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Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer

Nikki L Burdett1,2,3, Madelynne O Willis1, Kathryn Alsop1,2

  • 1Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Nature Genetics
|February 28, 2023
PubMed

Insights

High-grade serous ovarian cancer (HGSC) with DNA repair defects often develops resistance to treatment. This study reveals diverse resistance mechanisms and immune escape in advanced HGSC, explaining treatment failure.

Area of Science:

  • Oncology
  • Genomics
  • Cancer Biology

Background:

  • High-grade serous ovarian cancer (HGSC) frequently exhibits homologous recombination (HR) DNA repair deficiency.
  • While initially sensitive to treatment, acquired resistance is a significant challenge in managing HGSC.

Purpose of the Study:

  • To investigate the molecular diversity and resistance mechanisms in end-stage, HR-deficient HGSC.
  • To understand the evolutionary trajectory of HGSC in the context of treatment resistance.

Main Methods:

  • Multiomics analysis of multiple autopsy samples from 15 women with HR-deficient HGSC.
  • Characterization of tumor heterogeneity, resistance mechanisms, and immune microenvironment.

Main Results:

  • Identified polyclonal disease with multiple resistance mechanisms within individual patients.
  • Observed reversion mutations, alternative HR restoration pathways, frequent whole-genome duplication, and immune escape.
  • Demonstrated significant global changes in immune cell composition.

Conclusions:

  • HGSC evolves through diverse mechanisms to evade therapy, leading to treatment failure.
  • Understanding these evolutionary changes is crucial for developing effective therapeutic strategies against advanced HGSC.

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