New Challenges in Tumor Mutation Heterogeneity in Advanced Ovarian Cancer by a Targeted Next-Generation Sequencing (NGS) Approach

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Abstract

Next-generation sequencing (NGS) technology has advanced knowledge of the genomic landscape of ovarian cancer, leading to an innovative molecular classification of the disease. However, patient survival and response to platinum-based treatments are still not predictable based on the tumor genetic profile. This retrospective study characterized the repertoire of somatic mutations in advanced ovarian cancer to identify tumor genetic markers predictive of platinum chemo-resistance and prognosis. Using targeted NGS, 79 primary advanced (III-IV stage, tumor grade G2-3) ovarian cancer tumors, including 64 high-grade serous ovarian cancers (HGSOCs), were screened with a 26 cancer-genes panel. Patients, enrolled between 1995 and 2011, underwent primary debulking surgery (PDS) with optimal residual disease (RD <1 cm) and platinum-based chemotherapy as first-line treatment. We found a heterogeneous mutational landscape in some uncommon ovarian histotypes and in HGSOC tumor samples with relevance in predicting platinum sensitivity. In particular, we identified a poor prognostic signature in patients with HGSOC harboring concurrent mutations in two driver actionable genes of the panel. The tumor heterogeneity described, sheds light on the translational potential of targeted NGS approach for the identification of subgroups of patients with distinct therapeutic vulnerabilities, that are modulated by the specific mutational profile expressed by the ovarian tumor.
Original languageEnglish
Article number584
Number of pages23
JournalCells
Volume8
Issue number6
DOIs
Publication statusPublished - Jun 14 2019

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Keywords

  • *HGSOC
  • *NGS
  • *TP53
  • *advanced ovarian cancer
  • *concurrent somatic mutations
  • *driver actionable genes
  • *platinum sensitivity
  • *translational medicine
  • *tumor profile
  • Adult
  • Aged
  • Aged, 80 and over
  • Cystadenocarcinoma, Serous/drug therapy/genetics/pathology
  • Female
  • *Genetic Heterogeneity
  • High-Throughput Nucleotide Sequencing/*methods
  • Humans
  • Middle Aged
  • Mutation/*genetics
  • Mutation Rate
  • Neoplasm Staging
  • Ovarian Neoplasms/drug therapy/*genetics/*pathology
  • Platinum/therapeutic use
  • Treatment Outcome
  • Tumor Suppressor Protein p53/genetics

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