Project description:Background: The amplification event occurring at chromosome locus 11q13, reported in several different cancers, includes a number of potential oncogenes. We have previously reported amplification of one such oncogene, CCND1, to be correlated with an adverse effect of tamoxifen in premenopausal breast cancer patients. Overexpression of cyclin D1 protein however, confers tamoxifen resistance but not a tamoxifen induced adverse effect. Potentially, co-amplification of an additional 11q13 gene, with a resulting protein overexpression, is required to cause an agonistic effect. Moreover, during 11q13 amplification a deletion of the distal 11q region has been described. In order to assess the potential impact of the deletion we have examined a selected marker for this event. Methods: Array CGH analysis was employed to identify and confirm changes in the gene expression of a number of different genes mapping to the 11q chromosomal region, associated with CCND1 amplification. The subsequent protein expression of these candidate genes was then examined in a clinical material of 500 primary breast cancers from premenopausal patients randomized to either tamoxifen or no adjuvant treatment. The protein expression was also compared to the CGH data in a subset of 56 breast cancer samples. Results: Cortactin and FADD overexpression was linked to CCND1 amplification, determined by FISH, but was not associated with a diminished effect of tamoxifen. However, deletion of distal chromosome 11q, defined as downregulation of the marker Chk1, was associated with an impaired tamoxifen response, and interestingly, also with low proliferative breast cancer of low grade. For Pak1 and cyclin D1 the protein expression corresponded to the gene expression data from the CGH analysis. Conclusions: The results indicate that many 11q13 associated gene products are overexpressed in conjunction with cyclin D1 but not linked to an agonistic effect of tamoxifen. Finally, the deletion of distal 11q, linked to 11q13 amplification, might be an important event affecting breast cancer outcome and tamoxifen response. Keywords: comparative genomic hybridisation 56 samples with 11q13 amplification have been analysed and compared with protein expression results from immunohistochemical analyses.

Project description:Background: The amplification event occurring at chromosome locus 11q13, reported in several different cancers, includes a number of potential oncogenes. We have previously reported amplification of one such oncogene, CCND1, to be correlated with an adverse effect of tamoxifen in premenopausal breast cancer patients. Overexpression of cyclin D1 protein however, confers tamoxifen resistance but not a tamoxifen induced adverse effect. Potentially, co-amplification of an additional 11q13 gene, with a resulting protein overexpression, is required to cause an agonistic effect. Moreover, during 11q13 amplification a deletion of the distal 11q region has been described. In order to assess the potential impact of the deletion we have examined a selected marker for this event. Methods: Array CGH analysis was employed to identify and confirm changes in the gene expression of a number of different genes mapping to the 11q chromosomal region, associated with CCND1 amplification. The subsequent protein expression of these candidate genes was then examined in a clinical material of 500 primary breast cancers from premenopausal patients randomized to either tamoxifen or no adjuvant treatment. The protein expression was also compared to the CGH data in a subset of 56 breast cancer samples. Results: Cortactin and FADD overexpression was linked to CCND1 amplification, determined by FISH, but was not associated with a diminished effect of tamoxifen. However, deletion of distal chromosome 11q, defined as downregulation of the marker Chk1, was associated with an impaired tamoxifen response, and interestingly, also with low proliferative breast cancer of low grade. For Pak1 and cyclin D1 the protein expression corresponded to the gene expression data from the CGH analysis. Conclusions: The results indicate that many 11q13 associated gene products are overexpressed in conjunction with cyclin D1 but not linked to an agonistic effect of tamoxifen. Finally, the deletion of distal 11q, linked to 11q13 amplification, might be an important event affecting breast cancer outcome and tamoxifen response. Keywords: comparative genomic hybridisation

Project description:OBJECTIVES: Amplification of the 11q13 locus is commonly observed in a number of human cancers including both breast and ovarian cancer. Cyclin D1 and EMS1 have been implicated as candidate oncogenes involved in the emergence of amplification at this locus. Detailed analysis of the 11q13 amplicon in breast cancer led to the discovery of four regions of amplification suggesting the involvement of other genes. Here, we investigate the role of EMSY, a recently described BRCA2 interacting protein, as a key element of the 11q13 amplicon in ovarian cancer. EMSY maps to 11q13.5 and is amplified in 13% of breast and 17% of ovarian carcinomas. METHODS: EMSY amplification was assessed by fluorescent in-situ hybridization (FISH) in 674 ovarian cancers in a tissue microarray and correlated with histopathological subtype and tumor grade. A detailed map of the 11q13 amplicon in 51 cases of ovarian cancer was obtained using cDNA-array-based comparative genomic hybridization (aCGH). To further characterize the role of EMSY within this amplicon, we evaluated both the amplification profiles and RNA expression levels of EMSY and two other genes from the 11q13 amplicon in an additional series of 22 ovarian carcinomas. : EMSY amplification was seen in 52/285 (18%) high grade papillary serous carcinomas, 4/27 (15%) high grade endometrioid carcinomas, 3/38 (8%) clear cell carcinomas, and 3/10 (30%) undifferentiated carcinomas. aCGH mapping of 11q13 in ovarian cancer showed that EMSY localized to the region with the highest frequency of copy number gain. Cyclin D1 and EMS1 showed a lower frequency of copy number gain. A highly significant correlation between EMSY gene amplification and RNA expression was also observed (P = 0.0001). This was a stronger correlation than for other genes at 11q13 including Cyclin D1 and PAK1. CONCLUSIONS: These findings support the role of EMSY as a key oncogene within the 11q13 amplicon in ovarian cancer. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set

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Characterization of amplification patterns and target genes at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumors

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