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 Pishas; Sumitra 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

doi:10.1038/s41588-023-01320-2

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

Nat Genet. 2023 Mar;55(3):437-450. doi: 10.1038/s41588-023-01320-2. Epub 2023 Feb 27.

Authors

Nikki L Burdett^{1

2

3}, Madelynne O Willis¹, Kathryn Alsop^{1

2}, Allison L Hunt^{4

5}, Ahwan Pandey¹, Phineas T Hamilton⁶, Tamara Abulez^{5

7}, Xuan Liu⁸, Therese Hoang¹, Stuart Craig¹, Sian Fereday^{1

2}, Joy Hendley¹, Dale W Garsed^{1

2}, Katy Milne⁶, Shreena Kalaria⁶, Ashley Marshall⁶, Brian L Hood^{5

7}, Katlin N Wilson^{5

7}, Kelly A Conrads^{5

7}, Kathleen I Pishas^{1

2}, Sumitra Ananda^{1

9

10

11}, Clare L Scott^{1

12}, Yoland Antill^{13

14

15}, Orla McNally^{16

17}, Linda Mileshkin^{1

2}, Anne Hamilton^{1

2

16}, George Au-Yeung^{1

2}, Lisa Devereux^{1

2}, Heather Thorne^{1

2}, Andrea Bild¹⁸, Nicholas W Bateman^{5

7

19}, G Larry Maxwell^{4

5

19}, Jeffrey T Chang⁸, Thomas P Conrads^{5

7

19}, Brad H Nelson^{6

20

21}, David D L Bowtell^{1

2}, Elizabeth L Christie^{22

23}

Affiliations

¹ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
² Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
³ Department of Medical Oncology, Eastern Health, Box Hill, Victoria, Australia.
⁴ Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Annandale, Victoria, USA.
⁵ Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA.
⁶ Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada.
⁷ The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
⁸ Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, TX, USA.
⁹ Department of Medical Oncology, Western Health, St Albans, Victoria, Australia.
¹⁰ Department of Medicine, Western Health, The University of Melbourne, St Albans, Victoria, Australia.
¹¹ Epworth Healthcare, East Melbourne, Victoria, Australia.
¹² Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
¹³ Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
¹⁴ Cabrini Health, Malvern, Victoria, Australia.
¹⁵ Department of Medical Oncology, Peninsula health, Frankston, Victoria, Australia.
¹⁶ The Royal Women's Hospital, Parkville, Victoria, Australia.
¹⁷ Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁸ Department of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.
¹⁹ The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, Bethesda, MD, USA.
²⁰ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
²¹ Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
²² Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. [email protected].
²³ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. [email protected].

PMID: 36849657
DOI: 10.1038/s41588-023-01320-2

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Ovarian Epithelial
Cystadenocarcinoma, Serous* / genetics
Female
Homologous Recombination / genetics
Humans
Multiomics
Ovarian Neoplasms* / genetics

Abstract

Publication types

MeSH terms

Grants and funding