Brown Lindsay A, Kalloger Steve E, Miller Melinda A, Shih Ie-Ming, McKinney Steven E, Santos Jennifer L, Swenerton Ken, Spellman Paul T, Gray Joe, Gilks C Blake, Huntsman David G
Department of Pathology, Vancouver Coastal Health Research Institute, Genetic Pathology Evaluation Centre, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada.
Genes Chromosomes Cancer. 2008 Jun;47(6):481-9. doi: 10.1002/gcc.20549.
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.
11q13位点的扩增在乳腺癌、卵巢癌、头颈癌、口腔癌和食管癌中普遍存在。对该区域的研究发现了多个扩增子，其中包含多个潜在的癌基因，如EMSY、PAK1、RSF1和GAB2。在此，我们研究上述四个基因的扩增及其在组织学和临床定义的卵巢癌亚组中的预后意义。通过荧光原位杂交技术，在包含538例具有12年随访数据的临床注释卵巢癌组织芯片中，评估了这四个基因的扩增情况。总体而言，在整个队列中，269例中有44例（16%）EMSY扩增，255例中有38例（15%）PAK1扩增，310例中有37例（12%）RSF1扩增，255例中有41例（16%）GAB2扩增。EMSY、PAK1、RSF1和GAB2的扩增彼此高度相关，且与浆液性组织学相关。单因素生存分析表明，EMSY和RSF1扩增的肿瘤预后明显较差。然后，使用分子倒置探针阵列研究了33例高级别浆液性癌中的11q13扩增子。扩增子的核心定位于一个6兆碱基区域，包含EMSY、PAK1、RSF1和GAB2。然而，还观察到了第二个更靠近端粒的扩增子，尚未确定其候选基因。总之，早期卵巢癌中11q13的这四个推定癌基因的扩增与浆液性组织学相关，在EMSY和RSF1的情况下，预后较差。这些发现支持了这样的假设，即卵巢癌中的11q13扩增子可能由一组基因驱动，而不是由单个癌基因驱动。本文包含可在http://www.interscience.wiley.com/jpages/1045-2257/suppmat获取的补充材料。
