Biallelic BRCA Loss and Homologous Recombination Deficiency in Nonbreast/Ovarian Tumors in Germline BRCA1/2 Carriers
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Published:2023-08
Issue:7
Volume:
Page:
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ISSN:2473-4284
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Container-title:JCO Precision Oncology
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language:en
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Short-container-title:JCO Precision Oncology
Author:
Wineland Dylane1, Le Anh N.2, Hausler Ryan2, Kelly Gregory2, Barrett Emanuel2ORCID, Desai Heena2, Wubbenhorst Bradley3ORCID, Pluta John3, Bastian Paul3, Symecko Heather2, D'Andrea Kurt3ORCID, Doucette Abigail4ORCID, Gabriel Peter45ORCID, Reiss Kim A.24, Nayak Anupma6, Feldman Michael6, Domchek Susan M.24ORCID, Nathanson Katherine L.347ORCID, Maxwell Kara N.247ORCID, 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, ,
Affiliation:
1. Arcadia University and Chester County Hospital, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 2. Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 3. Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 4. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 5. Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 6. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 7. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Abstract
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.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Cited by
6 articles.
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