Redefinition of familial intestinal gastric cancer: Clinical and genetic perspectives
| Autor: | Sara Pinto Teles, Patrícia Oliveira, David G. Huntsman, Carla Oliveira, Samantha Hansford, Franco Roviello, Joana Carvalho, Diana Lemos, Janine Senz, Hugo Pinheiro, Celina São José, Valeria Pascale, Marta Ferreira, Giovanni Corso |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Proband Adult Male medicine.medical_specialty Multifactorial Inheritance Biology Germline 03 medical and health sciences 0302 clinical medicine Stomach Neoplasms Molecular genetics Genetics medicine diagnostics Humans Genetic Predisposition to Disease Age of Onset Genetics (clinical) Germ-Line Mutation Aged Aged 80 and over evidence based practice Cancer Microsatellite instability Middle Aged medicine.disease Pedigree 030104 developmental biology cancer: gastric clinical genetics molecular genetics 030220 oncology & carcinogenesis Medical genetics Female Hereditary diffuse gastric cancer Age of onset Tumor Suppressor Protein p53 |
| Popis: | BackgroundFamilial intestinal gastric cancer (FIGC) remains genetically unexplained and without testing/clinical criteria. Herein, we characterised the age of onset and disease spectrum of 50 FIGC families and searched for genetic causes potentially underlying a monogenic or an oligogenic/polygenic inheritance pattern.MethodsNormal and tumour DNA from 50 FIGC probands were sequenced using Illumina custom panels on MiSeq, and their respective germline and somatic landscapes were compared with corresponding landscapes from sporadic intestinal gastric cancer (SIGC) and hereditary diffuse gastric cancer cohorts.ResultsThe most prevalent phenotype in FIGC families was gastric cancer, detected in 138 of 208 patients (50 intestinal gastric cancer probands and 88 unknown gastric cancer histology relatives), followed by colorectal and breast cancers. After excluding benign and intronic variants lacking impact in splicing, 12 rare high-quality variants were found exclusively in 11 FIGC probands. Only two probands carried potentially deleterious variants, but lacked somatic second-hits, weakly supporting the monogenic hypothesis for FIGC. However, FIGC probands developed gastric cancer at least 10 years earlier and carried more TP53 germline common variants than SIGC (p=4.5E-03); FIGC and SIGC could be distinguished by specific germline and somatic variant profiles; there was an excess of FIGC tumours presenting microsatellite instability (38%); and FIGC tumours displayed significantly more somatic common variants than SIGC tumours (p=4.2E-06).ConclusionThis study proposed the first data-driven testing criteria for FIGC families, and supported FIGC as a genetically determined, likely polygenic, gastric cancer-predisposing disease, with earlier onset and distinct from patients with SIGC at the germline and somatic levels. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|