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Ovarian cancer onset across different BRCA mutation types: a view to a more tailored approach for BRCA mutated patients
  1. Claudia Marchetti1,2,
  2. Beyhan Ataseven3,4,
  3. Chiara Cassani5,6,
  4. Carolina Maria Sassu1,
  5. Luigi Congedo2,
  6. Marco D'Indinosante2,
  7. Serena Cappuccio1,
  8. Kerstin Rhiem7,
  9. Eric Hahnen7,
  10. Emanuela Lucci Cordisco8,9,
  11. Eloisa Arbustini10,
  12. Philipp Harter3,
  13. Angelo Minucci11,
  14. Giovanni Scambia1,2 and
  15. Anna Fagotti1,2
  1. 1Dipartimento Scienze della Salute della Donna e del Bambino, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
  2. 2Dipartimento Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italy
  3. 3Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung Essen-Huttrop, Essen, Germany
  4. 4Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Germany
  5. 5Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
  6. 6Unit of Obstetrics and Gynecology, IRCCS, Fondazione Policlinico San Matteo, Pavia, Italy
  7. 7Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Koln, Germany
  8. 8UOC Genetica Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
  9. 9Medicina Genomica, Dipartimento Scienze della Vita e Sanità Pubblica, Universita Cattolica del Sacro Cuore, Roma, Italy
  10. 10Center for Inherited Cardiovascular Disease, IRCCS, Fondazione Policlinico San Matteo, Pavia, Italy
  11. 11Molecular and Genomic Diagnostics Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
  1. Correspondence to Professor Giovanni Scambia, Dipartimento Scienze della Salute della Donna e del Bambino, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma 00168, Italy; giovanni.scambia{at}policlinicogemelli.it

Abstract

Objective To evaluate the role of different specific types of germline breast cancer susceptibility BRCA mutations on the age of onset of high grade serous ovarian cancer.

Methods This was a multicenter, international, retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations in BRCA1/2 genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type of BRCA1/2 genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared.

Results Excluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. The BRCA1 gene was affected in 324 (68.4%) cases, while BRCA2 was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer between BRCA1 and BRCA2 patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in the BRCA1 and BRCA2 subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55).

Conclusion Different types of germline BRCA mutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer.

  • Ovarian Cancer
  • BRCA1 Protein
  • BRCA2 Protein
  • Surgical Oncology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

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  • Contributors CM, BA, CC, CMS, LC, MD, SC, KR, EH, EA, and PH were mainly involved in data conceptualization, collection, and analysis. AM and ELC were experts in genetics, and supervised and reviewed the collection of detailed genetic data. CM, GS, and AF were mainly involved in planning the study and surveying the staff. All the authors have read, reviewed, edited, and approved the manuscript before submission. CM is responsible for the overall content as the guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.