Molecular Cytogenetics in Sporadic Breast Cancer

University dissertation from Department of Oncology; Jubileum Institute; Lund University; SE-221 85 Lund; Sweden

Abstract: In recent time breast cancer has become the most common form of female cancer in the western world. It has been estimated that the lifetime risk of women falling ill from the disease is 10%. The number of patients diagnosed each year has been increasing steadily since the 1970s. In 2002 the number of Swedish women diagnosed with breast cancer was 6,600, constituting every third female cancer diagnosed.Little is known about the order of appearance of different types of genetic aberrations, how they relate to each other, what their role is in the defining the clinical outcome of the patient, and which aberrations underlie therapy resistance. A comparative study between cytogenetics and CGH was conducted in 29 invasive breast cancers (paper I). The differences seen in the comparison of cytogenetic and CGH karyotyping can best be explained by the difficulties of culturing breast carcinoma cells in vitro. The gains and losses found by CGH may represent the predominant (often aneuploid) clone, whereas the G-banding karyotypes represents minor abnormal, near-diploid cell clone(s), which, for unknown reasons, has a growth advantage in short term culture. To explore the order of appearance of genetic aberrations in a direct manner, tumor cells from 21 non-diploid breast carcinomas were sorted for their DNA content by flow cytometry, and then analyzed separately by FISH (paper II). Data from these uncultured interphase cells showed that oncogene amplification, which is biologically and prognostically a very important genetic defect in breast cancer, takes place already before aneuploidization. The simultaneous presence of diploid and non-diploid malignant cells is also a clear indication of heterogeneity in the genetic composition of breast carcinoma. In order to shed light on how copy number aberrations (CNA) patterns are composed, a CGH analysis of 305 breast cancer tumors was conducted (paper III). Two different statistical approaches were able to identify the exact same CNA pattern groups, indicating that the groups are true biological entities, rather than reflection of the statistical modeling technique used. These different groups were correlated to distinct clinicopathological features and patient prognosis, and could predict patient outcome just as well as the traditional prognostic factors. In paper IV, characterization of the new and intrinsically Herceptin® resistant cell line JIMT-1, revealed an aberration pattern characteristic for aggressive breast cancers. Molecular cytogenetic techniques revealed numerous regions of CNA. Many of the genes in the aberrant regions are implicated in cancer development and drug/hormone metabolizing. In conclusion, the results from the studies presented herein, indicate that the genetic aberrations of breast cancer are complex, and not detected by conventional cytogenetic techniques. Implementation of molecular cytogenetic techniques in a large breast cancer material, identified specific patterns of aberrations, and these patterns are linked to patient prognosis. Characterization of a Herceptin® resistant cell line by use of microarray techniques revealed amplification and upregulation of several genes that are linked to the promotion of breast cancer.

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