Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomas

Abstract

Purpose: The importance of the BRCA gene products in maintaining genomic stability led us to hypothesize that BRCA-associatedand 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 matchedcontrol. Loss of heterozygosity andcopy number abnormalities were summarizedto define regions of amplification, deletion, or uniparental disomy (UPD), defined as loss of one allele and duplication of the remaining allele. Genomic abnormalities were comparedbetween BRCA-associated and sporadic tumors. Results: We compared6 BRCA-associated with 14 sporadic papillary serous ovarian carcinomas. Genetic instability, measuredby percentage of genome altered, was more pronounced in BRCA-associatedtumors (median, 86.6%; range, 54-100%) than sporadic tumors (median, 43.6%; range, 2-83%; P = 0.009). We usedfrequency plots to show the proportion of cases affectedby 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 foundin 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 observeddistinct genetic patterns between BRCA-associatedand sporadic ovarian cancers, suggesting that these papillary serous tumors arise from different molecular pathways. © 2008 American Association for Cancer Research.