title: Amplification of 11q13 in ovarian carcinoma.
abstract: Amplification at the 11q13 locus is commonly observed in breast, ovarian, head and neck, oral, and esophageal cancer. Studies of this region led to the identification of multiple amplicons containing several potential oncogenes including EMSY, PAK1, RSF1, and GAB2. Here, we investigate the amplification of the above four genes and their prognostic significance in histologically and clinically defined subsets of ovarian cancer. Amplification of all four genes was assessed by fluorescent in situ hybridization in tissue microarrays containing 538 clinically annotated ovarian carcinomas with 12 years of follow-up data. Overall, for the entire cohort, EMSY was amplified in 44 (16%) of 269 cases, PAK1 was amplified in 38 (15%) of 255 cases, RSF1 was amplified in 37 (12%) of 310 cases, and GAB2 was amplified in 41 (16%) of 255 cases. Amplification of EMSY, PAK1, RSF1, and GAB2 were all highly correlated with each other and with a serous histology. Univariate survival analysis showed that tumors with EMSY and RSF1 amplification were associated with a significantly worse outcome. A molecular inversion probe array was then used to study the 11q13 amplicon in 33 high grade serous carcinomas. The core of the amplicon mapped to a 6-Mb region encompassing EMSY, PAK1, RSF1, and GAB2. However, a second more telomeric amplicon was also observed for which no candidate genes have been identified. In summary, amplification of these four putative oncogenes from 11q13 in early ovarian cancer is associated with a serous histology and in the case of EMSY and RSF1 a poor outcome. These findings support the hypothesis that the11q13 amplicon in ovarian cancer is likely driven by a cassette of genes rather than by a single oncogene. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
authors.affiliation: Department of Pathology, Vancouver Coastal Health Research Institute, Genetic Pathology Evaluation Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Brown
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Miller
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.forename: Steven E
authors.initials: SE
authors.lastname: McKinney
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Santos
authors.forename: Ken
authors.initials: K
authors.lastname: Swenerton
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.forename: Joe
authors.initials: J
authors.lastname: Gray
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D005810:Multigene Family / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D054462:p21-Activated Kinases / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C480344:EMSY protein, human; C490895:GAB2 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C452851:RSF1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; C515903:PAK1 protein, human; D054462:p21-Activated Kinases