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Genome-Wide Loss of Heterozygosity and Uniparental Disomy in BRCA1/2-Associated Ovarian Carcinomas

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cedars-Sinai Women's Cancer Research Institute, and ² Department of Medicine, Cedars-Sinai Medical Center Division of Hematologic Oncology, Samuel Oschin Comprehensive Cancer Institute, David Geffen School of Medicine at UCLA, Los Angeles, California; ³ Department of Hematology/Oncology, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan; and ⁴ Center for Research in Women's Health, Sunnybrook Women's College Health Science Center, University of Toronto, Canada

Requests for reprints: Christine S. Walsh, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cedars-Sinai Women's Cancer Research Institute, Samuel Oschin Comprehensive Cancer Institute, David Geffen School of Medicine at UCLA, 8700 Beverly Boulevard, Suite 160W, Los Angeles, CA 90048. Phone: 310-423-3599; Fax: 310-423-0155; E-mail: walshc{at}cshs.org.

Purpose: The importance of the BRCA gene products in maintaining genomic stability led us to hypothesize that BRCA-associated and sporadic ovarian cancers would have distinctive genetic profiles despite similarities in histologic appearance.

Experimental Design: A whole-genome copy number analysis of fresh, frozen, papillary serous ovarian cancer DNA was done using the Affymetrix 50K Xba Mapping Array using each patient's normal genomic DNA as the matched control. Loss of heterozygosity and copy number abnormalities were summarized to define regions of amplification, deletion, or uniparental disomy (UPD), defined as loss of one allele and duplication of the remaining allele. Genomic abnormalities were compared between BRCA-associated and sporadic tumors.

Results: We compared 6 BRCA-associated with 14 sporadic papillary serous ovarian carcinomas. Genetic instability, measured by percentage of genome altered, was more pronounced in BRCA-associated tumors (median, 86.6%; range, 54-100%) than sporadic tumors (median, 43.6%; range, 2-83%; P = 0.009). We used frequency plots to show the proportion of cases affected by each type abnormality at each genomic region. BRCA-associated tumors showed genome-wide loss of heterozygosity primarily due to the occurrence of UPD rather than deletion. UPD was found in 100% of the BRCA-associated and 50% of the sporadic tumors profiled.

Conclusions: This study reports on a previously underappreciated genetic phenomenon of UPD, which occurs frequently in ovarian cancer DNA. We observed distinct genetic patterns between BRCA-associated and sporadic ovarian cancers, suggesting that these papillary serous tumors arise from different molecular pathways.