Genetic approaches to improve hereditary cancer diagnosis based on next-generation sequencing data

Abstract

The overarching aim of the present thesis project is to implement new testing strategies and develop new tools that will contribute to improve the genetic diagnosis of hereditary cancer, with the ultimate goal of individualizing the risk estimations of patients and their families in order to personalize prevention, follow-up, treatment and prophylactic recommendations.

This study has been mainly focused on the two most prevalent HC syndromes: hereditary breast and ovarian cancer and hereditary colorectal cancer, although data on other less prevalent cancer syndromes are also presented.

Specific aims

1. To elucidate the role of new candidate cancer-predisposing genes and to devise new genotype-phenotype correlations.

2. To improve the classification of VUS.

3. To increase the mutation detection rate of the studied genes, following two different approaches: 3.1. Implementation of somatic testing in unsolved hereditary cancer patients with two goals: to assess the prevalence of mosaicism and to evaluate the frequency of double somatic hits among Lynch-like syndrome patients. 3.2. Implementation of new testing strategies complementary to DNA-based sequencing to address mutational discovery in previously unexplored regions.