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.
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.
Authors: V P Yu; M Koehler; C Steinlein; M Schmid; L A Hanakahi; A J van Gool; S C West; A R Venkitaraman Journal: Genes Dev Date: 2000-06-01 Impact factor: 11.361
Authors: D O Ferguson; J M Sekiguchi; S Chang; K M Frank; Y Gao; R A DePinho; F W Alt Journal: Proc Natl Acad Sci U S A Date: 2000-06-06 Impact factor: 11.205
Authors: S Thiagalingam; S Laken; J K Willson; S D Markowitz; K W Kinzler; B Vogelstein; C Lengauer Journal: Proc Natl Acad Sci U S A Date: 2001-02-13 Impact factor: 11.205
Authors: K Lindblad-Toh; D M Tanenbaum; M J Daly; E Winchester; W O Lui; A Villapakkam; S E Stanton; C Larsson; T J Hudson; B E Johnson; E S Lander; M Meyerson Journal: Nat Biotechnol Date: 2000-09 Impact factor: 54.908
Authors: A Tutt; D Bertwistle; J Valentine; A Gabriel; S Swift; G Ross; C Griffin; J Thacker; A Ashworth Journal: EMBO J Date: 2001-09-03 Impact factor: 11.598
Authors: H A Risch; J R McLaughlin; D E Cole; B Rosen; L Bradley; E Kwan; E Jack; D J Vesprini; G Kuperstein; J L Abrahamson; I Fan; B Wong; S A Narod Journal: Am J Hum Genet Date: 2001-02-15 Impact factor: 11.025
Authors: Lucia Guidugli; Aura Carreira; Sandrine M Caputo; Asa Ehlen; Alvaro Galli; Alvaro N A Monteiro; Susan L Neuhausen; Thomas V O Hansen; Fergus J Couch; Maaike P G Vreeswijk Journal: Hum Mutat Date: 2013-12-03 Impact factor: 4.878
Authors: Zhigang C Wang; Nicolai Juul Birkbak; Aedín C Culhane; Ronny Drapkin; Aquila Fatima; Ruiyang Tian; Matthew Schwede; Kathryn Alsop; Kathryn E Daniels; Huiying Piao; Joyce Liu; Dariush Etemadmoghadam; Alexander Miron; Helga B Salvesen; Gillian Mitchell; Anna DeFazio; John Quackenbush; Ross S Berkowitz; J Dirk Iglehart; David D L Bowtell; Ursula A Matulonis Journal: Clin Cancer Res Date: 2012-08-21 Impact factor: 12.531
Authors: Junichi Soh; Naoki Okumura; William W Lockwood; Hiromasa Yamamoto; Hisayuki Shigematsu; Wei Zhang; Raj Chari; David S Shames; Ximing Tang; Calum MacAulay; Marileila Varella-Garcia; Tõnu Vooder; Ignacio I Wistuba; Stephen Lam; Rolf Brekken; Shinichi Toyooka; John D Minna; Wan L Lam; Adi F Gazdar Journal: PLoS One Date: 2009-10-14 Impact factor: 3.240