Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer
Nikki Burdett, Madelynne O. Willis, Ahwan Pandey, Laura Twomey, Sara Alaei, Australian Ovarian Cancer Study Group, Management Group, David D.L. Bowtell, Georgia Chenevix‐Trench, A Green, Penelope M. Webb, A. DeFazio, Dorota M. Gertig, Project and Data Managers, Nadia Traficante, Sián Fereday, Sue Moore, Jillian A. Hung, K.R. Harrap, T. Sadkowsky, Nirmala Pandeya, Leanne Bowes, Laura Galletta, Daniel A. Giles, Joy Hendley, Kathryn Alsop, B. Alexander, P. Ashover, Scott D. Brown, T. Corrish, Laura Green, L. M. Jackman, Kaltin Ferguson, Karla Martin, A. Martyn, B. Ranieri, M. Malt, Yoke-Eng Chiew, Annie Stenlake, Harold C. Sullivan, A. Mellon, R. Paul Robertson, T. Vanden Bergh, Michelle R. Jones, P. Mackenzie, J. Maidens, K. Nattress, Jeff White, V. Jayde, Pamela Mamers, Thomas Schmidt, H. Shirley, S. Viduka, Hang Tran, Sanela Bilic, Lydia Glavinas, C. Ball, Christian D. Young, Julia Brooks, Linda Mileshkin, George Au‐Yeung, Kelly‐Anne Phillips, Danny Rischin, Nikki Burdett, Rachel Delahunty, Elizabeth L. Christie, Dale W. Garsed, Stephen B. Fox, Daryl Johnson, Stephen Lade, Maurice B. Loughrey, N. O’Callaghan, William K. Murray, D. Purdie, David C. Whiteman, Anthony Proietto, Stephen Braye, Geoff Otton, C. Camaris, R. Crouch, L. Edwards, Neville F. Hacker, Donald E. Marsden, G.M. Robertson, David Bell, Sally Baron‐Hay, A. Ferrier, G. Gard, David Nevell, Nick Pavlakis, Sue Valmadre, Bridget Young, Philip Beale, Jane Beith, Jonathan Carter, Christopher Dalrymple, R. Houghton, Peter Russell, Margaret Davy, Martin K. Oehler
Abstract
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.