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

• Published in: Oncotarget 2017-11, Vol.8 (60), p.101325-101332
• Main Authors: Ratajska, Magdalena, Koczkowska, Magdalena, Żuk, Monika, Gorczyński, Adam, Kuźniacka, Alina, Stukan, Maciej, Biernat, Wojciech, Limon, Janusz, Wasąg, Bartosz
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.20722

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