Identification and assessment of variants of uncertain significance in familial cancer syndromes

[摘要] The identification of the causative mutation(s) in individuals with familial cancer syndromes informs their clinical management and allows cascade testing of family members, which informs their clinical management in turn. The advent of next generation sequencing (NGS) has revolutionised diagnostic genetic analysis, demonstrated by this thesis. Three novel NGS assays have been developed. The first two assays allowed more comprehensive analysis of two genetically heterogeneous tumours, phaeochromocytoma/parganglioma and renal cell carcinoma, by creation of NGS-based gene panel tests. These assays allowed increased detection of germline mutations at a lower cost per gene and reduced processing time compared to previous methods of analysis. The third assay also uses NGS but, instead, to more thoroughly analyse a single gene. The full gene region for VHL was examined at mosaic detection level, with a clinically actionable mutation identified in 18% of patients with von Hippel-Lindau disease in whom a mutation could not be identified by conventional analysis. The difficulty of providing more comprehensive genetic analysis is the concurrent increase in identification of variants of uncertain significance (VUSs). In depth variant analysis was conducted for all VUSs identified during this research. The reassignment of 17% of these VUSs as pathogenic or benign was enabled.

[发布机构] University:University of Birmingham;Department:School of Clinical and Experimental Medicine

[关键词] Q Science;QH Natural history;QH426 Genetics