andrews, Yoland Catherine Antill, Rosemary L. Balleine, Jonathan Beesley, Anneke C. Blackburn, Michael R. Bogwitz, Melissa Brown, Matthew Burgess, Jo Burke, Phyllis Nancy Butow, Liz Caldon, Ian Campbell, Alice Christian, Christine L. Clarke, Paul Andrew Cohen, Ashley Crook, James Cui, Margaret C. Cummings, Sarah‐Jane Dawson, Anna de Fazio, Martin Bruce Delatycki, Alexander Dobrovic, Tracy E Dudding, Pascal H. G. Duijf, Edward Edkins, Stacey L. Edwards, Gelareh Farshid, Andrew Fellows, Michael J. Field, James M. Flanagan, Peter C.C. Fong, John Forbes, Laura Elenor Forrest, Stephen B. Fox, Juliet D. French, Michael Leonard Friedlander, David Gallego‐Ortega, Michael R. Gattas, Graham G. Giles, Grantley Gill, Margaret A. Gleeson, Sian Greening, Eric Haan, Marion Harris, Nick Hayward, Ian Bernard Hickie, John Llewelyn Hopper, Clare Elizabeth Hunt, Paul Andrew James, Mark A. Jenkins, Rick Kefford, Maira Kentwell, Judy Kirk, James Kollias, Sunil R. Lakhani, Geoffrey J. Lindeman, Lara Rachel Lipton, Lizz Lobb, Sheau Wen Lok, Finlay Macrea, Graham J. Mann, Deb Marsh, Sue‐Anne McLachlan, Bettina Meiser, Roger Laughlin Milne, Sophie S. Nightingale, Shona O’Connell, Nick Pachter, Briony Patterson, Kelly Phillips, Mona Saleh, Elizabeth Salisbury, Christobel Mary Saunders, Jodi M. Saunus, Clare L. Scott, Rodney J. Scott, Adrienne Sexton, Andrew Neil Shelling, Peter T. Simpson, Allan D. Spigelman, Mandy Spurdle, Jennifer L. Stone, Jessica Averitt Taylor, Heather Thorne, Alison H. Trainer, Georgia Chenevix‐Trench, Kathy Tucker, Jane E. Visvader, Logan C. Walker, Mathew Wallis, Rachael Williams, Ingrid Winship, Kathy H. C. Wu, Mary Anne Young · 发表于：npj Breast Cancer · 年份：2019 · DOI：10.1038/s41523-019-0115-9 · 被引用次数：59 · 研究领域：DNA Repair Mechanisms、BRCA gene mutations in cancer、Cancer Genomics and Diagnostics

Abstract Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that...