Genetic characterization of malignant melanoma and breast cancer
Sammanfattning: Malignant melanoma and breast cancer are common malignant diseases characterized by considerable heterogeneity with respect to genetics, histopathology, biology and clinical course. In breast cancer, two major susceptibility genes have been identified, BRCA1 and BRCA2, which account for a significant proportion of high-risk breast cancer families. Breast tumors arising in BRCA1 or BRCA2 mutation carriers typically have distinct histopathological and molecular features, suggesting that tumor genotype and phenotype can be used to trace genetic origin also in non-BRCA1/2 familial cases. In melanoma, one major susceptibility gene, CDKN2A, is responsible for approximately 25% of multi-case melanoma families. Kindreds with cases of both ocular and cutaneous malignant melanoma are predominantly CDKN2A negative, implying that additional melanoma susceptibility genes exist. Tumors from both malignant melanoma patients and breast cancer patients harbor numerous genomic alterations, which pinpoint genes of importance for tumor development, and may be used as tools for improved diagnostics and prediction of clinical course. The advent of the microarray technology for comparative genomic hybridization (CGH) has increased the resolution dramatically for analysis of DNA copy number changes. The current thesis is focused on analysis of DNA copy number changes in tumors and genetic linkage analysis of breast cancer and malignant melanoma. A novel melanoma susceptibility locus was mapped to chromosome 9q21.32 by genome wide linkage analysis of two unique Danish pedigrees with multiple cases of ocular and cutaneous malignant melanoma (PAPER I). To investigate chromosomal aberration patterns in cancer cells we constructed a high-resolution BAC microarray platform with tiling and contiguous coverage of the human genome and used CGH analysis of breast cancer cell lines to reveal novel amplifications and homozygous deletions (PAPER IV). Using tiling array CGH, we further characterized the genomic profiles of 40 melanoma cell lines, again revealing novel aberrations and patterns/combinations of chromosomal changes, suggesting specific genomic programs in melanoma development (PAPER II). In PAPER III we investigated whether DNA copy number analysis can be used for classification of inherited breast cancer. Array CGH analysis was shown to discriminate BRCA1, BRCA2 associated and sporadic breast cancers. This implicates that an underlying genetic predisposition may give rise to specific chromosomal aberration patterns during tumor progression. Taken together, our results have provided novel insights into the genetic and genomic mechanisms of malignant melanoma and breast cancer development.
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