Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers

作者：Dylane Wineland, Anh N. Le, Ryan Hausler, Gregory J. Kelly, Emanuel Barrett, Heena Desai, Bradley Wubbenhorst, John Pluta, Paul Bastian, Heather Symecko, Kurt D’Andrea, Abigail Doucette, Peter Gabriel, Kim A. Reiss, Anupma Nayak, Michael D. Feldman, Susan M. Domchek, Katherine L. Nathanson, Kara N. Maxwell, Penn Medicine Biobank, Adam J. Mansfield, Adam E. Locke, Afiya Poindexter, Alan R. Shuldiner, Alexander Li, Alexander Lopez, Alicia Hawes, Amelia Averitt, Amy Damask, Andrew Deubler, Andrey Ziyatdinov, Anthony Marcketta, Anurag Verma, Arden Moscati, Ariane Ayer, Aris Baras, Aris N. Economides, Arkopravo Ghosh, Ashlei Brock, Ashley Kloter, Ayesha Rasool, Ayşegül Güvenek, Bin Ye, Blair Zhang, Boris Boutkov, Caitlin Forsythe, Carlo Sidore, Charles Paulding, Christina Beechert, Christopher E. Gillies, Colleen Morse, Dadong Li, Daniel J. Rader, Daren Liu, Deepika Sharma, Eli A. Stahl, Eric Jorgenson, Erin D. Fuller, Esteban Chen, Evan K. Maxwell, Fred Vadivieso, Gannie Tzoneva, George Hindy, George Mitra, Giovanni Coppola, Gisu Eom, Gonçalo R. Abecasis, Hyun Min Kang, Jack A. Kosmicki, Jaimee Hernandez, Jan Freudenberg, Jason Mighty, Jeffrey Staples, Jeffrey G. Reid, Joelle Mbatchou, JoEllen Weaver, John D. Overton, Jonas Bovijn, Jonathan Marchini, Joseph Dunn, Joshua Backman, Juan Rodriguez-Flores, Katherine Siminovitch, Kathie Sun, Kavita Praveen, K D Husain, Kia Manoochehri, Kyoko Watanabe, Lauren Gurski, Lee Dobbyn, Linda Morrel, Louis Widom, Luca A. Lotta, Lukas Habegger, Lyndon J. Mitnaul, Manasi Pradhan, Manav Kapoor, Manuel Allen Revez Ferreira, Marcus B. Jones, Maria Sotiropoulos Padilla, Marjorie Risman, Mary E. Haas, Marylyn D. Ritchie, Max Orelus, Meghan Livingstone, Michael Cantor, Michael D. Feldman, Michael D. Kessler, Michael Lattari, Michelle G. LeBlanc, Moeen Riaz, Mona Nafde, Nadia Rana, Nan Lin, Ned Haubein, Niek Verweij, Nilanjana Banerjee, Nirupama Nishtala, Olga Krasheninina, Olukayode Sosina, Parsa Akbari, Priyanka Nakka, Razvan Panea, Renae Judy, Ricardo H. Ulloa, Rouel Lanche, Sahar Gelfman, Sameer Malhotra, Sarah E. Wolf, Scott Dudek, Sean O’Keeffe, Shareef Khalid, Shefali S. Verma, Siying Chen, Stephanie DerOhannessian, Suganthi Balasubramanian, Sujit Gokhale, Suying Bao, Tanima De, Teo Tran, Theodore G. Drivas, Thomas D. Schleicher, Tommy Polanco, Veera M. Rajagopal, William Salerno, Xiaodong Bai, Yi-An Ko, Yuki Bradford, Zhenhua Gu · 发表于：JCO Precision Oncology · 年份：2023 · DOI：10.1200/po.23.00036 · 被引用次数：13 · 研究领域：PARP inhibition in cancer therapy、BRCA gene mutations in cancer、CRISPR and Genetic Engineering

PURPOSE Breast and ovarian tumors in germline BRCA1/2 carriers undergo allele-specific loss of heterozygosity, resulting in homologous recombination deficiency (HRD) and sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. This study investigated whether biallelic loss and HRD also occur in primary nonbreast/ovarian tumors that arise in germline BRCA1/2 carriers. METHODS A clinically ascertained cohort of BRCA1/2 carriers with a primary nonbreast/ovarian cancer was identified, including canonical (prostate and pancreatic cancers) and noncanonical (all other) tumor types. Whole-exome sequencing or clinical sequencing results (n = 45) were analyzed. A pan-cancer analysis of nonbreast/ovarian primary tumors from germline BRCA1/2 carriers from The Cancer Genome Atlas (TCGA, n = 73) was used as a validation cohort. RESULTS Ages of nonbreast/ovarian cancer diagnosis in germline BRCA1/2 carriers were similar to controls for the majority of cancer types. Nine of 45 (20%) primary nonbreast/ovarian tumors from germline BRCA1/2 carriers had biallelic loss of BRCA1/2 in the clinical cohort, and 23 of 73 (32%) in the TCGA cohort. In the combined cohort, 35% and 27% of primary canonical and noncanonical BRCA tumor types, respectively, had biallelic loss. High HRD scores (HRDex > 42) were detected in 81% of tumors with biallelic BRCA loss compared with 22% ( P < .001) of tumors without biallelic BRCA loss. No differences in genomic profile, including mutational signatures, mut...