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

• Published in: Clinical cancer research Vol. 14; no. 23; pp. 7645 - 7651
• Main Authors: WALSH, Christine S, OGAWA, Seishi, SCOLES, Daniel R, MILLER, Carl W, KAWAMATA, Norihiko, NAROD, Steven A, KOEFFLER, H. Phillip, KARLAN, Beth Y
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2008
• Subjects: Aged; Antineoplastic agents; Biological and medical sciences; BRCA1; BRCA1 Protein - genetics; BRCA2; BRCA2 Protein - genetics; Cystadenocarcinoma, Papillary - genetics; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Loss of heterozygosity; Loss of Heterozygosity - genetics; Medical sciences; Middle Aged; Oligonucleotide Array Sequence Analysis; Ovarian cancer; Ovarian Neoplasms - genetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Tumors; Uniparental disomy; Uniparental Disomy - genetics; Whole-genome analysis; Chromosomal aberration; Ovary carcinoma; Allelic imbalance; Ovary cancer; Malignant tumor; Female genital diseases; Ovarian diseases; Uniparental disomy; BRCA2 gene; Loss of heterozygosity; Genetics; Genome; BRCA1 gene; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1291

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.