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. 2024 Mar 5;9(1):19.
doi: 10.1038/s41525-024-00395-y.

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

Dhanya Ramachandran  1 Jonathan P Tyrer  2 Stefan Kommoss  3 Anna DeFazio  4   5   6   7 Marjorie J Riggan  8 AOCS GroupPenelope M Webb  9 Peter A Fasching  10 Diether Lambrechts  11   12 María J García  13 Cristina Rodríguez-Antona  14   15 Marc T Goodman  16 Francesmary Modugno  17   18   19 Kirsten B Moysich  20 Beth Y Karlan  21 Jenny Lester  21 Susanne K Kjaer  22   23 Allan Jensen  22 Estrid Høgdall  24 Ellen L Goode  25 William A Cliby  26 Amanika Kumar  26 Chen Wang  27 Julie M Cunningham  28 Stacey J Winham  27 Alvaro N Monteiro  29 Joellen M Schildkraut  30 Daniel W Cramer  31   32 Kathryn L Terry  31   32 Linda Titus  33 Line Bjorge  34   35 Liv Cecilie Vestrheim Thomsen  34   35 OPAL Study GroupTanja Pejovic  36   37 Claus K Høgdall  23 Iain A McNeish  38   39 Taymaa May  40 David G Huntsman  41   42 Jacobus Pfisterer  43 Ulrich Canzler  44   45 Tjoung-Won Park-Simon  1 Willibald Schröder  46   47 Antje Belau  48   49 Lars Hanker  50   51 Philipp Harter  52 Jalid Sehouli  53 Rainer Kimmig  54 Nikolaus de Gregorio  55   56 Barbara Schmalfeldt  57 Klaus Baumann  58   59 Felix Hilpert  60   61 Alexander Burges  62 Boris Winterhoff  63 Peter Schürmann  1 Lisa-Marie Speith  1 Peter Hillemanns  1 Andrew Berchuck  8 Sharon E Johnatty  64 Susan J Ramus  65   66 Georgia Chenevix-Trench  64 Paul D P Pharoah  2   67   68 Thilo Dörk  69 Florian Heitz  70   71   72
Collaborators, Affiliations

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

Dhanya Ramachandran et al. NPJ Genom Med. .

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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Conflict of interest statement

U.C. received honoraria for lectures from Lilly and AstraZeneca and is on the advisory board of AstraZeneca. J.P. received honoraria from Roche Pharma AG, AstraZeneca, Amgen, Clovis Oncology, MSD Oncology, GSK, Chugai Pharma, Teva, Medupdate, SAI MedPartners, Decision Resources, Simon-Kucher and partners, Juniper, Bionest partners, Vox Bio, Axiom healthcare strategies, Prosapient, iMed Institut, Lilly, and is a consultant/advisor for AstraZeneca, Roche, Pharma AG, Tesaro, Clovis Oncology, MSD Oncology. P.A.F. conducts research funded by Amgen, Novartis and Pfizer and received Honoraria from Roche, Novartis and Pfizer. None of these sponsors had any role in the design, data acquisition or interpretation of results in the present study.

Figures

Fig. 1
Fig. 1. Workflow of the GWAS and follow-up study.
a Study workflow combining three analyses of OCAC GWAS data for overall, invasive-only and high-grade serous ovarian cancer (left) with AGO-OVAR 11 and TCGA gene expression and clinical datasets. b Manhattan plot depicting GWAS results in high-grade serous ovarian cancer (unadjusted for stage) with rs72845444 as the top hit. Blue line: p = 1 × 10−5, red line: p = 5 × 10−8. c Locus Zoom regional association plot for variant rs72845444, close to MGMT.
Fig. 2
Fig. 2. MAGMA gene-based association analyses.
Manhattan plots for the MAGMA gene-based association analyses in high-grade serous ovarian cancer without or with adjustment for stage (a, c) and in overall ovarian cancers after adjustment for stage (b). Indicated are the top genes CABLES1 (a), FAM35A (b), and PPP2R5C (c), respectively.
Fig. 3
Fig. 3. Methylation-QTL and correlation with expression.
CpG sites that were nominally significant met-QTLs and also correlated with gene expression at (a) MGMT and (b) PPP2R5C in overall, high-grade serous (HGSOC), HGSOC optimal or sub-optimal groups. Plotted are methylation intensity levels (y-axis) vs genotype of the specified SNP (x-axis), or log2 normalised gene expression levels of the corresponding gene transcript (x-axis). The CpG sites are indicated by Illumina cg-Probe IDs, and the Illumina probe per gene is specified by ILMN IDs. p values are indicated after unpaired t tests between two groups, or following Pearson’s correlation R2 values and number of samples (N).
Fig. 4
Fig. 4. Progression-free survival analysis stratified by debulking status.
a Kaplan-Meier plots for patients in AGO-OVAR 11 with optimal (RD = 0, top) or suboptimal (RD > 0, bottom) debulking stratified by rs72845444 genotype. b Kaplan-Meier plots for high-grade serous patients with optimal (top) or suboptimal (bottom) debulking stratified by PPP2R5C mRNA levels in the AGO-OVAR 11 (top panel, RD = 0 vs RD > 0) and the TCGA cohort (bottom panel, RD < = 1 cm vs RD > 1 cm). PPP2R5C mRNA levels were measured by four different probes per study as indicated within the figures (Illumina IDs from the AGO-OVAR 11 dataset or specific probe set from the TCGA data accessed via KM-Plotter). For the TCGA dataset, patients were split by auto-selected best cutoff, and high-grade serous patients were chosen, followed by further selection of debulking status. Probe ID ILMN_1780913 captured PPP2R5C isoform 1, ILMN_1789283 mapped onto isoforms 1, 2, and 3, ILMN_2364971 matched isoforms 1, 2, and 3, and ILMN_1795846 matched isoform 3. Transcript isoforms indicated represent NM_002719 (1), NM_178586 (2) and NM_178587 (3) in the NCBI Genbank, respectively.

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