Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer

作者：Nikki L. Burdett, Madelynne O. Willis, Ahwan Pandey, Sián Fereday, AOCS Study Group, Management Group, David D.L. Bowtell, Georgia Chenevix‐Trench, A. Green, Penelope M. Webb, Anna DeFazio, Dorota M. Gertig, Project and Data Managers, Nadia Traficante, Sián Fereday, Suzanne Moore, Jillian A. Hung, K.R. Harrap, T. Sadkowsky, Nirmala Pandeya, Maryrose K. Malt, A. Mellon, R. Robertson, T. Vanden Bergh, M. Jones, Penny Mackenzie, J. Maidens, K. Nattress, Yoke-Eng Chiew, Annie Stenlake, Harold Clifford Sullivan, Beulah H. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L. M. Jackman, Kaltin Ferguson, Karla J. Martin, Adam C. Martyn, Beatrice Ranieri, J. White, Victoria Jayde, Pamela M. Mamers, Leanne Bowes, Laura Galletta, Daniel A. Giles, Joy Hendley, Kathryn Alsop, T. Schmidt, H. Shirley, C. Ball, Christian D. Young, S. Viduka, Hoa Thi Tuyet Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R. Stuart‐Harris, Fred Kirsten, Jay Rutovitz, P. Clingan, Akisha Glasgow, Anthony M. Proietto, Stephen G. Braye, Geoffrey R. Otton, Jenny Shannon, Tony Bonaventura, James Stewart, Stephen D. Begbie, Michael Leonard Friedlander, Debra Bell, Sally E. Baron-Hay, A. Ferrier, Gregory B. Gard, David F. Nevell, Nick Pavlakis, Susan Valmadre, Barry De Young, Catherine Camaris, R. Crouch, Lyndal S. Edwards, Neville F. Hacker, Donald E. Marsden, Greg Robertson, Philip James Beale, Jane McNeil Beith, Jonathan R. Carter, Chris Dalrymple, Roger S. Houghton, Prudence Anne Russell, Matthew Jon Links, John J. Grygiel, Jane A Hill, Alison H. Brand, Karen Byth, Richard C. Jaworski, Paul R. Harnett, Ragwha Sharma, Gerard Wain, B.G. Ward, D. Papadimos, Alexander J. Crandon, M. Cummings, K. Horwood, Andreas Obermair, Lewis C Perrin, David Wyld, James Nicklin, Marcus W. Davy, Martin Klaus Oehler, Cathrine M. Hall, Tom Dodd, Timothy M. Healy, Keir Pittman, D C Henderson, Jessica Anne Miller, J. Pierdes, Penny I. Blomfield, D. Challis, Rachel L. McIntosh, Alyssa Parker, Robert Eldon Brown, Robert M Rome, D. Allen, Peter Grant, Simon E. Hyde, R. Laurie, Melissa J. Robbie, David L. Healy, Tom W. Jobling, Tom Manolitsas, J. McNealage, Peter A. W. Rogers, Beatrice J. Susil, Eric Sumithran, Ian J. Simpson, Linda Mileshkin, George Au‐Yeung, Kelly‐Anne Phillips, Danny Rischin, Stephen B. Fox, Debi Johnson, Stephen Lade, Maurice Bernard Loughrey, Neil O’Callaghan, William K. Murray, Paul Waring, Virginia R. Billson, Jan M. Pyman, Deborah E. Neesham, Michael A. Quinn, Craig R. Underhill, Rachel Bell, L. F. Ng, Robert helmut Blum, Vinod Ganju, Ian G Hammond, Yee Chit Leung, Anthony J. McCartney, Martin Buck, I. Haviv, D. Purdie, David C. Whiteman, Nikolajs Zeps, Anna DeFazio, David D.L. Bowtell, Elizabeth L. Christie · 发表于：Scientific Reports · 年份：2023 · DOI：10.1038/s41598-023-48153-x · 被引用次数：5 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、Ovarian cancer diagnosis and treatment

While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.