Identification of SPRY4 as a novel candidate susceptibility gene for familial nonmedullary thyroid cancer

Inês J. Marques, Inês Gomes, Marta Pojo, Carolina Pires, Margarida M. Moura, Rafael Cabrera, Catarina Santos, Wilfred F.J. van Ijcken, Manuel R. Teixeira, José S. Ramalho, Valeriano Leite, Branca M. Cavaco*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1366-1375
Number of pages10
JournalThyroid
Volume31
Issue number9
DOIs
Publication statusPublished - 7 Sep 2021

Bibliographical note

Funding Information:
This study was funded by Liga Portuguesa Contra o Cancro—Núcleo Regional do Sul (LPCC-NRS), Televisão Independente, Instituto Português de Oncologia de Lisboa Francisco Gentil, iNOVA4Health—UIDB/04462/2020, a program financially supported by Fundac¸ão para a Ciência e Tecnologia/Ministério da Educac¸ão e Ciência, and Asso-ciac¸ão de Endocrinologia Oncológica. The authors are thankful to LPCC-NRS that granted the researcher Marta Pojo. Inês J. Marques was a recipient of a PhD scholarship from the PhD Programme ProRegeM (Mechanisms of Disease and Regenerative Medicine) approved by Fundac¸ão para a Ciência e Tecnologia (FCT) - PD/BD/108086/2015, and Carolina Pires was granted with a PhD scholarship by FCT - 2020.07120.BD.

Publisher Copyright:
© Mary Ann Liebert, Inc.

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