Molekulare Genomanalysen des invasiven Mammakarzinoms und Untersuchung des Einflusses chromosomaler Imbalancen auf die Genexpression

Comparative genomic hybridization (CGH) was used to make detailed resolutions of cytogenetic aberrations in invasive breast cancer. The most frequent changes found were gains of 1q, 8q, chromosome 20, and losses involving 16q, 19p, 17p and chromosome 22. The chromosomal imbalances correlated neither with extent of tumour growth, grade or differentiation. Analysis of intratumoral heterogeneity showed that in well advanced tumours, the karyotype of a single cell clone was mostly representative for the entire tumour cell population. Statistically, common intra- and interchromosomal aberrations were frequently detected, suggesting the existence of isochromosomes i(8)(q), i(1)(q), and unbalanced translocation t(1;16)(q;p). Several hints of potential tumour suppressor genes and oncogenes in the tumorigenesis of breast cancers were found. The two different tumour groups revealed common chromosomal aberrations, and also differences involving specific chromosome regions. Comparatively, lobular cancers showed higher incidences of loss of 16q and 22q, and lower incidences of gain of 8q, than their ductal counterparts. Evidence of gene activation and inactivation were detected in the form of minimal deviations of gene copy numbers, and amplifications. A linear dependancy of gene copy number was detected for CDH1 (16q22; E-Cadherin) and MYC (8q24; c-myc). Activation through high-level gene amplification was found for the growth factor receptors EGFR (7p12; EGF receptor) and ERBB2 (17q11.2-12; c-erbB2). Fourteen candidate genes for mammary tumorigenesis were identified, whose involvement in the malignant processes of breast cancers are only partly understood and still remain the targets of further investigations