Somatic Variants in DNA Damage Response Genes in Ovarian Cancer Patients Using Whole-exome Sequencing

• Published in: Anticancer research Vol. 43; no. 5; pp. 1891 - 1900
• Main Authors: Lopacinska-Joergensen, Joanna, Oliveira, Douglas V N P, Poulsen, Tim Svenstrup, Hoegdall, Claus K, Hoegdall, Estrid V
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.05.2023
• Subjects: Adenocarcinoma; Adenosine diphosphate; Biomarkers; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Breast cancer; Cancer; Chemotherapy; Clinical trials; Damage; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; Exome Sequencing; Female; Genes; Genomes; Health services; Homologous recombination; Humans; Nucleotides; Ovarian cancer; Ovarian Neoplasms - pathology; p53 Protein; Patients; Platinum; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Ribose; Somatic variants; DNA damage response; ovarian cancer
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.16348

Several clinical trials have investigated homologous recombination deficiency and BRCA1/2 status to select ovarian cancer patients for treatment with poly(ADP-ribose) polymerase-inhibitors (PARPi), but less attention has been given to other DNA-damage response (DDR) pathways. Therefore, we investigated somatic single/multiple nucleotide variants and small insertions/deletions in exonic and splice-site regions of 356 DDR genes to examine whether genes other than BRCA1/2 are altered. Whole-exome sequencing data from eight high-grade serous adenocarcinoma (HGSC) and four clear cell carcinoma (oCCC) patients were analyzed. Forty-two variants (pathogenic, likely pathogenic or variants of uncertain significance) in 28 genes from DDR pathways were identified. Seven out of nine TP53 variants were previously described in The Cancer Genome Atlas Ovarian Cancer; other variants were found in 23 out of 28 unique genes, whereas no variants were reported in FAAP24, GTF2H4, POLE4, RPA3, and XRCC4. As the identified variants were not only limited to well-known TP53, BRCA1/2, and HR-associated genes, our study might contribute to the better understanding of which DDR pathways potentially influence disease progression. Moreover, they may display a potential role as biomarkers to predict platinum-based chemotherapy or PARPi treatment response or disease progression, as differences in disrupted DDR pathways were observed between patients with long and short overall survival in HGSC and oCCC groups.