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UBC Theses and Dissertations

Characterization of hereditary cancer syndromes Schrader, Kasmintan Alexandra

Abstract

Hereditary cancer syndromes predispose to early-onset or multiple cancers in a person or family, follow Mendelian inheritance patterns and demonstrate stereotyped patterns of tumor development. Genotype-phenotype correlations direct clinical genetic testing and provide guidance for hereditary cancer management. This thesis began by examining the association of lobular breast cancer with germline mutations in CDH1, the gene encoding the epithelial cell-cell adhesion molecule E-cadherin and tested whether CDH1 represented a high-frequency breast cancer susceptibility gene, apart from its association with hereditary diffuse gastric cancer. In addition it examined other genotype-phenotype correlations including the association between granular cell tumors and a multiple congenital anomaly syndrome, the specific correlation between a recurrent somatic mutation in a transcription factor and adult-type granulosa cell tumors and the strong association of germline BRCA1 and BRCA2 mutations with high-grade serous epithelial ovarian cancer. These candidate gene analyses were performed using low-throughput molecular technologies. With the advent of cheaper DNA-sequencing capabilities, the application of these new technologies to novel Mendelian disease gene discovery and hereditary cancer management became the subsequent focus of the thesis. Objectives: To determine the frequency of germline CDH1 mutations in women with lobular breast cancer unselected for familial gastric cancer; to define the associations between several alternative genotype-phenotype correlations; and, to apply next-generation sequencing to determine the basis of a Mendelian disorder, in order to determine its utility as a potential familial cancer gene discovery and clinical tool. Selected Methods: Single amplicon mutation screening and sequence analysis of a large cohort of women with early-onset or familial lobular breast cancer. Next-generation sequencing analysis of a family with multiple individuals cosegregating spondyloepiphyseal dysplasia and retinitis pigmentosa. Results: Without a selective history of diffuse gastric cancer, potentially pathogenic germline mutations in CDH1 occured in women with early-onset or hereditary lobular breast cancer in less than two percent of individuals. Diagnosis of a Mucolipidosis type III gamma was possible using new sequencing technologies. Conclusion: There is utility in understanding genotype-phenotype correlations in order to direct genetic testing and novel gene identification. Next-generation sequencing technologies can succesfully be applied to Mendelian disorders with clear phenotypes for gene discovery.

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