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

Nikki L. Burdett, Madelynne O. Willis, Kathryn Alsop, Allison L. Hunt, Ahwan Pandey, Phineas T. Hamilton, Tamara Abulez, Xuan Liu, Therese Hoang, Stuart Craig, Sian Fereday, Joy Hendley, Dale W. Garsed, Katy Milne, Shreena Kalaria, Ashley Marshall, Brian L. Hood, Katlin N. Wilson, Kelly A. Conrads, Kathleen I. PishasSumitra Ananda, Clare L. Scott, Yoland Antill, Orla McNally, Linda Mileshkin, Anne Hamilton, George Au-Yeung, Lisa Devereux, Heather Thorne, Andrea Bild, Nicholas W. Bateman, G. Larry Maxwell, Jeffrey T. Chang, Thomas P. Conrads, Brad H. Nelson, David D.L. Bowtell, Elizabeth L. Christie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

Original languageEnglish
Pages (from-to)437-450
Number of pages14
JournalNature Genetics
Volume55
Issue number3
DOIs
StatePublished - Mar 2023
Externally publishedYes

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