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Thyroid. 2019 Aug 13. doi: 10.1089/thy.2019.0065. [Epub ahead of print]

Characterization of activating mutations of the <i>MEK1</i> gene in papillary thyroid carcinomas.

Author information

1
University of Pittsburgh, Department of Pathology, Pittsburgh, Pennsylvania, United States; dott.niclaborrelli@gmail.com.
2
University of Pittsburgh, Department of Pathology, Scaife Hall A-721, 3550 Terrace Street, Pittsburgh, Pennsylvania, United States, 15261; panebiancof@upmc.edu.
3
University of Pittsburgh, 6614, Department of Pathology, Pittsburgh, Pennsylvania, United States; Vic40@pitt.edu.
4
Brigham and Women's Hospital, Department of Pathology, Boston, Massachusetts, United States; jbarletta@bwh.harvard.edu.
5
University of Pittsburgh Medical Center, Department of Pathology, 3477 Euler Way, Pittsburgh, Pennsylvania, United States, 15213; kayac@upmc.edu.
6
University of Pittsburgh, Endocrine Surgery, Pittsburgh, Pennsylvania, United States; yipl@upmc.edu.
7
University of Pittsburgh, Pathology, Pittsburgh, United States; nikiforovamn@upmc.edu.
8
University of Pittsburgh, Department of Pathology, 3477 Euler Way, CLB Room 8031, Pittsburgh, Pennsylvania, United States, 15213; nikiforovye@upmc.edu.

Abstract

INTRODUCTION:

Genetic alterations activating the mitogen-activated protein kinase (MAPK) signaling pathway, most commonly <i>BRAF </i>and <i>RAS </i>mutations, are common in papillary thyroid carcinoma (PTC). Somatic mutations of the <i>MEK </i>gene, also known as mitogen-activated protein kinase 1 (<i>MAP2K1</i>), 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 <i>MEK1 </i>mutations occur in thyroid cancer.

METHODS:

We analyzed <i>MEK1 </i>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 Hürthle cell carcinomas and 32 follicular adenomas were studied. The occurrence of <i>MEK1 </i>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 <i>MEK1 </i>mutations in 2/101 (2%) of PTCs that otherwise had no known genetic alterations and in 0/64 follicular and Hürthle cell carcinomas 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 <i>MEK1 </i>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 for changes in gene expression, these tumors were RAS-like and showed high thyroid differentiation score. Phenotypically, the <i>MEK1</i>-positive PTCs were all encapsulated and had predominantly or exclusively follicular architecture, being diagnosed as classic papillary type with significant follicular pattern (x2) or follicular variant PTC (x1). Follow-up was available for 2 patients, with no evidence of disease found 2 and 10 years post-surgery.

CONCLUSIONS:

In this study, we report the occurrence of functional <i>MEK1 </i>mutations in papillary thyroid cancer. All mutations are in-frame deletion in exon 3 of <i>MEK1</i>, representing another mechanism of activation of the MAPK pathway in papillary carcinomas with predominantly follicular growth pattern.

PMID:
31407636
DOI:
10.1089/thy.2019.0065

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