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BRCA1/2 Mutation Status Influences Somatic Genetic Progression in Inherited and Sporadic Epithelial Ovarian Cancer Cases¹

Department of Oncology, Strangeways Research Laboratories, Cambridge, United Kingdom [S. J. R., P. D. P. P., P. H., C. P., B. A. J. P.]; Department of Pathology, Inova Fair Oaks Hospital, Fairfax, Virginia [B. W.]; Department of Pathology, Addenbrookes Hospital, Cambridge, United Kingdom [L. B.]; Cancer Research United Kingdom Translational Oncology Laboratory, John Vane Science Centre, Charterhouse Square, London, United Kingdom [A. A., S. A. G.]; University College London, Department of Obstetrics and Gynaecology, London, United Kingdom [D. W.]; Department of Obstetrics and Gynaecology, Meir Hospital, Sapier Medical Centre, Meyir Hospital, Kfar-Saba, Israel [A. F.]; Department of Clinical Oncology, Royal Marsden Hospital, London, United Kingdom [M. G.]; Department of Cancer Genetics Roswell Park Cancer Institute Buffalo, New York [R. D., M. S. P.]; and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California [A. S. W.]

Metaphase comparative genomic hybridization was used to analyze the spectrum of genetic alterations in 141 epithelial ovarian cancers from BRCA1 and BRCA2 mutation carriers, individuals with familial non-BRCA1/2 epithelial ovarian cancer, and women with nonfamilial epithelial ovarian cancer. Multiple genetic alterations were identified in almost all tumors. The high frequency with which some alterations were identified suggests the location of genes that are commonly altered during ovarian tumor development. In multiple chromosome regions, there were significant differences in alteration frequency between the four tumor types suggesting that BRCA1/2 mutation status and a family history of ovarian cancer influences the somatic genetic pathway of ovarian cancer progression. These findings were supported by hierarchical cluster analysis, which identified genetic events that tend to occur together during tumorigenesis and several alterations that were specific to tumors of a particular type. In addition, some genetic alterations were strongly associated with differences in tumor differentiation and disease stage. Taken together, these data provide molecular genetic evidence to support previous findings from histopathological studies, which suggest that clinical features of ovarian and breast tumors differ with respect to BRCA1/2 mutation status and/or cancer family history.

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