Karolin Heinze1, Matthias Rengsberger1, Mieczyslaw Gajda2, Lars Jansen1, Linea Osmers1, Leticia Oliveira-Ferrer3, Barbara Schmalfeldt3, Matthias Dürst1, Norman Häfner4, Ingo B Runnebaum5. 1. Department of Gynecology and Reproduction Medicine, Jena University Hospital-Friedrich Schiller University Jena, 07747, Jena, Germany. 2. Department of Forensic Medicine, Section of Pathology, Jena University Hospital - Friedrich Schiller University Jena, 07747, Jena, Germany. 3. Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. 4. Department of Gynecology and Reproduction Medicine, Jena University Hospital-Friedrich Schiller University Jena, 07747, Jena, Germany. norman.haefner@med.uni-jena.de. 5. Department of Gynecology and Reproduction Medicine, Jena University Hospital-Friedrich Schiller University Jena, 07747, Jena, Germany. ingo.runnebaum@med.uni-jena.de.
Abstract
BACKGROUND: To date, no predictive or prognostic molecular biomarkers except BRCA mutations are clinically established for epithelial ovarian cancer (EOC) despite being the deadliest gynecological malignancy. Aim of this biomarker study was the analysis of DNA methylation biomarkers for their prognostic value independent from clinical variables in a heterogeneous cohort of 203 EOC patients from two university medical centers. RESULTS: The marker combination CAMK2N1/RUNX3 exhibited a significant prognostic value for progression-free (PFS) and overall survival (OS) of sporadic platinum-sensitive EOC (n = 188) both in univariate Kaplan-Meier (LogRank p < 0.05) and multivariate Cox regression analysis (p < 0.05; hazard ratio HR = 1.587). KRT86 methylation showed a prognostic value only in univariate analysis because of an association with FIGO staging (Fisher's exact test p < 0.01). Thus, it may represent a marker for EOC staging. Dichotomous prognostic values were observed for KATNAL2 methylation depending on BRCA aberrations. KATNAL2 methylation exhibited a negative prognostic value for PFS in sporadic EOC patients without BRCA1 methylation (HR 1.591, p = 0.012) but positive prognostic value in sporadic EOC with BRCA1 methylation (HR 0.332, p = 0.04) or BRCA-mutated EOC (HR 0.620, n.s.). CONCLUSION: The retrospective analysis of 188 sporadic platinum-sensitive EOC proved an independent prognostic value of the methylation marker combination CAMK2N1/RUNX3 for PFS and OS. If validated prospectively this combination may identify EOC patients with worse prognosis after standard therapy potentially benefiting from intensive follow-up, maintenance therapies or inclusion in therapeutic studies. The dichotomous prognostic value of KATNAL2 should be validated in larger sample sets of EOC.
BACKGROUND: To date, no predictive or prognostic molecular biomarkers except BRCA mutations are clinically established for epithelial ovarian cancer (EOC) despite being the deadliest gynecological malignancy. Aim of this biomarker study was the analysis of DNA methylation biomarkers for their prognostic value independent from clinical variables in a heterogeneous cohort of 203 EOC patients from two university medical centers. RESULTS: The marker combination CAMK2N1/RUNX3 exhibited a significant prognostic value for progression-free (PFS) and overall survival (OS) of sporadic platinum-sensitive EOC (n = 188) both in univariate Kaplan-Meier (LogRank p < 0.05) and multivariate Cox regression analysis (p < 0.05; hazard ratio HR = 1.587). KRT86 methylation showed a prognostic value only in univariate analysis because of an association with FIGO staging (Fisher's exact test p < 0.01). Thus, it may represent a marker for EOC staging. Dichotomous prognostic values were observed for KATNAL2 methylation depending on BRCA aberrations. KATNAL2 methylation exhibited a negative prognostic value for PFS in sporadic EOC patients without BRCA1 methylation (HR 1.591, p = 0.012) but positive prognostic value in sporadic EOC with BRCA1 methylation (HR 0.332, p = 0.04) or BRCA-mutated EOC (HR 0.620, n.s.). CONCLUSION: The retrospective analysis of 188 sporadic platinum-sensitive EOC proved an independent prognostic value of the methylation marker combination CAMK2N1/RUNX3 for PFS and OS. If validated prospectively this combination may identify EOC patients with worse prognosis after standard therapy potentially benefiting from intensive follow-up, maintenance therapies or inclusion in therapeutic studies. The dichotomous prognostic value of KATNAL2 should be validated in larger sample sets of EOC.
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: Daniel Kritsch; Franziska Hoffmann; Daniel Steinbach; Lars Jansen; Stella Mary Photini; Mieczyslaw Gajda; Alexander S Mosig; Jürgen Sonnemann; Sven Peters; Margarita Melnikova; Jürgen Thomale; Matthias Dürst; Ingo B Runnebaum; Norman Häfner Journal: Int J Cancer Date: 2017-07-12 Impact factor: 7.396
Authors: Christopher A Maxwell; Javier Benítez; Laia Gómez-Baldó; Ana Osorio; Núria Bonifaci; Ricardo Fernández-Ramires; Sylvain V Costes; Elisabet Guinó; Helen Chen; Gareth J R Evans; Pooja Mohan; Isabel Català; Anna Petit; Helena Aguilar; Alberto Villanueva; Alvaro Aytes; Jordi Serra-Musach; Gad Rennert; Flavio Lejbkowicz; Paolo Peterlongo; Siranoush Manoukian; Bernard Peissel; Carla B Ripamonti; Bernardo Bonanni; Alessandra Viel; Anna Allavena; Loris Bernard; Paolo Radice; Eitan Friedman; Bella Kaufman; Yael Laitman; Maya Dubrovsky; Roni Milgrom; Anna Jakubowska; Cezary Cybulski; Bohdan Gorski; Katarzyna Jaworska; Katarzyna Durda; Grzegorz Sukiennicki; Jan Lubiński; Yin Yao Shugart; Susan M Domchek; Richard Letrero; Barbara L Weber; Frans B L Hogervorst; Matti A Rookus; J Margriet Collee; Peter Devilee; Marjolijn J Ligtenberg; Rob B van der Luijt; Cora M Aalfs; Quinten Waisfisz; Juul Wijnen; Cornelis E P van Roozendaal; Douglas F Easton; Susan Peock; Margaret Cook; Clare Oliver; Debra Frost; Patricia Harrington; D Gareth Evans; Fiona Lalloo; Rosalind Eeles; Louise Izatt; Carol Chu; Diana Eccles; Fiona Douglas; Carole Brewer; Heli Nevanlinna; Tuomas Heikkinen; Fergus J Couch; Noralane M Lindor; Xianshu Wang; Andrew K Godwin; Maria A Caligo; Grazia Lombardi; Niklas Loman; Per Karlsson; Hans Ehrencrona; Anna von Wachenfeldt; Rosa Bjork Barkardottir; Ute Hamann; Muhammad U Rashid; Adriana Lasa; Trinidad Caldés; Raquel Andrés; Michael Schmitt; Volker Assmann; Kristen Stevens; Kenneth Offit; João Curado; Hagen Tilgner; Roderic Guigó; Gemma Aiza; Joan Brunet; Joan Castellsagué; Griselda Martrat; Ander Urruticoechea; Ignacio Blanco; Laima Tihomirova; David E Goldgar; Saundra Buys; Esther M John; Alexander Miron; Melissa Southey; Mary B Daly; Rita K Schmutzler; Barbara Wappenschmidt; Alfons Meindl; Norbert Arnold; Helmut Deissler; Raymonda Varon-Mateeva; Christian Sutter; Dieter Niederacher; Evgeny Imyamitov; Olga M Sinilnikova; Dominique Stoppa-Lyonne; Sylvie Mazoyer; Carole Verny-Pierre; Laurent Castera; Antoine de Pauw; Yves-Jean Bignon; Nancy Uhrhammer; Jean-Philippe Peyrat; Philippe Vennin; Sandra Fert Ferrer; Marie-Agnès Collonge-Rame; Isabelle Mortemousque; Amanda B Spurdle; Jonathan Beesley; Xiaoqing Chen; Sue Healey; Mary Helen Barcellos-Hoff; Marc Vidal; Stephen B Gruber; Conxi Lázaro; Gabriel Capellá; Lesley McGuffog; Katherine L Nathanson; Antonis C Antoniou; Georgia Chenevix-Trench; Markus C Fleisch; Víctor Moreno; Miguel Angel Pujana Journal: PLoS Biol Date: 2011-11-15 Impact factor: 8.029
Authors: J Millstein; T Budden; E L Goode; M S Anglesio; A Talhouk; M P Intermaggio; H S Leong; S Chen; W Elatre; B Gilks; T Nazeran; M Volchek; R C Bentley; C Wang; D S Chiu; S Kommoss; S C Y Leung; J Senz; A Lum; V Chow; H Sudderuddin; R Mackenzie; J George; S Fereday; J Hendley; N Traficante; H Steed; J M Koziak; M Köbel; I A McNeish; T Goranova; D Ennis; G Macintyre; D Silva De Silva; T Ramón Y Cajal; J García-Donas; S Hernando Polo; G C Rodriguez; K L Cushing-Haugen; H R Harris; C S Greene; R A Zelaya; S Behrens; R T Fortner; P Sinn; E Herpel; J Lester; J Lubiński; O Oszurek; A Tołoczko; C Cybulski; J Menkiszak; C L Pearce; M C Pike; C Tseng; J Alsop; V Rhenius; H Song; M Jimenez-Linan; A M Piskorz; A Gentry-Maharaj; C Karpinskyj; M Widschwendter; N Singh; C J Kennedy; R Sharma; P R Harnett; B Gao; S E Johnatty; R Sayer; J Boros; S J Winham; G L Keeney; S H Kaufmann; M C Larson; H Luk; B Y Hernandez; P J Thompson; L R Wilkens; M E Carney; B Trabert; J Lissowska; L Brinton; M E Sherman; C Bodelon; S Hinsley; L A Lewsley; R Glasspool; S N Banerjee; E A Stronach; P Haluska; I Ray-Coquard; S Mahner; B Winterhoff; D Slamon; D A Levine; L E Kelemen; J Benitez; J Chang-Claude; J Gronwald; A H Wu; U Menon; M T Goodman; J M Schildkraut; N Wentzensen; R Brown; A Berchuck; G Chenevix-Trench; A deFazio; S A Gayther; M J García; M J Henderson; M A Rossing; A Beeghly-Fadiel; P A Fasching; S Orsulic; B Y Karlan; G E Konecny; D G Huntsman; D D Bowtell; J D Brenton; J A Doherty; P D P Pharoah; S J Ramus Journal: Ann Oncol Date: 2020-05-28 Impact factor: 51.769