Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives.
J Med Genet
; 58(1): 1-11, 2021 01.
Article
en En
| MEDLINE
| ID: mdl-32066632
ABSTRACT
BACKGROUND:
Familial 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.METHODS:
Normal 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.RESULTS:
The 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).CONCLUSION:
This 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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Gástricas
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Proteína p53 Supresora de Tumor
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Predisposición Genética a la Enfermedad
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Herencia Multifactorial
Límite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Med Genet
Año:
2021
Tipo del documento:
Article
País de afiliación:
Portugal