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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...

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Autores principales: Swami, Umang, Zimmerman, Raquel Mae, Nussenzveig, Roberto H., Hernandez, Edgar Javier, Jo, Yeonjung, Sayegh, Nicolas, Wesolowski, Sergiusz, Kiedrowski, Lesli A., Barata, Pedro C., Lemmon, Gordon Howard, Bilen, Mehmet A., Heath, Elisabeth I., Nandagopal, Lakshminarayan, Babiker, Hani M., Pal, Sumanta K., Lilly, Michael, Maughan, Benjamin L., Haaland, Benjamin, Yandell, Mark, Sartor, Oliver, Agarwal, Neeraj
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521349/
https://www.ncbi.nlm.nih.gov/pubmed/36185208
http://dx.doi.org/10.3389/fonc.2022.966534
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author Swami, Umang
Zimmerman, Raquel Mae
Nussenzveig, Roberto H.
Hernandez, Edgar Javier
Jo, Yeonjung
Sayegh, Nicolas
Wesolowski, Sergiusz
Kiedrowski, Lesli A.
Barata, Pedro C.
Lemmon, Gordon Howard
Bilen, Mehmet A.
Heath, Elisabeth I.
Nandagopal, Lakshminarayan
Babiker, Hani M.
Pal, Sumanta K.
Lilly, Michael
Maughan, Benjamin L.
Haaland, Benjamin
Yandell, Mark
Sartor, Oliver
Agarwal, Neeraj
author_facet Swami, Umang
Zimmerman, Raquel Mae
Nussenzveig, Roberto H.
Hernandez, Edgar Javier
Jo, Yeonjung
Sayegh, Nicolas
Wesolowski, Sergiusz
Kiedrowski, Lesli A.
Barata, Pedro C.
Lemmon, Gordon Howard
Bilen, Mehmet A.
Heath, Elisabeth I.
Nandagopal, Lakshminarayan
Babiker, Hani M.
Pal, Sumanta K.
Lilly, Michael
Maughan, Benjamin L.
Haaland, Benjamin
Yandell, Mark
Sartor, Oliver
Agarwal, Neeraj
author_sort Swami, Umang
collection PubMed
description 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.
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spelling pubmed-95213492022-09-30 Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA Swami, Umang Zimmerman, Raquel Mae Nussenzveig, Roberto H. Hernandez, Edgar Javier Jo, Yeonjung Sayegh, Nicolas Wesolowski, Sergiusz Kiedrowski, Lesli A. Barata, Pedro C. Lemmon, Gordon Howard Bilen, Mehmet A. Heath, Elisabeth I. Nandagopal, Lakshminarayan Babiker, Hani M. Pal, Sumanta K. Lilly, Michael Maughan, Benjamin L. Haaland, Benjamin Yandell, Mark Sartor, Oliver Agarwal, Neeraj Front Oncol Oncology 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 Media S.A. 2022-09-15 /pmc/articles/PMC9521349/ /pubmed/36185208 http://dx.doi.org/10.3389/fonc.2022.966534 Text en Copyright © 2022 Swami, Zimmerman, Nussenzveig, Hernandez, Jo, Sayegh, Wesolowski, Kiedrowski, Barata, Lemmon, Bilen, Heath, Nandagopal, Babiker, Pal, Lilly, Maughan, Haaland, Yandell, Sartor and Agarwal https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Swami, Umang
Zimmerman, Raquel Mae
Nussenzveig, Roberto H.
Hernandez, Edgar Javier
Jo, Yeonjung
Sayegh, Nicolas
Wesolowski, Sergiusz
Kiedrowski, Lesli A.
Barata, Pedro C.
Lemmon, Gordon Howard
Bilen, Mehmet A.
Heath, Elisabeth I.
Nandagopal, Lakshminarayan
Babiker, Hani M.
Pal, Sumanta K.
Lilly, Michael
Maughan, Benjamin L.
Haaland, Benjamin
Yandell, Mark
Sartor, Oliver
Agarwal, Neeraj
Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA
title Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA
title_full Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA
title_fullStr Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA
title_full_unstemmed Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA
title_short Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA
title_sort genomic landscape of advanced prostate cancer patients with brca1 versus brca2 mutations as detected by comprehensive genomic profiling of cell-free dna
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521349/
https://www.ncbi.nlm.nih.gov/pubmed/36185208
http://dx.doi.org/10.3389/fonc.2022.966534
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