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


METHODS
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.
Walsh
Christine S
CS
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cedars-Sinai Women's Cancer Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA. walshc@cshs.org
Ogawa
Seishi
S
Scoles
Daniel R
DR
Miller
Carl W
CW
Kawamata
Norihiko
N
Narod
Steven A
SA
Koeffler
H Phillip
HP
Karlan
Beth Y
BY
D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D018283:Cystadenocarcinoma, Papillary / Q000235:genetics*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D024182:Uniparental Disomy / Q000235:genetics*
D019313:BRCA1 Protein; D024682:BRCA2 Protein