Ramachandran, Dhanya and Tyrer, Jonathan P. and Kommoss, Stefan and DeFazio, Anna and Riggan, Marjorie J. and Webb, Penelope M. and Fasching, Peter A. and Lambrechts, Diether and García, María J. and Rodríguez-Antona, Cristina and Goodman, Marc T. and Modugno, Francesmary and Moysich, Kirsten B. and Karlan, Beth Y. and Lester, Jenny and Kjaer, Susanne K. and Jensen, Allan and Høgdall, Estrid and Goode, Ellen L. and Cliby, William A. and Kumar, Amanika and Wang, Chen and Cunningham, Julie M. and Winham, Stacey J. and Monteiro, Alvaro N. and Schildkraut, Joellen M. and Cramer, Daniel W. and Terry, Kathryn L. and Titus, Linda and Bjorge, Line and Thomsen, Liv Cecilie Vestrheim and Pejovic, Tanja and Høgdall, Claus K. and Mcneish, Iain A. and May, Taymaa and Huntsman, David G. and Pfisterer, Jacobus and Canzler, Ulrich and Park-Simon, Tjoung-Won and Schröder, Willibald and Belau, Antje and Hanker, Lars and Harter, Philipp and Sehouli, Jalid and Kimmig, Rainer and de Gregorio, Nikolaus and Schmalfeldt, Barbara and Baumann, Klaus and Hilpert, Felix and Burges, Alexander and Winterhoff, Boris and Schürmann, Peter and Speith, Lisa-Marie and Hillemanns, Peter and Berchuck, Andrew and Johnatty, Sharon E. and Ramus, Susan J. and Chenevix-Trench, Georgia and Pharoah, Paul D.P. and Dörk, Thilo and Heitz, Florian (2024) Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease. npj Genomic Medicine, 9 (1): 19. ISSN 2056-7944

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Abstract

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10−8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

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