Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA.

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher's exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. These hypothesis-generating data may explain the differential response to PARP inhibition and guide towards the development of combinatorial drug regimens in those with BRCA1 mutation.

Frontiers in oncology. 2022 Sep 15*** epublish ***

Umang Swami, Raquel Mae Zimmerman, Roberto H Nussenzveig, Edgar Javier Hernandez, Yeonjung Jo, Nicolas Sayegh, Sergiusz Wesolowski, Lesli A Kiedrowski, Pedro C Barata, Gordon Howard Lemmon, Mehmet A Bilen, Elisabeth I Heath, Lakshminarayan Nandagopal, Hani M Babiker, Sumanta K Pal, Michael Lilly, Benjamin L Maughan, Benjamin Haaland, Mark Yandell, Oliver Sartor, Neeraj Agarwal

Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States., Human Genetics, University of Utah, Salt Lake City, UT, United States., Division of Oncology and Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States., Department of Medical Affairs, Guardant Health, Redwood City, CA, United States., Deming Department of Medicine, Section of Hematology/Oncology, Tulane University Medical School, New Orleans, LA, United States., Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States., Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States., Department of Medical Oncology, University of Alabama Medical Center, Birmingham, AL, United States., Department of Medical Oncology, Mayo Clinic Florida, Jacksonville, FL, United States., Genitourinary Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, United States., Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States., Tulane Cancer Center, Tulane Medical School, New Orleans, LA, United States.

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