Identification of SPRY4 as a Novel Candidate Susceptibility Gene for Familial Nonmedullary Thyroid Cancer.
Thyroid
; 31(9): 1366-1375, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-33906393
ABSTRACT
Background:
The molecular basis of familial nonmedullary thyroid cancer (FNMTC) is still poorly understood, representing a limitation for molecular diagnosis and clinical management. In this study, we aimed to identify new susceptibility genes for FNMTC through whole-exome sequencing (WES) analysis of leukocyte DNA of patients from a highly informative FNMTC family.Methods:
We selected six affected family members to conduct WES analysis. Bioinformatic analyses were undertaken to filter and select the genetic variants shared by the affected members, which were subsequently validated by Sanger sequencing. To select the most likely pathogenic variants, several studies were performed, including family segregation analysis, in silico impact characterization, and gene expression (messenger RNA and protein) depiction in databases. For the most promising variant identified, we performed in vitro studies to validate its pathogenicity.Results:
Several potentially pathogenic variants were identified in different candidate genes. After filtering with appropriate criteria, the variant c.701C>T, p.Thr234Met in the SPRY4 gene was prioritized for in vitro functional characterization. This SPRY4 variant led to an increase in cell viability and colony formation, indicating that it confers a proliferative advantage and potentiates clonogenic capacity. Phosphokinase array and Western blot analyses suggested that the effects of the SPRY4 variant were mediated through the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, which was further supported by a higher responsiveness of thyroid cancer cells with the SPRY4 variant to a MEK inhibitor.Conclusions:
WES analysis in one family identified SPRY4 as a likely novel candidate susceptibility gene for FNMTC, allowing a better understanding of the cellular and molecular mechanisms underlying thyroid cancer development.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Tiroides
/
Biomarcadores de Tumor
/
Péptidos y Proteínas de Señalización Intracelular
/
Cáncer Papilar Tiroideo
/
Proteínas del Tejido Nervioso
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
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Female
/
Humans
/
Male
Idioma:
En
Revista:
Thyroid
Asunto de la revista:
ENDOCRINOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Portugal