Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse

Abstract BRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing w...

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Autores principales:	Shelly Sorrells, Kelly E. McKinnon, Ashleigh McBratney, Christopher Sumey
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/36355c8205f84120b0841747327b4cc3
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spelling	oai:doaj.org-article:36355c8205f84120b0841747327b4cc32021-12-02T10:59:46ZLongitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse10.1038/s41525-021-00181-02056-7944https://doaj.org/article/36355c8205f84120b0841747327b4cc32021-02-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00181-0https://doaj.org/toc/2056-7944Abstract BRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.Shelly SorrellsKelly E. McKinnonAshleigh McBratneyChristopher SumeyNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-6 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Shelly Sorrells Kelly E. McKinnon Ashleigh McBratney Christopher Sumey Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse
description	Abstract BRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.
format	article
author	Shelly Sorrells Kelly E. McKinnon Ashleigh McBratney Christopher Sumey
author_facet	Shelly Sorrells Kelly E. McKinnon Ashleigh McBratney Christopher Sumey
author_sort	Shelly Sorrells
title	Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse
title_short	Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse
title_full	Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse
title_fullStr	Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse
title_full_unstemmed	Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse
title_sort	longitudinal and multi-tissue molecular diagnostics track somatic brca2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/36355c8205f84120b0841747327b4cc3
work_keys_str_mv	AT shellysorrells longitudinalandmultitissuemoleculardiagnosticstracksomaticbrca2reversionmutationsthatcorrecttheopenreadingframeofgermlinealterationuponclinicalrelapse AT kellyemckinnon longitudinalandmultitissuemoleculardiagnosticstracksomaticbrca2reversionmutationsthatcorrecttheopenreadingframeofgermlinealterationuponclinicalrelapse AT ashleighmcbratney longitudinalandmultitissuemoleculardiagnosticstracksomaticbrca2reversionmutationsthatcorrecttheopenreadingframeofgermlinealterationuponclinicalrelapse AT christophersumey longitudinalandmultitissuemoleculardiagnosticstracksomaticbrca2reversionmutationsthatcorrecttheopenreadingframeofgermlinealterationuponclinicalrelapse
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Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse

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