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Pathology of Ovarian Cancers in BRCA1 and BRCA2 Carriers

¹ The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom; ² The Royal Marsden Hospital, London, United Kingdom; ³ Department of Cellular Pathology, John Radcliffe Hospital, Oxford, United Kingdom; ⁴ Centre Jean Perrin, Clermont-Ferrand, France; ⁵ Department of Pathology, Royal Free & University College, London, United Kingdom; ⁶ Service d’Anatomie Pathologique, Centre G-F Leclerc, Dijon, France; ⁷ Cancer Research U.K. Genetic Epidemiology Unit, Cambridge, United Kingdom; ⁸ Department of Experimental Oncology Istituto Nazionale Tumori, Milan, Italy; ⁹ Department of Pathology, Istituto Nazionale Tumori, Milan, Italy; ¹⁰ Department of Obstetrics and Gynaecology, General Hospital, University of Vienna, Vienna, Austria; ¹¹ Department of Clinical Genetics, Oulu University Hospital/University of Oulu, Oulu, Finland; ¹² Institute of Pathology and Molecular Immunology, University of Porto, R. Robert Frias, Porto, Portugal; ¹³ Laboratoire de Genetique, Lyon, France; ¹⁴ Mac-Delbruck-Centrum, Berlin, Germany; ¹⁵ Deutsches Krebsforschungszentrum, Divisions of Epidemiology and Molecular Genome Analysis, Heidelberg, Germany; ¹⁶Department of Genetics and Pathology, Leiden University, Leiden, the Netherlands; ¹⁷Department of Clinical Genetics and Medical Oncology, Daniel den Hoed Cancer Centre, Erasmus University Medical Centre Rotterdam, Rotterdam, the Netherlands; ¹⁸Department of Genetic Oncology and Cancer Control, Paoli-Calmettes Institute, Marseille, France; ¹⁹Cancer Research UK (CRUK) Genetic Epidemiology Laboratory and ²⁰Department of Gynaecological Oncology, St. James University Hospital, Leeds, United Kingdom; ²¹CRUK Human Cancer Genetics Research Group, Cambridge, United Kingdom; ²²Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania; ²³Unite de Genetique Oncologique, Institut Curie, Paris, France; ²⁴Division Epidemiology, Department of Medicine, University of California Irvine, Irvine California; ²⁵Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland; ²⁶Department of Pathology, University of Helsinki, Helsinki, Finland; ²⁷Laboratorio di Biologia Oncologica, Ospedale Infermi, Rimini, Italy

Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer.

Experimental Design: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated.

Results: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21–2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P < 0.0001), had a higher percentage solid component (P = 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers.

Conclusions: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively aggressive and may be expected to have poor prognosis, although this may be treatment dependent.

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