Amplicon profiles in ovarian serous carcinomas

Abstract

Ovarian serous carcinoma is the most common and lethal type of ovarian cancer and its molecular etiology remains poorly understood. As an ongoing effort to elucidate the pathogenesis of ovarian serous carcinomas, we assessed the DNA copy number changes in 33 high-grade serous carcinomas and 10 low-grade serous tumors by using a genome-wide technique, single nucleotide polymorphism array, performed on affinity-purified tumor cells from fresh surgical specimens. Compared to low-grade tumors, highgrade serous carcinomas showed widespread DNA copy number changes. The most frequent alterations were in loci harboring candidate oncogenes: cyclin E1 (CCNE1), AKT2, Notch3 and PIK3CA as well as in novel loci, including 12p13, 8q24, 12p13 and 12q15. Seven amplicons were selected for dual color fluorescence in situ hybridization analysis in 90 high-grade serous carcinomas and 26 low-grade serous tumors, and a high level of DNA copy number gain (amplification) was found in CCNE1, Notch3, HBXAP/Rsf-1, AKT2, PIK3CA and chr12p13 occurring in 36.1%, 7.8%, 15.7%, 13.6%, 10.8% and 7.3% of high-grade serous carcinomas. In contrast, we did not observe high level of ERBB2 amplification in any of the samples. Low-grade tumors did not show DNA copy number gain in any of the loci, except in 2 (8%) of 24 low-grade tumors showing low copy number gain in the Notch3 locus. Taken together, our results provide the first comprehensive analysis of DNA copy number changes in highly pure ovarian serous carcinoma. These findings may have important biological and clinical implications. ' 2007 Wiley-Liss, Inc.

Overexpression of a Chromatin Remodeling Factor, RSF-1/HBXAP, Correlates with Aggressive Oral Squamous Cell Carcinoma

“…10 -12 We have demonstrated that RSF1 is located in the ch11q13.5 region, which is frequently amplified in several types of carcinoma, including ovarian highgrade serous carcinoma. 10,13,14 As compared to other genes within the ch11q13.5 amplicon, RSF1 exhibited the highest correlation between DNA amplification and RNA copy number, and it was responsible for cell growth in the presence of chemotherapeutic agents in ovarian cancer tissues, 10,15 suggesting that RSF1 serves as the "driver" gene within the ch11q13.5 amplicon. RSF-1 overexpression was highly associated with the most aggressive type of ovarian cancer, high-grade serous carcinoma, and shorter overall survival.…”

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

“…The latter two have the advantage of providing an unbiased genome wide assessment of copy number variation and have been widely used to characterize the complex genomic alterations attributable to ovarian cancer and reveal it to be a heterogeneous group of diseases , Meinhold-Heerlein et al 2005, Nakayama et al 2007, Staebler et al 2002. Recent studies of the genomic alterations between invasive serous carcinomas and low grade or borderline serous tumors have identified dramatic differences in DNA copy number changes (MeinholdHeerlein et al 2005, Nakayama et al 2007, Staebler et al 2002. High-grade serous carcinomas uniformly exhibited more extensive DNA copy number variations than borderline tumors or low-grade serous carcinomas (Figure 2).…”

“…DNA copy number changes are represented as pseudocolor gradients corresponding to the folds of increase (red boxes) and decrease (blue boxes), as compared to pooled normal samples. Reproduced with permission (Nakayama et al 2007).…”

“…High level Notch3 amplificati o n h a s b e e n o b s e r v e d i n 7 . 8 % o f h i g h -g r a d e s e r o u s carcinomas (Nakayama et al 2007), while high level protein overexpression was found in 63% of serous carcinomas and was significantly correlated with advanced stage, likelihood of metastasis, chemoresistance and poor overall survival (Jung et al 2010). Overexpression of the Notch ligands, Jagged-1 and Jagged-2, has also been identified in ovarian tumor cells lending support that activation of the Notch pathway promotes ovarian cancer proliferation and that inhibition of this pathway may be a viable therapeutic approach (Choi et al 2008, Hopfer et al 2005.…”

“…Studies in epithelial ovarian cancer have shown inconsistent associations between individual cell cycle regulatory protein expression and patient outcome (reviewed in Nam and Kim (Nam and Kim 2008)). Among the best studied in ovarian cancer is cyclin E. Amplification of the cyclin E gene occurs in 7-65% of ovarian cancers, typically resulting in overexpression of the cyclin E protein (Cancer Genome Atlas Research Network, 2011, Courjal et al 1996 1998, Mayr et al 2006, Nakayama et al 2007, Nakayama et al 2010, Schraml et al 2003a. Cyclin E expression has been found in as many as 97% of ovarian cancer/primary peritoneal cancer samples .…”