Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma

Feng Ye, Hongwei Gao, Lin Xiao, Zhixiang Zuo, Yueping Liu, Qi Zhao, Huijiao Chen, Weiyi Feng, Bo Fu, Linyong Sun, Xiaolin Jiang, Du He, He Jiang, Mei Yang, Li Li, Fei Chen, Xiang Liu, Shuang Li, Zhihui Li, Yong JiangLiang Cheng, Hong Bu

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Although the genotype–phenotype for familial medullary thyroid carcinoma (FMTC) is well studied, only few low susceptibility risk loci were identified for familial non-medullary thyroid carcinoma (FNMTC). The aim of this study is to screen and identify high-penetrate genes for FNMTC. A total of 34 families with more than two first-degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of MAP2K5 variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of MAP2K5 c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P < 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5–ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1/2(MEK1/2)–ERK1/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of MAP2K5 for molecular diagnosis as well as early prevention.

Original languageEnglish (US)
Pages (from-to)1321-1330
Number of pages10
JournalInternational Journal of Cancer
Volume144
Issue number6
DOIs
StatePublished - Mar 15 2019

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Keywords

  • Familial medullary thyroid carcinoma
  • MAP2K1/2-ERK1/2 signaling
  • MAP2K5-ERK5 signaling
  • familial non-medullary thyroid carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ye, F., Gao, H., Xiao, L., Zuo, Z., Liu, Y., Zhao, Q., Chen, H., Feng, W., Fu, B., Sun, L., Jiang, X., He, D., Jiang, H., Yang, M., Li, L., Chen, F., Liu, X., Li, S., Li, Z., ... Bu, H. (2019). Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma. International Journal of Cancer, 144(6), 1321-1330. https://doi.org/10.1002/ijc.31825