Characterization of Activating Mutations of the MEK1 Gene in Papillary Thyroid Carcinomas

Background: Genetic alterations activating the mitogen-activated protein kinase (MAPK) signaling pathway, most commonly BRAF and RAS mutations, are common in papillary thyroid carcinoma (PTC). Somatic mutations of the MEK gene, also known as mitogen-activated protein kinase kinase 1 (MAP2K1), coding for a signaling protein downstream of BRAF, have been found in several cancer types. The goal of this study was to investigate if functional MEK1 mutations occur in thyroid cancer (TC). Methods: We analyzed MEK1 mutation status in a series of 101 PTCs lacking other known driver mutations using Sanger sequencing and targeted next-generation sequencing. In addition, 64 follicular and Hurthle cell carcinomas and 32 follicular adenomas were studied. The occurrence of MEK1 mutations was evaluated using another series of thyroid tumors studied by targeted next-generation sequencing. Western blot and RNA-seq analyses were performed on selected tumors. Results: We detected MEK1 mutations in 2/101 (2%) PTCs that otherwise had no known genetic alterations, in 0/64 follicular and Hurthle cell carcinomas, and in 0/32 follicular adenomas. Two positive tumors carried the same in-frame deletion p.L98_I103del; K104I (c.292_309del18; c.311A>T) located in exon 3 of the gene. One additional MEK1 mutation was identified following routine molecular tumor profiling. The tumor had an in-frame deletion p.I99_K104del (c.294_311del18) also located in exon 3. Western blot analysis of one of the tumors showed activation of the MAPK pathway. Using RNA-seq analysis to evaluate changes in gene expression, these tumors were RAS-like and showed a high thyroid differentiation score. Phenotypically, the MEK1-positive PTCs were all encapsulated and had a predominantly or exclusively follicular architecture, being diagnosed as a classic papillary type with a significant follicular pattern ( x 2) or follicular variant PTC ( x 1). Follow-up was available for 2 patients, with no evidence of disease found 2 and 10 years postsurgery. Conclusions: In this study, we report the occurrence of functional MEK1 mutations in PTC. All mutations are in-frame deletions in exon 3 of MEK1, representing another mechanism of activation of the MAPK pathway in papillary carcinomas with a predominantly follicular growth pattern.