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.

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

“…GAB2 resides on the fourth most significant amplicon in high-grade serous ovarian cancer (3), the focal peak located on 11q14.1. This amplified region has been identified as a recurrent alteration in breast (9,22) and ovarian cancer (19) as well as in metastatic melanoma (24). Across over 6,300 different TCGA samples, this region is among the 26 most amplified regions in all cancers (21).…”

“…In ovarian cancer, the 11q14.1 amplicon at is smaller and centered over GAB2. Although prior studies in ovarian cancer have highlighted the 11q14.1 amplification (3,19), the identities of the candidate gene targets of amplification were not well clarified. These studies do not preclude the possibility that several genes on the same amplicon may cooperate to drive oncogenic programs.…”

“…Prior work identified 11q14.1 as recurrently amplified in ovarian cancer (19), but several genes including CCND1, PAK1, and GAB2 have been nominated as potential targets of this amplification. We used the Genomic Identification of Significant Targets in Cancer Version 2.0 (GISTIC 2.0) algorithm (20) to identify recurrent copy number alterations in 562 samples within TCGA ovarian cancer dataset (3,21).…”

Genetic profiles distinguish different types of hereditary ovarian cancer

“…Mutations of EMSY are associated with poor outcome and serous histology. Candidate genes involved in tumor suppression included BRCA2 in the sporadic subset, GATA4 and FANCA in the BRCA1 tumors (34). Loss of FANCA proteins implicates that inhibition of the DNA damage signalling poly (ADP-ribose) polymerase (PARP) protein may be useful in a subset of sporadic tumors (35).…”

Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion

“…[4][5][6][7] Overexpression of Pak1 has been found in several human cancers, 7 such as breast and colorectal cancers, and amplification of Pak1 at 11q13 has been reported in bladder and ovarian cancers. [8][9][10] Moreover, activation of Pak1 by phosphorylation at Thr 212 (p-Pak1 Thr…”