Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

IF 4.7 2区医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2024-03-05 DOI:10.1038/s41525-024-00395-y

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

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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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对接受初级切除手术的卵巢癌患者进行全基因组关联分析，找出残留疾病的候选基因。

卵巢癌的存活率取决于初次手术后的切除情况。我们对 7705 例卵巢癌患者（包括 4954 例高级别浆液性癌（HGSOC）患者）的切除状态进行了全基因组关联分析，以确定与残留疾病相关的变异。在 HGSOC 中，MGMT 上游的 rs72845444 与切除状态的关系最为明显（p = 3.9 × 10-8）。在基于基因的分析中，经分期调整后，PPP2R5C 是与 HGSOC 最密切相关的基因。在来自 AGO-OVAR 11 研究的一组独立的 378 例卵巢肿瘤中，MGMT 和 PPP2R5C 附近的变异与甲基化和转录水平相关，PPP2R5C mRNA 水平可预测残留疾病患者的无进展生存期。MGMT 编码一种 DNA 修复酶，PPP2R5C 编码 PP2A 肿瘤抑制因子的 B56γ 亚基。我们的研究结果将这两个位点的遗传变异与 HGSOC 的切除状况联系起来。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.