Konstantin Weber-Lassalle1, Corinna Ernst1, Alexander Reuss2, Kathrin Möllenhoff3, Klaus Baumann4, Christian Jackisch5, Jan Hauke1, Dimo Dietrich6, Julika Borde1, Tjoung-Won Park-Simon7, Lars Hanker8, Katharina Prieske9, Sandra Schmidt1, Nana Weber-Lassalle1, Esther Pohl-Rescigno1, Stefan Kommoss10, Frederik Marmé11, Florian Heitz12,13,14, Julia C Stingl15, Rita K Schmutzler1, Philipp Harter12, Eric Hahnen1. 1. Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. 2. Coordinating Center for Clinical Trials, Philipps-University Marburg, Marburg, Germany. 3. Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany. 4. Department of Gynecology, Medical Center Ludwigshafen, Ludwigshafen, Germany. 5. Department of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany. 6. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Bonn (UKB), Bonn, Germany. 7. Department of Gynecology & Gynecologic Oncology, Medizinische Hochschule Hannover, Hannover, Germany. 8. Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Lübeck, Germany. 9. Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 10. Department Gynecology & Gynecologic Oncology, University of Tübingen, Tübingen, Germany. 11. Center for Tumor Disease, Department of Gynecology, University of Heidelberg, Heidelberg, Germany. 12. Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte (KEM) Evang, Huyssens-Stiftung/Knappschaft GmbH, Essen, Germany. 13. Department for Gynecology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany. 14. Berlin Institute of Health, Berlin, Germany. 15. Institute of Clinical Pharmacology, University Hospital of Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
Abstract
BACKGROUND: Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. METHODS: We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. RESULTS: Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. CONCLUSIONS: A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.
BACKGROUND: Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. METHODS: We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. RESULTS: Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. CONCLUSIONS: A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.
Authors: Kathryn P Pennington; Tom Walsh; Maria I Harrell; Ming K Lee; Christopher C Pennil; Mara H Rendi; Anne Thornton; Barbara M Norquist; Silvia Casadei; Alexander S Nord; Kathy J Agnew; Colin C Pritchard; Sheena Scroggins; Rochelle L Garcia; Mary-Claire King; Elizabeth M Swisher Journal: Clin Cancer Res Date: 2013-11-15 Impact factor: 12.531
Authors: Eric Hahnen; Jan Hauke; Christoph Engel; Guido Neidhardt; Kerstin Rhiem; Rita K Schmutzler Journal: Breast Care (Basel) Date: 2017-02-24 Impact factor: 2.860
Authors: Jan Hauke; Eric Hahnen; Stephanie Schneider; Alexander Reuss; Lisa Richters; Stefan Kommoss; André Heimbach; Frederik Marmé; Sandra Schmidt; Katharina Prieske; Heidrun Gevensleben; Alexander Burges; Julika Borde; Nikolaus De Gregorio; Peter Nürnberg; Ahmed El-Balat; Holger Thiele; Felix Hilpert; Janine Altmüller; Werner Meier; Dimo Dietrich; Rainer Kimmig; Birgid Schoemig-Markiefka; Karin Kast; Elena Braicu; Klaus Baumann; Christian Jackisch; Tjoung-Won Park-Simon; Corinna Ernst; Lars Hanker; Jacobus Pfisterer; Andreas Schnelzer; Andreas du Bois; Rita K Schmutzler; Philipp Harter Journal: J Med Genet Date: 2019-04-12 Impact factor: 6.318
Authors: Andrés Poveda; Anne Floquet; Jonathan A Ledermann; Rebecca Asher; Richard T Penson; Amit M Oza; Jacob Korach; Tomasz Huzarski; Sandro Pignata; Michael Friedlander; Alessandra Baldoni; Tjoung-Won Park-Simon; Kenji Tamura; Gabe S Sonke; Alla Lisyanskaya; Jae-Hoon Kim; Elias Abdo Filho; Tsveta Milenkova; Elizabeth S Lowe; Phil Rowe; Ignace Vergote; Eric Pujade-Lauraine Journal: Lancet Oncol Date: 2021-03-18 Impact factor: 41.316
Authors: Giulio Genovese; Anna K Kähler; Robert E Handsaker; Johan Lindberg; Samuel A Rose; Samuel F Bakhoum; Kimberly Chambert; Eran Mick; Benjamin M Neale; Menachem Fromer; Shaun M Purcell; Oscar Svantesson; Mikael Landén; Martin Höglund; Sören Lehmann; Stacey B Gabriel; Jennifer L Moran; Eric S Lander; Patrick F Sullivan; Pamela Sklar; Henrik Grönberg; Christina M Hultman; Steven A McCarroll Journal: N Engl J Med Date: 2014-11-26 Impact factor: 91.245
Authors: Mansoor R Mirza; B Benigno; A Dørum; S Mahner; P Bessette; I Bover Barceló; D Berton-Rigaud; J A Ledermann; B J Rimel; J Herrstedt; S Lau; A du Bois; A Casado Herráez; E Kalbacher; J Buscema; D Lorusso; I Vergote; T Levy; P Wang; F A de Jong; D Gupta; U A Matulonis Journal: Gynecol Oncol Date: 2020-09-25 Impact factor: 5.482
Authors: Joanne I Hsu; Tajhal Dayaram; Ayala Tovy; Etienne De Braekeleer; Mira Jeong; Feng Wang; Jianhua Zhang; Timothy P Heffernan; Sonal Gera; Jeffrey J Kovacs; Joseph R Marszalek; Christopher Bristow; Yuanqing Yan; Guillermo Garcia-Manero; Hagop Kantarjian; George Vassiliou; P Andrew Futreal; Lawrence A Donehower; Koichi Takahashi; Margaret A Goodell Journal: Cell Stem Cell Date: 2018-11-01 Impact factor: 24.633
Authors: Ryan N Ptashkin; Teng Gao; Ahmet Zehir; Elli Papaemmanuil; Kelly L Bolton; Lior Braunstein; Sean M Devlin; Daniel Kelly; Minal Patel; Antonin Berthon; Aijazuddin Syed; Mariko Yabe; Catherine C Coombs; Nicole M Caltabellotta; Mike Walsh; Kenneth Offit; Zsofia Stadler; Diana Mandelker; Jessica Schulman; Akshar Patel; John Philip; Elsa Bernard; Gunes Gundem; Juan E Arango Ossa; Max Levine; Juan S Medina Martinez; Noushin Farnoud; Dominik Glodzik; Sonya Li; Mark E Robson; Choonsik Lee; Paul D P Pharoah; Konrad H Stopsack; Barbara Spitzer; Simon Mantha; James Fagin; Laura Boucai; Christopher J Gibson; Benjamin L Ebert; Andrew L Young; Todd Druley; Koichi Takahashi; Nancy Gillis; Markus Ball; Eric Padron; David M Hyman; Jose Baselga; Larry Norton; Stuart Gardos; Virginia M Klimek; Howard Scher; Dean Bajorin; Eder Paraiso; Ryma Benayed; Maria E Arcila; Marc Ladanyi; David B Solit; Michael F Berger; Martin Tallman; Montserrat Garcia-Closas; Nilanjan Chatterjee; Luis A Diaz; Ross L Levine; Lindsay M Morton Journal: Nat Genet Date: 2020-10-26 Impact factor: 41.307