Literature DB >> 30979843

Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883).

Jan Hauke1, Eric Hahnen2, Stephanie Schneider3, Alexander Reuss4, Lisa Richters1, Stefan Kommoss5, André Heimbach6, Frederik Marmé7, Sandra Schmidt1, Katharina Prieske8, Heidrun Gevensleben9, Alexander Burges10, Julika Borde1, Nikolaus De Gregorio11, Peter Nürnberg12,13, Ahmed El-Balat14, Holger Thiele12,15, Felix Hilpert16,17, Janine Altmüller12,15, Werner Meier18, Dimo Dietrich19, Rainer Kimmig20, Birgid Schoemig-Markiefka21, Karin Kast22,23, Elena Braicu24, Klaus Baumann25,26, Christian Jackisch27, Tjoung-Won Park-Simon28, Corinna Ernst1, Lars Hanker29, Jacobus Pfisterer30, Andreas Schnelzer31,32, Andreas du Bois3, Rita K Schmutzler1, Philipp Harter3.   

Abstract

BACKGROUND: For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy?
METHODS: Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included.
RESULTS: The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles.
CONCLUSION: Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors. TRIAL REGISTRATION NUMBER: NCT02222883. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Entities:  

Keywords:  germline variant; methylation; ovarian cancer; somatic variant; targeted therapy

Mesh：

Substances：

Year:  2019        PMID： 30979843     DOI： 10.1136/jmedgenet-2018-105930

Source DB:  PubMed          Journal:  J Med Genet        ISSN： 0022-2593            Impact factor:   6.318


  11 in total

1.  Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients With Ovarian Cancer.

Authors:  Konstantin Weber-Lassalle; Corinna Ernst; Alexander Reuss; Kathrin Möllenhoff; Klaus Baumann; Christian Jackisch; Jan Hauke; Dimo Dietrich; Julika Borde; Tjoung-Won Park-Simon; Lars Hanker; Katharina Prieske; Sandra Schmidt; Nana Weber-Lassalle; Esther Pohl-Rescigno; Stefan Kommoss; Frederik Marmé; Florian Heitz; Julia C Stingl; Rita K Schmutzler; Philipp Harter; Eric Hahnen
Journal:  J Natl Cancer Inst       Date:  2022-04-11       Impact factor: 13.506

2.  Long-term survival of a BRCA2 mutation carrier following second ovarian cancer relapse using PARPi therapy: A case report.

Authors:  Kathrin Bredow; Britta Blümcke; Stephanie Schneider; Michael Püsken; Rita Schmutzler; Kerstin Rhiem
Journal:  Mol Clin Oncol       Date:  2022-07-21

3.  Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Authors:  Filipe Correia Martins; Dominique-Laurent Couturier; Anna Paterson; Anthony N Karnezis; Christine Chow; Tayyebeh M Nazeran; Adekunle Odunsi; Aleksandra Gentry-Maharaj; Aleksandra Vrvilo; Alexander Hein; Aline Talhouk; Ana Osorio; Andreas D Hartkopf; Angela Brooks-Wilson; Anna DeFazio; Anna Fischer; Arndt Hartmann; Brenda Y Hernandez; Bryan M McCauley; Chloe Karpinskyj; Christiani B de Sousa; Claus Høgdall; Daniel G Tiezzi; Esther Herpel; Florin Andrei Taran; Francesmary Modugno; Gary Keeney; Gregg Nelson; Helen Steed; Honglin Song; Hugh Luk; Javier Benitez; Jennifer Alsop; Jennifer M Koziak; Jenny Lester; Joseph H Rothstein; Jurandyr M de Andrade; Lene Lundvall; Luis Paz-Ares; Luis Robles-Díaz; Lynne R Wilkens; Maria J Garcia; Maria P Intermaggio; Marie-Lyne Alcaraz; Mary A Brett; Matthias W Beckmann; Mercedes Jimenez-Linan; Michael Anglesio; Michael E Carney; Michael Schneider; Nadia Traficante; Nadja Pejovic; Naveena Singh; Nhu Le; Peter Sinn; Prafull Ghatage; Ramona Erber; Robert Edwards; Robert Vierkant; Roberta B Ness; Samuel Leung; Sandra Orsulic; Sara Y Brucker; Scott H Kaufmann; Sian Fereday; Simon Gayther; Stacey J Winham; Stefan Kommoss; Tanja Pejovic; Teri A Longacre; Valerie McGuire; Valerie Rhenius; Weiva Sieh; Yurii B Shvetsov; Alice S Whittemore; Annette Staebler; Beth Y Karlan; Cristina Rodriguez-Antona; David D Bowtell; Ellen L Goode; Estrid Høgdall; Francisco J Candido Dos Reis; Jacek Gronwald; Jenny Chang-Claude; Kirsten B Moysich; Linda E Kelemen; Linda S Cook; Marc T Goodman; Peter A Fasching; Robin Crawford; Suha Deen; Usha Menon; David G Huntsman; Martin Köbel; Susan J Ramus; Paul D P Pharoah; James D Brenton
Journal:  Br J Cancer       Date:  2020-06-18       Impact factor: 7.640

4.  Clinical Performance Comparison of Two In-Vitro Diagnostic Multivariate Index Assays (IVDMIAs) for Presurgical Assessment for Ovarian Cancer Risk.

Authors:  Lee P Shulman; Marra Francis; Rowan Bullock; Todd Pappas
Journal:  Adv Ther       Date:  2019-07-05       Impact factor: 3.845

Review 5.  PTEN and Gynecological Cancers.

Authors:  Camilla Nero; Francesca Ciccarone; Antonella Pietragalla; Giovanni Scambia
Journal:  Cancers (Basel)       Date:  2019-09-28       Impact factor: 6.639

6.  CAMK2N1/RUNX3 methylation is an independent prognostic biomarker for progression-free and overall survival of platinum-sensitive epithelial ovarian cancer patients.

Authors:  Karolin Heinze; Matthias Rengsberger; Mieczyslaw Gajda; Lars Jansen; Linea Osmers; Leticia Oliveira-Ferrer; Barbara Schmalfeldt; Matthias Dürst; Norman Häfner; Ingo B Runnebaum
Journal:  Clin Epigenetics       Date:  2021-01-22       Impact factor: 6.551

7.  Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population-based testing program.

Authors:  Melanie Care; Jeanna McCuaig; Blaise Clarke; Sylvie Grenier; Raymond H Kim; Marjan Rouzbahman; Natalie Stickle; Marcus Bernardini; Tracy L Stockley
Journal:  Mol Oncol       Date:  2020-10-22       Impact factor: 6.603

8.  Tumor BRCA Testing in Epithelial Ovarian Cancers: Past and Future-Five-Years' Single-Institution Experience of 762 Consecutive Patients.

Authors:  Caterina Fumagalli; Ilaria Betella; Alessandra Rappa; Maria di Giminiani; Michela Gaiano; Luigi Antonio De Vitis; Benedetta Zambetti; Davide Vacirca; Francesco Multinu; Konstantinos Venetis; Nicoletta Colombo; Massimo Barberis; Elena Guerini Rocco
Journal:  Cancers (Basel)       Date:  2022-03-23       Impact factor: 6.639

9.  BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer.

Authors:  Maha Elazezy; Katharina Prieske; Lan Kluwe; Leticia Oliveira-Ferrer; Sven Peine; Volkmar Müller; Linn Woelber; Barbara Schmalfeldt; Klaus Pantel; Simon A Joosse
Journal:  Mol Oncol       Date:  2021-10-12       Impact factor: 6.603

10.  Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in BRCA1/2: results of the observational AGO-TR1 study (NCT02222883).

Authors:  Jan Hauke; Philipp Harter; Corinna Ernst; Alexander Burges; Sandra Schmidt; Alexander Reuss; Julika Borde; Nikolaus De Gregorio; Dimo Dietrich; Ahmed El-Balat; Mohamad Kayali; Heidrun Gevensleben; Felix Hilpert; Janine Altmüller; André Heimbach; Werner Meier; Birgid Schoemig-Markiefka; Holger Thiele; Rainer Kimmig; Peter Nürnberg; Karin Kast; Lisa Richters; Jalid Sehouli; Rita K Schmutzler; Eric Hahnen
Journal:  J Med Genet       Date:  2020-12-03       Impact factor: 6.318
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