Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer
Authors: Burdett Nikki L. , Willis Madelynne O. , Pandey Ahwan , Twomey Laura , Alaei Sara ,   Australian Ovarian Cancer Study Group,   Management Group, Bowtell D. , Chenevix-Trench G. , Green A. , Webb P. , DeFazio A. , Gertig D. ,   Project and Data Managers, Traficante N. , Fereday S. , Moore S. , Hung J. , Harrap K. , Sadkowsky T. , Pandeya N. ,   Research Nurses and Assistants, Bowes L. , Galletta L. , Giles D. , Hendley J. , Alsop K. , Alexander B. , Ashover P. , Brown S. , Corrish T. , Green L. , Jackman L. , Ferguson K. , Martin K. , Martyn A. , Ranieri B. , Malt M. , Chiew Y. E. , Stenlake A. , Sullivan H. , Mellon A. , Robertson R. , Bergh T. Vanden , Jones M. , Mackenzie P. , Maidens J. , Nattress K. , White J. , Jayde V. , Mamers P. , Schmidt T. , Shirley H. , Viduka S. , Tran H. , Bilic S. , Glavinas L. , Ball C. , Young C. , Brooks J. ,   Clinical and Scientific Collaborators, Mileshkin L. , Au-Yeung G. , Phillips K. , Rischin D. , Burdett N. , Delahunty R. , Christie E. , Garsed D. , Fox S. , Johnson D. , Lade S. , Loughrey M. , O’Callaghan N. , Murray W. , Purdie D. , Whiteman D. , Proietto A. , Braye S. , Otton G. , Camaris C. , Crouch R. , Edwards L. , Hacker N. , Marsden D. , Robertson G. , Bell D. , Baron-Hay S. , Ferrier A. , Gard G. , Nevell D. , Pavlakis N. , Valmadre S. , Young B. , Beale P. , Beith J. , Carter J. , Dalrymple C. , Houghton R. , Russell P. , Davy M. , Oehler M. K. , Hall C. , Dodd T. , Blomfield P. , Challis D. , McIntosh R. , Parker A. , Healy D. , Jobling T. , Manolitsas T. , McNealage J. , Rogers P. , Susil B. , Sumithran E. , Simpson I. , Zeps N. , Hammond I. , Leung Y. , McCartney A. , Stuart-Harris R. , Kirsten F. , Rutovitz J. , Clingan P. , Shannon J. , Bonaventura T. , Stewart J. , Begbie S. , Glasgow A. , Friedlander M. , Links M. , Grygiel J. , Hill J. , Brand A. , Byth K. , Harnett P. , Wain G. , Jaworski R. , Sharma R. , Ward B. , Papadimos D. , Crandon A. , Cummings M. , Horwood K. , Obermair A. , Perrin L. , Wyld D. , Nicklin J. , Healy T. , Pittman K. , Henderson D. , Miller J. , Pierdes J. , Brown B. , Rome R. , Allen D. , Grant P. , Hyde S. , Laurie R. , Robbie M. , Waring P. , Billson V. , Pyman J. , Neesham D. , Quinn M. , Underhill C. , Bell R. , Ng L. F. , Blum R. , Ganju V. , Buck M. , Haviv I. , Bowtell David D. L. , Christie Elizabeth L. 
Published: July 2024

Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting.