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

Jan Hauke; Eric Hahnen; Stephanie Schneider; Alexander Reuss; Lisa Richters; Stefan Kommoss; André Heimbach; Frederik Marmé; Sandra Schmidt; Katharina Prieske; Heidrun Gevensleben; Alexander Burges; Julika Borde; Nikolaus De Gregorio; Peter Nürnberg; Ahmed El-Balat; Holger Thiele; Felix Hilpert; Janine Altmüller; Werner Meier; DImo DIetrich; Rainer Kimmig; Birgid Schoemig-Markiefka; Karin Kast; Elena Braicu; Klaus Baumann; Christian Jackisch; Tjoung Won Park-Simon; Corinna Ernst; Lars Hanker; Jacobus Pfisterer; Andreas Schnelzer; Andreas Du Bois; Rita K. Schmutzler; Philipp Harter

doi:10.1136/jmedgenet-2018-105930

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

Jan Hauke, Eric Hahnen^*, Stephanie Schneider, Alexander Reuss, Lisa Richters, Stefan Kommoss, André Heimbach, Frederik Marmé, Sandra Schmidt, Katharina Prieske, Heidrun Gevensleben, Alexander Burges, Julika Borde, Nikolaus De Gregorio, Peter Nürnberg, Ahmed El-Balat, Holger Thiele, Felix Hilpert, Janine Altmüller, Werner MeierDImo DIetrich, Rainer Kimmig, Birgid Schoemig-Markiefka, Karin Kast, Elena Braicu, Klaus Baumann, Christian Jackisch, Tjoung Won Park-Simon, Corinna Ernst, Lars Hanker, Jacobus Pfisterer, Andreas Schnelzer, Andreas Du Bois, Rita K. Schmutzler, Philipp Harter

^*Corresponding author for this work

Clinic of Gynecology and Obstetrics

10 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medical Genetics
Volume	56
Issue number	9
Pages (from-to)	574-580
Number of pages	7
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2018-105930
Publication status	Published - 01.09.2019

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)
Centers: University Cancer Center Schleswig-Holstein (UCCSH)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/jmedgenet-2018-105930

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Hauke, J., Hahnen, E., Schneider, S., Reuss, A., Richters, L., Kommoss, S., Heimbach, A., Marmé, F., Schmidt, S., Prieske, K., Gevensleben, H., Burges, A., Borde, J., De Gregorio, N., Nürnberg, P., El-Balat, A., Thiele, H., Hilpert, F., Altmüller, J., ... Harter, P. (2019). Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: Results of the observational AGO-TR1 study (NCT02222883). Journal of Medical Genetics, 56(9), 574-580. https://doi.org/10.1136/jmedgenet-2018-105930

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title = "Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: Results of the observational AGO-TR1 study (NCT02222883)",

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 = "Jan Hauke and Eric Hahnen and Stephanie Schneider and Alexander Reuss and Lisa Richters and Stefan Kommoss and Andr{\'e} Heimbach and Frederik Marm{\'e} and Sandra Schmidt and Katharina Prieske and Heidrun Gevensleben and Alexander Burges and Julika Borde and {De Gregorio}, Nikolaus and Peter N{\"u}rnberg and Ahmed El-Balat and Holger Thiele and Felix Hilpert and Janine Altm{\"u}ller and Werner Meier and DImo DIetrich and Rainer Kimmig and Birgid Schoemig-Markiefka and Karin Kast and Elena Braicu and Klaus Baumann and Christian Jackisch and Park-Simon, {Tjoung Won} and Corinna Ernst and Lars Hanker and Jacobus Pfisterer and Andreas Schnelzer and {Du Bois}, Andreas and Schmutzler, {Rita K.} and Philipp Harter",

year = "2019",

month = sep,

day = "1",

doi = "10.1136/jmedgenet-2018-105930",

language = "English",

volume = "56",

pages = "574--580",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

number = "9",

}

Hauke, J, Hahnen, E, Schneider, S, Reuss, A, Richters, L, Kommoss, S, Heimbach, A, Marmé, F, Schmidt, S, Prieske, K, Gevensleben, H, Burges, A, Borde, J, De Gregorio, N, Nürnberg, P, El-Balat, A, Thiele, H, Hilpert, F, Altmüller, J, Meier, W, DIetrich, DI, Kimmig, R, Schoemig-Markiefka, B, Kast, K, Braicu, E, Baumann, K, Jackisch, C, Park-Simon, TW, Ernst, C, Hanker, L, Pfisterer, J, Schnelzer, A, Du Bois, A, Schmutzler, RK & Harter, P 2019, 'Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: Results of the observational AGO-TR1 study (NCT02222883)', Journal of Medical Genetics, vol. 56, no. 9, pp. 574-580. https://doi.org/10.1136/jmedgenet-2018-105930

TY - JOUR

T1 - Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: 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

PY - 2019/9/1

Y1 - 2019/9/1

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.

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U2 - 10.1136/jmedgenet-2018-105930

DO - 10.1136/jmedgenet-2018-105930

M3 - Journal articles

C2 - 30979843

AN - SCOPUS:85064276507

SN - 0022-2593

VL - 56

SP - 574

EP - 580

JO - Journal of Medical Genetics

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IS - 9

ER -

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

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