Coexisting Germline CHEK2 and Somatic BRAFV600E Mutations in Papillary Thyroid Cancer and Their Association with Clinicopathological Features and Disease Course.

Danuta Gąsior-Perczak,Artur Kowalik,Iwona Pałyga,Estera Mikina,Janusz Kopczyński,Aldona Kowalska,Monika Siołek,Krzysztof Gruszczyński,Tomasz Trybek,Agnieszka Walczyk,Ryszard Mężyk,Stanisław Góźdź

doi:10.3390/cancers11111744

Danuta Gąsior-Perczak, Artur Kowalik + Show 10 more

Open Access

https://doi.org/10.3390/cancers11111744

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Journal: Cancers	Publication Date: Nov 7, 2019
Citations: 14	License type: CC BY 4.0

Affiliation: Holy Cross University, Jan Kochanowski University

Abstract

BRAFV600E is the most common somatic mutation in papillary thyroid carcinoma (PTC) and the majority of evidence indicates that it is associated with an aggressive clinical course. Germline mutations of the CHEK2 gene impair the DNA damage repair process and increase the risk of PTC. Coexistence of both mutations is expected to be associated with poorer clinical course. We evaluated the prevalence of concomitant CHEK2 and BRAFV600E mutations and their associations with clinicopathological features, treatment response, and disease course in PTC patients. The study included 427 unselected PTC patients (377 women and 50 men) from one center. Relationships among clinicopathological features, mutation status, treatment response, and disease outcomes were assessed. Mean follow-up was 10 years. CHEK2 mutations were detected in 15.2% and BRAFV600E mutations in 64.2% patients. Neither mutation was present in 31.4% cases and both BRAFV600E and CHEK2 mutations coexisted in 10.8% patients. No significant differences in clinicopathological features, initial risk, treatment response, or disease outcome were detected among these patient groups. CHEK2 mutations were significantly associated with older age, while BRAFV600E was significantly associated with older age and extrathyroidal extension. The coexistence of both mutations was not associated with more aggressive clinicopathological features of PTC, poorer treatment response, or disease outcome.

Highlights

Papillary thyroid carcinoma (PTC) is the most common histopathologic type of thyroid cancer, accounting for approximately 80%–85% of all thyroid cancers, and its incidence is rapidly increasing across the world [1,2,3]
Constitutive activation of the mitogen activated protein kinase (MAPK) pathway is key to the oncogenic processes underlying PTC and can be initiated by various genetic events
CHK2 is activated by the ataxia telangiectasia mutated (ATM) serine-threonine kinase when double-stranded

Summary

Introduction

Papillary thyroid carcinoma (PTC) is the most common histopathologic type of thyroid cancer, accounting for approximately 80%–85% of all thyroid cancers, and its incidence is rapidly increasing across the world [1,2,3]. Constitutive activation of the mitogen activated protein kinase (MAPK) pathway is key to the oncogenic processes underlying PTC and can be initiated by various genetic events. The BRAFV600E mutation has been reported to occur in 27%–87% of PTC cases [6,7,8] and is considered to contribute to oncogenic transformation in thyroid cancer, potentially functioning to silence specific tumor suppressor and differentiation genes by methylation, thereby causing PTC cells to be insensitive to radioiodine treatment, which can lead to persistent or recurrent disease [9]. Checkpoint kinase 2 (CHEK2) is a tumor suppressor gene that encodes the serine/threonine protein kinase CHK2, a key regulator of the cell cycle that influences apoptosis and cell aging [10,11]. CHK2 is activated by the ataxia telangiectasia mutated (ATM) serine-threonine kinase when double-stranded

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