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Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity

PURPOSE: BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline BRCA1/2 alterations (BRCA1/2-associated cancers: breast, ovarian, pa...

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Autores principales: Sokol, Ethan S., Pavlick, Dean, Khiabanian, Hossein, Frampton, Garrett M., Ross, Jeffrey S., Gregg, Jeffrey P., Lara, Primo N., Oesterreich, Steffi, Agarwal, Neeraj, Necchi, Andrea, Miller, Vincent A., Alexander, Brian, Ali, Siraj M., Ganesan, Shridar, Chung, Jon H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Clinical Oncology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446440/
https://www.ncbi.nlm.nih.gov/pubmed/32903788
http://dx.doi.org/10.1200/PO.19.00345
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author Sokol, Ethan S.
Pavlick, Dean
Khiabanian, Hossein
Frampton, Garrett M.
Ross, Jeffrey S.
Gregg, Jeffrey P.
Lara, Primo N.
Oesterreich, Steffi
Agarwal, Neeraj
Necchi, Andrea
Miller, Vincent A.
Alexander, Brian
Ali, Siraj M.
Ganesan, Shridar
Chung, Jon H.
author_facet Sokol, Ethan S.
Pavlick, Dean
Khiabanian, Hossein
Frampton, Garrett M.
Ross, Jeffrey S.
Gregg, Jeffrey P.
Lara, Primo N.
Oesterreich, Steffi
Agarwal, Neeraj
Necchi, Andrea
Miller, Vincent A.
Alexander, Brian
Ali, Siraj M.
Ganesan, Shridar
Chung, Jon H.
author_sort Sokol, Ethan S.
collection PubMed
description PURPOSE: BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline BRCA1/2 alterations (BRCA1/2-associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non–BRCA1/2-associated) cancer types, the association between BRCA1/2 alteration and HRD is less clear. METHODS: A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. RESULTS: BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2-associated and 37.2% of non–BRCA1/2-associated cancers. The fraction of BRCA1/2-altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2-associated (89.9%) versus non–BRCA1/2-associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency (BRCA1/2-associated cancers, 8.9%; non–BRCA1/2-associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2; predicted germline or somatic mutations were both associated with elevated gLOH. CONCLUSION: Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.
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spelling pubmed-74464402020-09-03 Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity Sokol, Ethan S. Pavlick, Dean Khiabanian, Hossein Frampton, Garrett M. Ross, Jeffrey S. Gregg, Jeffrey P. Lara, Primo N. Oesterreich, Steffi Agarwal, Neeraj Necchi, Andrea Miller, Vincent A. Alexander, Brian Ali, Siraj M. Ganesan, Shridar Chung, Jon H. JCO Precis Oncol Original Reports PURPOSE: BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline BRCA1/2 alterations (BRCA1/2-associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non–BRCA1/2-associated) cancer types, the association between BRCA1/2 alteration and HRD is less clear. METHODS: A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. RESULTS: BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2-associated and 37.2% of non–BRCA1/2-associated cancers. The fraction of BRCA1/2-altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2-associated (89.9%) versus non–BRCA1/2-associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency (BRCA1/2-associated cancers, 8.9%; non–BRCA1/2-associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2; predicted germline or somatic mutations were both associated with elevated gLOH. CONCLUSION: Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity. American Society of Clinical Oncology 2020-04-30 /pmc/articles/PMC7446440/ /pubmed/32903788 http://dx.doi.org/10.1200/PO.19.00345 Text en © 2020 by American Society of Clinical Oncology https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Reports
Sokol, Ethan S.
Pavlick, Dean
Khiabanian, Hossein
Frampton, Garrett M.
Ross, Jeffrey S.
Gregg, Jeffrey P.
Lara, Primo N.
Oesterreich, Steffi
Agarwal, Neeraj
Necchi, Andrea
Miller, Vincent A.
Alexander, Brian
Ali, Siraj M.
Ganesan, Shridar
Chung, Jon H.
Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity
title Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity
title_full Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity
title_fullStr Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity
title_full_unstemmed Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity
title_short Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity
title_sort pan-cancer analysis of brca1 and brca2 genomic alterations and their association with genomic instability as measured by genome-wide loss of heterozygosity
topic Original Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446440/
https://www.ncbi.nlm.nih.gov/pubmed/32903788
http://dx.doi.org/10.1200/PO.19.00345
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