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

Abstract

Approximately 25% of patients with ovarian cancer harbor a pathogenic <i>BRCA1/2</i> 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 <i>BRCA1/2</i> alterations is estimated at 13-15% and 3-10%, respectively. A high incidence of <i>BRCA1/2</i> 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 <i>BRCA1/2</i> mutational analysis by next generation sequencing. A total number of patients carrying the pathogenic <i>BRCA1/2</i> 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 <i>BRCA1</i> and/or <i>BRCA2</i> alterations were identified in 7/30 individuals. The most recurrent mutations were detected in the <i>BRCA1</i> 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 <i>BRCA1/2</i> pathogenic mutations have been identified. Our results clearly demonstrate that the detection of both germline and somatic <i>BRCA1/2</i> 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 <i>BRCA1/2</i> mutations.