Deleterious somatic variants in 473 consecutive individuals with ovarian cancer
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Deleterious somatic variants in 473 consecutive individuals with ovarian cancer : results of the observational AGO-TR1 study (NCT02222883). / Hauke, Jan; Hahnen, Eric; Schneider, Stephanie; Reuss, Alexander; Richters, Lisa; Kommoss, Stefan; Heimbach, André; Marmé, Frederik; Schmidt, Sandra; Prieske, Katharina; Gevensleben, Heidrun; Burges, Alexander; Borde, Julika; De Gregorio, Nikolaus; Nürnberg, Peter; El-Balat, Ahmed; Thiele, Holger; Hilpert, Felix; Altmüller, Janine; Meier, Werner; Dietrich, Dimo; Kimmig, Rainer; Schoemig-Markiefka, Birgid; Kast, Karin; Braicu, Elena; Baumann, Klaus; Jackisch, Christian; Park-Simon, Tjoung-Won; Ernst, Corinna; Hanker, Lars; Pfisterer, Jacobus; Schnelzer, Andreas; du Bois, Andreas; Schmutzler, Rita K; Harter, Philipp.
in: J MED GENET, Jahrgang 56, Nr. 9, 09.2019, S. 574-580.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Deleterious somatic variants in 473 consecutive individuals with ovarian cancer
T2 - results of the observational AGO-TR1 study (NCT02222883)
AU - Hauke, Jan
AU - Hahnen, Eric
AU - Schneider, Stephanie
AU - Reuss, Alexander
AU - Richters, Lisa
AU - Kommoss, Stefan
AU - Heimbach, André
AU - Marmé, Frederik
AU - Schmidt, Sandra
AU - Prieske, Katharina
AU - Gevensleben, Heidrun
AU - Burges, Alexander
AU - Borde, Julika
AU - De Gregorio, Nikolaus
AU - Nürnberg, Peter
AU - El-Balat, Ahmed
AU - Thiele, Holger
AU - Hilpert, Felix
AU - Altmüller, Janine
AU - Meier, Werner
AU - Dietrich, Dimo
AU - Kimmig, Rainer
AU - Schoemig-Markiefka, Birgid
AU - Kast, Karin
AU - Braicu, Elena
AU - Baumann, Klaus
AU - Jackisch, Christian
AU - Park-Simon, Tjoung-Won
AU - Ernst, Corinna
AU - Hanker, Lars
AU - Pfisterer, Jacobus
AU - Schnelzer, Andreas
AU - du Bois, Andreas
AU - Schmutzler, Rita K
AU - Harter, Philipp
N1 - © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2019/9
Y1 - 2019/9
N2 - 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.
AB - 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.
U2 - 10.1136/jmedgenet-2018-105930
DO - 10.1136/jmedgenet-2018-105930
M3 - SCORING: Journal article
C2 - 30979843
VL - 56
SP - 574
EP - 580
JO - J MED GENET
JF - J MED GENET
SN - 0022-2593
IS - 9
ER -