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Whole-genome characterization of chemoresistant ovarian cancer

Ann-Marie Patch1, Elizabeth L Christie2, Dariush Etemadmoghadam3

  • 11] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.

Nature
|May 29, 2015
PubMed

Insights

High-grade serous ovarian cancer (HGSC) shows little survival improvement. Whole-genome sequencing reveals gene breakage inactivates tumor suppressors and contributes to chemotherapy resistance, with CCNE1 amplification in primary resistant disease.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • High-grade serous ovarian cancer (HGSC) has seen minimal survival improvements over 30 years, with platinum-based chemotherapy remaining the standard treatment.
  • Understanding the molecular underpinnings of treatment resistance is crucial for advancing HGSC patient outcomes.

Purpose of the Study:

  • To investigate the genomic drivers of clinical phenotypes in HGSC, focusing on primary resistance and acquired resistance to chemotherapy.
  • To identify specific genetic alterations associated with treatment failure and resistance mechanisms in HGSC.

Main Methods:

  • Whole-genome sequencing of tumor and germline DNA from 92 patients with primary refractory, resistant, sensitive, and acquired resistant HGSC.
  • Analysis of genetic alterations including gene breakage, copy number variations, and promoter alterations.

Main Results:

  • Gene breakage frequently inactivates tumor suppressors (RB1, NF1, RAD51B, PTEN) in HGSC, contributing to acquired chemotherapy resistance.
  • CCNE1 amplification was prevalent in primary resistant and refractory HGSC.
  • Acquired resistance mechanisms included BRCA1/BRCA2 reversion mutations, loss of BRCA1 promoter methylation, molecular subtype alterations, and MDR1 overexpression via promoter fusion.

Conclusions:

  • Genomic instability and specific genetic alterations like CCNE1 amplification are key drivers of primary resistance in HGSC.
  • Multiple distinct molecular events contribute to the development of acquired chemotherapy resistance in HGSC patients.
  • These findings provide insights into HGSC heterogeneity and potential therapeutic targets for overcoming treatment resistance.

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