Speaker 1: Arwa Alsaud, PhD student, University of Manchester
Title: Investigating the Molecular and Functional Consequences of Pathogenic NF2 Variants
Abstract: NF2-related schwannomatosis is a tumour predisposition disease caused by pathogenic variants in the NF2 gene, which encodes the tumour suppressor Merlin. However, the molecular and functional consequences of different classes of NF2variants are not always fully understood. My PhD project aims to characterise selected NF2 variants representing distinct molecular mechanisms, including large exon deletions, a 5′UTR variant, and a deep intronic variant. Using molecular and cellular approaches, the project will investigate how these variants affect NF2 transcript processing, Merlin expression, and function. Ultimately, this work aims to improve our understanding of NF2 variant pathogenicity and contribute towards approaches that could be applied to the functional characterisation of additional NF2 variants, including variants of uncertain significance.
Speaker 2: Benjamin Taylor, PhD student, University of Manchester
Title: The search for hidden breast cancer variants
Abstract: Hereditary breast and ovarian cancer syndrome (HBOC) accounts for ~5-10% of breast cancer cases, ~20% of which are caused by pathogenic variants within the BRCA1 and BRCA2 genes. However, ~20% of breast cancer cases are predicted to have a familial component, leaving ~50% of heritability unaccounted for. This project focuses on expanding the mutational and clinical spectrum of BRCA1/2 variants through frequency and genotype-phenotype analyses. Furthermore, we aim to provide functional evidence for a novel BRCA1 5’UTR variant, c.-107A>T, which confers heritable hypermethylation of the BRCA1 promoter leading to allelic silencing. Here, we present current progress for this work, including evidence of variant specific differences in breast and/or ovarian cancer onset, the differential distribution of variants across BRCA1/2, and the characterisation of a CRISPR-Cas9 engineered MCF10A BRCA1 c.-107A>T -/- cell line.