Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers
Authors: Wineland Dylane , Le Anh N. , Hausler Ryan , Kelly Gregory , Barrett Emanuel , Desai Heena , Wubbenhorst Bradley , Pluta John , Bastian Paul , Symecko Heather , D'Andrea Kurt , Doucette Abigail , Gabriel Peter , Reiss Kim A. , Nayak Anupma , Feldman Michael , Domchek Susan M. , Nathanson Katherine L. , Maxwell Kara N. ,   on behalf of Regeneron Genetics Center,   Penn Medicine Biobank, Mansfield Adam J. , Locke Adam , Poindexter Afiya , Shuldiner Alan , Li Alexander , Lopez Alexander , Hawes Alicia , Averitt Amelia , Damask Amy , Deubler Andrew , Ziyatdinov Andrey , Marcketta Anthony , Verma Anurag , Moscati Arden , Ayer Ariane , Baras Aris , Economides Aris , Ghosh Arkopravo , Brock Ashlei , Kloter Ashley , Rasool Ayesha , Guvenek Aysegul , Ye Bin , Zhang Blair , Boutkov Boris , Forsythe Caitlin , Sidore Carlo , Paulding Charles , Beechert Christina , Gillies Christopher , Morse Colleen , Li Dadong , Rader Daniel J. , Liu Daren , Sharma Deepika , Stahl Eli , Jorgenson Eric , Fuller Erin D. , Chen Esteban , Maxwell Evan K. , Vadivieso Fred , Tzoneva Gannie , Hindy George , Mitra George , Coppola Giovanni , Eom Gisu , Abecasis Goncalo , Kang Hyun Min , Kosmicki Jack , Hernandez Jaimee , Freudenberg Jan , Mighty Jason , Staples Jeffrey C. , Reid Jeffrey G. , Mbatchou Joelle , Weaver JoEllen , Overton John D. , Bovijn Jonas , Marchini Jonathan , Dunn Joseph , Backman Joshua , Rodriguez-Flores Juan , Siminovitch Katherine , Sun Kathie , Praveen Kavita , Hu-Sain Khadijah , Manoochehri Kia , Watanabe Kyoko , Gurski Lauren , Dobbyn Lee , Morrel Linda , Widom Louis , Lotta Luca A. , Habegger Lukas , Mitnaul Lyndon J. , Pradhan Manasi , Kapoor Manav , Ferreira Manuel Allen Revez , Jones Marcus B. , Padilla Maria Sotiropoulos , Risman Marjorie , Haas Mary , Ritchie Marylyn D. , Orelus Max , Livingstone Meghan , Cantor Michael , Feldman Michael D. , Kessler Michael , Lattari Michael , LeBlanc Michelle G. , Riaz Moeen , Nafde Mona , Rana Nadia , Lin Nan , Haubein Ned , Verweij Niek , Banerjee Nilanjana , Nishtala Nirupama , Krasheninina Olga , Sosina Olukayode , Akbari Parsa , Nakka Priyanka , Panea Razvan , Judy Renae , Ulloa Ricardo H. , Lanche Rouel , Gelfman Sahar , Malhotra Sameer , Wolf Sarah E. , Dudek Scott , O'Keeffe Sean , Khalid Shareef , Verma Shefali S. , Chen Siying , DerOhannessian Stephanie , Balasubramanian Suganthi , Gokhale Sujit , Bao Suying , De Tanima , Tran Teo , Drivas Theodore , Schleicher Thomas D. , Polanco Tommy , Rajagopal Veera , Salerno William , Bai Xiaodong , Ko Yi-An , Bradford Yuki , Gu Zhenhua 
Published: August 2023

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, mutation spectrum, tumor mutational burden, or microsatellite instability, were found in primary nonbreast/ovarian tumors with or without biallelic BRCA1/2 loss. CONCLUSION A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.