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Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Weigelt, Britta and Comino-Méndez, Iñaki and de Bruijn, Ino and Tian, Lei and Meisel, Jane L. and García-Murillas, Isaac and Fribbens, Charlotte and Cutts, Ros and Martelotto, Luciano G. and Ng, Charlotte K. Y. and Lim, Raymond S. and Selenica, Pier and Piscuoglio, Salvatore and Aghajanian, Carol and Norton, Larry and Murali, Rajmohan and Hyman, David M. and Borsu, Laetitia and Arcila, Maria E. and Konner, Jason and Reis-Filho, Jorge S. and Greenberg, Roger A. and Robson, Mark E. and Turner, Nicholas C.. (2017) Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer. Clinical cancer research, 23 (21). pp. 6708-6720.

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Official URL: https://edoc.unibas.ch/68151/

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Abstract

Purpose:; Resistance to platinum-based chemotherapy or PARP inhibition in germline; BRCA1; or; BRCA2; mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether; BRCA1/2; reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or PARP inhibitors.; Experimental Design:; cfDNA from 24 prospectively accrued patients with germline; BRCA1; or; BRCA2; mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of; BRCA1; and; BRCA2; Functional studies were performed to assess the impact of the putative; BRCA1/2; reversion mutations on BRCA1/2 function.; Results:; Diverse and often polyclonal putative; BRCA1; or; BRCA2; reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%).; BRCA2; reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.; Conclusions:; Putative; BRCA1/2; reversion mutations can be detected by cfDNA sequencing analysis in patients with ovarian and breast cancer. Our findings warrant further investigation of cfDNA sequencing to identify putative; BRCA1/2; reversion mutations and to aid the selection of patients for PARP inhibition therapy.; Clin Cancer Res; 23(21); 6708-20. ©2017 AACR;.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Piscuoglio, Salvatore
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for Cancer Research
ISSN:1078-0432
e-ISSN:1557-3265
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:28 Jan 2019 14:17
Deposited On:28 Jan 2019 14:16

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