Penetrance estimation and clinical, demographic and genetic characterization of HDGC families sharing a founder variant followed at Centro Hospitalar Universitario São João (CHUSJ)

• Autor(a) principal: João Abel Rainho Fonseca
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://hdl.handle.net/10216/156463
• topic: Ciências da saúde; Health sciences

Hereditary diffuse gastric cancer (HDGC), caused by CDH1 germline pathogenic, or likely-pathogenic variants, predisposes to early onset diffuse gastric (DGC) and lobular breast cancer (LBC). The CDH1 c.1901C>T pathogenic variant was previously defined as founder variant in the Northern Portuguese population, reported among different families, sharing a common ancestor. The primary goal of this thesis is to characterize these HDGC families, through establishment of extended family pedigrees and an updated comprehensive database with relevant data, to be used in disease risk calculation for carriers of this variant. Secondly, we aim to uncover why some carriers of this pathogenic variant develop early onset aggressive HDGC phenotypes, and others remain asymptomatic throughout their lives. We seek to find a set of possible genetic modifiers and CDH1-regulators that may work as predisposing or protective for the disease outcome, by taking advantage of our clinical database for cases selection, and the access to a biobank with biological material from these families. Detailed clinical and demographic data of individuals from 11 known families carrying the c.1901C>T variant followed at Centro Hospitalar Universitário São João (CHUSJ) were compiled, followed by the development of a reference database with updated clinical records. Pedigrees were built using an open-source software, subsequently trimmed for penetrance estimation analysis, which was performed in its entirety with several R software packages and tools. Previously available DNA was sent for whole genome sequencing (WGS) and analyzed with an in-house developed pipeline. This approach proved feasible prioritizing of true-positive and disease-causing single-nucleotide and copy-number variants (SNVs, CNVs), with the use of different variant calling software. Statistical analysis was performed to find significant differences amongst affected and non-affected groups based on the data collected. Extended pedigree information was obtained for the 11 families through genetic testing in several hospitals and/or patient reports at genetic counseling appointments, resulting in a clinical database comprising a total of 401 individuals. Specifically, for the CDH1 c.1901C>T variant, 43% (173/401) individuals underwent genetic testing at CHUSJ, of whom 43% (74/173) were found positive. 18% (13/74) of all carriers developed HDGC related cancers with clinical manifestation (9 DGC, 5 LBC), with a mean age at diagnosis of 34.9±10.4 years for DGC cases and 51.8±7.1 for LBC. Additional 19 carriers were found to have early gastric cancer confirmed at risk-reducing gastrectomy. Seven carriers opting for endoscopic surveillance only, remained HDGC-free after 65 years of age. Regarding genetic modifiers, our findings reveal groups of SNVs and CNVs exclusive from the young-affected carriers that may be disease predisposing. A total of 25 SNV cluster regions were identified, defined by an enrichment of exclusive rare variants, some overlapping regulatory sites. Furthermore, we identified CNVs overlapping exonic regions that will likely disturb genes associated with cellular proliferation regulation, as well as tight junction pathways. This work represents a steppingstone in the first intrafamilial lifetime-risk estimations for carriers of a single founder variant (CDH1 c.1901C>T) in the Portuguese population. It is projected that this robust clinical database will guide current and future studies for genetic modifiers and penetrance estimations, producing results that will contribute for guidelines' development with implications in patients' management.