Research Papers:

Detection of BRCA1/2 mutations in circulating tumor DNA from patients with ovarian cancer

Magdalena Ratajska, Magdalena Koczkowska, Monika Żuk, Adam Gorczyński, Alina Kuźniacka, Maciej Stukan, Wojciech Biernat, Janusz Limon and Bartosz Wasąg _

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Oncotarget. 2017; 8:101325-101332. https://doi.org/10.18632/oncotarget.20722

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Magdalena Ratajska1, Magdalena Koczkowska1, Monika Żuk1,2, Adam Gorczyński3, Alina Kuźniacka1,2, Maciej Stukan4, Wojciech Biernat3, Janusz Limon1,2 and Bartosz Wasąg1,2

1Department of Biology and Medical Genetics, Medical University of Gdansk, Gdansk, Poland

2Laboratory of Clinical Genetics, University Clinical Centre, Gdansk, Poland

3Department of Pathology, Medical University of Gdansk, Gdansk, Poland

4Department of Gynecologic Oncology, Gdynia Oncology Center, Gdynia, Poland

Correspondence to:

Bartosz Wasąg, email: bwasag@gumed.edu.pl

Keywords: ovarian cancer; ctDNA; BRCA1/2; PARP1 inhibitor; next-generation sequencing

Received: May 26, 2017     Accepted: July 31, 2017     Published: September 08, 2017


Approximately 25% of patients with ovarian cancer harbor a pathogenic BRCA1/2 mutation that has been associated with favorable responses for targeted therapy with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors compared to wild-type individuals. The overall frequency of germline and somatic BRCA1/2 alterations is estimated at 13-15% and 3-10%, respectively. A high incidence of BRCA1/2 somatic variants significantly increases the number of patients eligible for treatment with PARP1 inhibitors. Here, we assessed circulating tumor DNA (ctDNA) from 121 patients with ovarian cancer for BRCA1/2 mutational analysis by next generation sequencing. A total number of patients carrying the pathogenic BRCA1/2 variants was 30/121 (24.8%), including 22 and 7 individuals with exclusively germline or somatic mutations, respectively and one patient with variants of both origin. Among this cohort, more than one known pathogenic BRCA1 and/or BRCA2 alterations were identified in 7/30 individuals. The most recurrent mutations were detected in the BRCA1 gene: c.5266dupC (p.Gln1756Profs*74) with the frequency of ~18%, followed by c.3756_3759del (p.Ser1253Argfs*10) and c.181T>G (p.Cys61Gly). In seven (5.8%) patients, coincidence of two or more BRCA1/2 pathogenic mutations have been identified. Our results clearly demonstrate that the detection of both germline and somatic BRCA1/2 mutations in ctDNA from ovarian cancer patients is feasible and may be a valuable complementary tool for identification of somatic alterations when the standard diagnostic procedures are insufficient. Finally, ctDNA can potentially allow to monitor the efficacy of PARP1 inhibitors and to detect a secondary reversion BRCA1/2 mutations.

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