Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

doi:10.1371/journal.pone.0186043

. 2017 Oct 20;12(10):e0186043.

doi: 10.1371/journal.pone.0186043. eCollection 2017.

Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Philipp Harter¹, Jan Hauke^{2

3}, Florian Heitz¹, Alexander Reuss⁴, Stefan Kommoss⁵, Frederik Marmé⁶, André Heimbach⁷, Katharina Prieske⁸, Lisa Richters^{2

3}, Alexander Burges⁹, Guido Neidhardt^{2

3}, Nikolaus de Gregorio¹⁰, Ahmed El-Balat¹¹, Felix Hilpert^{12

13}, Werner Meier¹⁴, Rainer Kimmig¹⁵, Karin Kast^{16

17

18}, Jalid Sehouli¹⁹, Klaus Baumann^{20

21}, Christian Jackisch²², Tjoung-Won Park-Simon²³, Lars Hanker²⁴, Sandra Kröber^{2

3}, Jacobus Pfisterer²⁵, Heidrun Gevensleben²⁶, Andreas Schnelzer²⁷, Dimo Dietrich²⁸, Tanja Neunhöffer²⁹, Mathias Krockenberger³⁰, Sara Y Brucker⁵, Peter Nürnberg^{31

32

33}, Holger Thiele³², Janine Altmüller^{31

32}, Josefin Lamla³⁴, Gabriele Elser³⁴, Andreas du Bois¹, Eric Hahnen^{2

3}, Rita Schmutzler^{2

3}

Affiliations

¹ Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
² Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Medical Faculty, Cologne, Germany.
³ Center for Integrated Oncology (CIO), University Hospital Cologne, Medical Faculty, Cologne, Germany.
⁴ Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany.
⁵ Department of Women's Health, Tübingen University Hospital, Tübingen, Germany.
⁶ National Center for Tumor Disease/Department of Gynecology, University of Heidelberg, Heidelberg, Germany.
⁷ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁸ Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁹ Department of Gynecology, University Hospital Munich-Großhadern. Munich, Germany.
¹⁰ Department of Gynecology, University of Ulm, Ulm, Germany.
¹¹ Department of Gynecology, University of Frankfurt, Frankfurt, Germany.
¹² Onkologisches Therapiezentrum, Krankenhaus Jerusalem, Hamburg, Germany/ Department of Gynecology, University of Kiel, Kiel, Germany.
¹³ Department of Gynecology, University of Kiel, Kiel, Germany.
¹⁴ Department of Gynecology, Evangelisches Krankenhaus, Duesseldorf, Germany.
¹⁵ Department of Gynecology, University of Essen, Essen, Germany.
¹⁶ Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁷ National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.
¹⁸ German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁹ Department of Gynecology and Gynecological Oncology, Charité, Campus Virchow, Berlin, Germany.
²⁰ Department of Gynecology and Obstetrics, Klinikum Ludwigshafen, Ludwigshafen, Germany.
²¹ Department of Gynecology, Gynecologic Endocrinology & Oncology, Philipps-University Marburg, Marburg, Germany.
²² Department of Gynecology and Obstetrics, Sana Klinikum, Offenbach, Germany.
²³ Department of Gynecology, Medizinische Hochschule Hannover, Hannover, Germany.
²⁴ Department of Gynecology & Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
²⁵ Center of Gynecological Oncology, Kiel, Germany.
²⁶ Institute of Pathology, University Hospital Bonn, Bonn, Germany.
²⁷ Department of Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
²⁸ University Hospital Bonn, Department of Otolaryngology, Head and Neck Surgery, Bonn, Germany.
²⁹ Department of Gynecology, Dr. Horst-Schmidt-Kliniken, Wiesbaden, Germany.
³⁰ Department of Gynecology, University of Würzburg, Würzburg, Germany.
³¹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
³² Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
³³ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
³⁴ AGO Study Group, Wiesbaden, Germany.

PMID: 29053726
PMCID: PMC5650145
DOI: 10.1371/journal.pone.0186043

Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Philipp Harter et al. PLoS One. 2017.

. 2017 Oct 20;12(10):e0186043.

doi: 10.1371/journal.pone.0186043. eCollection 2017.

Authors

Affiliations

¹ Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.
² Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Medical Faculty, Cologne, Germany.
³ Center for Integrated Oncology (CIO), University Hospital Cologne, Medical Faculty, Cologne, Germany.
⁴ Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany.
⁵ Department of Women's Health, Tübingen University Hospital, Tübingen, Germany.
⁶ National Center for Tumor Disease/Department of Gynecology, University of Heidelberg, Heidelberg, Germany.
⁷ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁸ Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁹ Department of Gynecology, University Hospital Munich-Großhadern. Munich, Germany.
¹⁰ Department of Gynecology, University of Ulm, Ulm, Germany.
¹¹ Department of Gynecology, University of Frankfurt, Frankfurt, Germany.
¹² Onkologisches Therapiezentrum, Krankenhaus Jerusalem, Hamburg, Germany/ Department of Gynecology, University of Kiel, Kiel, Germany.
¹³ Department of Gynecology, University of Kiel, Kiel, Germany.
¹⁴ Department of Gynecology, Evangelisches Krankenhaus, Duesseldorf, Germany.
¹⁵ Department of Gynecology, University of Essen, Essen, Germany.
¹⁶ Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁷ National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.
¹⁸ German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁹ Department of Gynecology and Gynecological Oncology, Charité, Campus Virchow, Berlin, Germany.
²⁰ Department of Gynecology and Obstetrics, Klinikum Ludwigshafen, Ludwigshafen, Germany.
²¹ Department of Gynecology, Gynecologic Endocrinology & Oncology, Philipps-University Marburg, Marburg, Germany.
²² Department of Gynecology and Obstetrics, Sana Klinikum, Offenbach, Germany.
²³ Department of Gynecology, Medizinische Hochschule Hannover, Hannover, Germany.
²⁴ Department of Gynecology & Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
²⁵ Center of Gynecological Oncology, Kiel, Germany.
²⁶ Institute of Pathology, University Hospital Bonn, Bonn, Germany.
²⁷ Department of Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
²⁸ University Hospital Bonn, Department of Otolaryngology, Head and Neck Surgery, Bonn, Germany.
²⁹ Department of Gynecology, Dr. Horst-Schmidt-Kliniken, Wiesbaden, Germany.
³⁰ Department of Gynecology, University of Würzburg, Würzburg, Germany.
³¹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
³² Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
³³ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
³⁴ AGO Study Group, Wiesbaden, Germany.

PMID: 29053726
PMCID: PMC5650145
DOI: 10.1371/journal.pone.0186043

Abstract

Background: Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in BRCA1/2 in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.

Methods: Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, NBN, PMS2, PTEN, PALB2, RAD51C, RAD51D, STK11, TP53) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.

Results: In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16-93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the BRCA1 (15.5%), BRCA2 (5.5%), RAD51C (2.5%) and PALB2 (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in BRCA1/2 (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients ≥60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for BRCA1/2 would miss in our series more than 5% of the patients with a deleterious variant in established risk genes.

Conclusions: 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to BRCA1/2 seems to be not sufficient.

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Conflict of interest statement

Competing Interests: The competing interests do not alter our policies on sharing data and materials as described below (#3): Philipp Harter, Consulting or Advisory Role—AstraZeneca; Roche/Genentech; Tesaro; Clovis; Pharmamar, Lilly, Sotio, Research Funding—AstraZeneca (Inst), Travel, Accommodations, Expenses—Medac. Stefan Kommoss, Honoraria: Astra Zeneca, Roche, Consulting or Advisory role: Roche. Alexander Burges, Honoraria – AstraZeneca, Roche, Consulting or Advisory Role – AstraZeneca, Roche, Response to Reviewers. Katharina Prieske, Travel, Research funding- Medac Oncology, Honoraria- Astra Zeneca, Roche. Nikolaus de Gregorio,, Consulting or Advisory Role—Roche Pharma AG, Astra Zeneca, Tesaro, Travel, Accommodations, Expenses—Astra Zeneca, Tesaro. Rainer Kimmig, Honoraria—AstraZeneca; Intuitive Surgical; Prostrakan; RIEMSER, Consulting or Advisory Role—Medtronic; Roche; Teva, Travel, Accommodations, Expenses—Cambridge Medical Robotics. Jalid Sehouli, Honoraria—AstraZeneca; PharmaMar; Roche; Tesaro, Consulting or Advisory Role—AstraZeneca; Clovis Oncology; Novocure; Roche; Tesaro, Research Funding—Amgen (Inst); Bayer (Inst); Lilly (Inst); Novartis (Inst). Ahmed El-Balat, Consulting or Advisory Role—AstraZeneca; Roche; Pharmamar; Olympus, Honoraria—Olympus, Travel, Accommodations, Expenses—Pharmamar; Olympus. Jacobus Pfisterer, Honoraria—Roche Pharma AG, Consulting or Advisory Role—Roche Pharma AG, Research Funding—Roche Pharma AG (Inst); Roche Pharma AG (Inst); Roche, Pharma AG (Inst), Travel, Accommodations, Expenses—Roche Pharma AG. Andreas Schnelzer, Honoraria: TEVA, Consulting or Advisory Role: AstraZeneca, Roche. Dimo Dietrich, Consulting or Advisory Role - Bayer; MDxHealth; r-biopharm, Research Funding—Metanomics (Inst), Patents, Royalties, Other Intellectual Property—Epigenomics AG. Andreas Du Bois, Consulting or Advisory Role—AstraZeneca; Pfizer; Pharmamar; Roche/Genentech, Advaxis, Clovis. Rita Schmutzler, Honoraria—AstraZeneca, Consulting or Advisory Role—AstraZeneca, Research Funding—AstraZeneca (Inst), Patents, Royalties, Other Intellectual Property—University of Cologne. Eric Hahnen, Honoraria—AstraZeneca, Consulting or Advisory Role—AstraZeneca, Research Funding—AstraZeneca (Inst). Jan Hauke, Florian Heitz, Alexander Reuss, Frederik Marme, Andre Heimbach, Lisa Richters, Guido Neidhardt,, Felix Hilpert, Werner Meier, Karin Kast, Klaus Baumann, Christian Jackisch, Tjoung-Won Park-Simon, Lars Hanker, Sandra Kroeber, Heidrun Gevensleben, Tanja Neunhöffer, Peter Nürnberg, Holger Thiele, Janine Altmüller, Mathias Krockenberger, Sara Y Brucker, Josefin Lamla, Gabriele Elser, No Relationships to Disclose.

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References

1. Sant M, Chirlaque Lopez MD, Agresti R, Sanchéz Pérez M, Holleczeck B, Bielska Lasota M, et al. Survival of women with cancers of breast and genital organs in Europe 1999–2007: results of the EUROCARE-5 study. Eur J Cancer. 2015. September 6. - PubMed
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1. Heitz F, Harter P, Barinoff J, Beutel B, Kannisto P, Grabowski JP, et al. Bevacizumab in the treatment of ovarian cancer. Adv Ther. 2012. September;29(9):723–35 doi: 10.1007/s12325-012-0041-9 - DOI - PubMed
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The study was funded by Astra Zeneca Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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[1] Sant M, Chirlaque Lopez MD, Agresti R, Sanchéz Pérez M, Holleczeck B, Bielska Lasota M, et al. Survival of women with cancers of breast and genital organs in Europe 1999–2007: results of the EUROCARE-5 study. Eur J Cancer. 2015. September 6. - PubMed

[2] Sant M, Chirlaque Lopez MD, Agresti R, Sanchéz Pérez M, Holleczeck B, Bielska Lasota M, et al. Survival of women with cancers of breast and genital organs in Europe 1999–2007: results of the EUROCARE-5 study. Eur J Cancer. 2015. September 6. - PubMed

[3] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016. July; 66(4):271–89 - PubMed

[4] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016. July; 66(4):271–89 - PubMed

[5] du Bois A, Lück HJ, Meier W, Adams HP, Möbus V, Costa S, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003. September 3; 95(17):1320–9. - PubMed

[6] du Bois A, Lück HJ, Meier W, Adams HP, Möbus V, Costa S, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003. September 3; 95(17):1320–9. - PubMed

[7] Heitz F, Harter P, Barinoff J, Beutel B, Kannisto P, Grabowski JP, et al. Bevacizumab in the treatment of ovarian cancer. Adv Ther. 2012. September;29(9):723–35 doi: 10.1007/s12325-012-0041-9 - DOI - PubMed

[8] Heitz F, Harter P, Barinoff J, Beutel B, Kannisto P, Grabowski JP, et al. Bevacizumab in the treatment of ovarian cancer. Adv Ther. 2012. September;29(9):723–35 doi: 10.1007/s12325-012-0041-9 - DOI - PubMed

[9] Hanker LC, Loibl S, Burchardi N, Pfisterer J, Meier W, Pujade-Lauraine E, et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012. October;23(10):2065–12. - PubMed

[10] Hanker LC, Loibl S, Burchardi N, Pfisterer J, Meier W, Pujade-Lauraine E, et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012. October;23(10):2065–12. - PubMed

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Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Affiliations

Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1)

Authors

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Abstract

Conflict of interest statement

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