Molecular and cytogenic studies of oncogene alterations in human breast and cervical carcinomas

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Oncology-Pathology

Sammanfattning: Characterization of human tumors with associated genetic changes is of importance for better understanding the tumor's basic biological behavior and of great value for clinical management of cancer patients. We therefore investigated oncogene amplifications in human breast and cervical carcinomas using molecular and cytogenetic methods, especially FISH. Genetic changes of one potential oncogene hTERT and its possible role in deregulation of telomerase activity in human cancers were also studied. In breast cancer, eight locus markers were analyzed. 17q showed complex rearrangement. Amplification of ERBB2, CCND1, CSH1(PL) and MYC accounts for nearly 90% of the tumors that exhibit amplified genes with a various frequencies from14 to 22%. Amplification of 20ql3, MDMX, MDM2 and Xq21 was detected at a relative low frequency (2-9%). Subsequent analyses showed that gene amplification was significantly correlated with aneuploidy and high proliferative activity. Co-amplification involving two or more genes was exclusively detected in aneuploid tumors with high proliferation rates. A large proportion of tumors also exhibited increased gene copy number. Tumors with gene amplification showed overall more genetic alterations than the tumors without gene amplification. We also observed an association between gene amplification and other prognostic parameters (tumor size, grade lymph node involvement and clinical stage). The data suggests that distinct patterns of gene amplification accompany different subgroups in terms of tumor behavior, which indicates that breast tumors with high malignant potential can be distinguished by detection of global oncogene amplification. In cervical cancer, low-level amplification with 3-7 copies of six locus markers was detected in 65% of the tumors. PIK3CA was altered in 43% of the tumors, followed by hTERT (33%), 20ql3.2 (30%), ERBB2 (29%), C-MYC (25%) and CCND1 (12%). Alterations of PIK3CA or complex changes involving three or more genes occur more frequently in advanced stage tumors. High-levels of protein expression of c-erbB2 and cmyc were observed predominantly in tumors with the corresponding gene amplified. A general trend was observed with increase of oncogene amplification in tumors with HPV infection, particularly for C-MYC and hTERT. The data thus indicates that HPV associated cervical carcinomas bear frequent alterations of oncogenes that might be involved in cervical cancer progression. Activation of hTERT is crucial for telomerase activity in human tumors. Genetic changes of hTERT were thus examined in both tumor cell lines and primary tumors. hTERT was amplified in about 30% of the samples and increased copy number of this gene was also frequently observed. Tumors with amplified hTERT in general showed high expression of its protein and telomerase activity, suggesting a potential role of this gene in upregulation of telomerase activity. 'Me close association of hTERT amplification with its protein expression and HPV infection suggest an interaction of HPV and hTERT in contributing to the dysregulation of this gene in carcinoma of the uterine cervix.

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