BRAF Exon 15 Mutations in Papillary Carcinoma and Adjacent Thyroid Parenchyma: A Search for the Early Molecular Events Associated with Tumor Development.

Giorgia Acquaviva,Antonio De Leo,Giovanni Tallini,Chiara Diquigiovanni,Kerry Jane Rhoden,Elena Bonora,Dario De Biase,Chiara Maria Argento,Annalisa Pession

doi:10.3390/cancers12020430

Giorgia Acquaviva, Antonio De Leo + Show 7 more

Open Access

https://doi.org/10.3390/cancers12020430

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Journal: Cancers	Publication Date: Feb 12, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: Azienda USL di Bologna, University of Bologna

Abstract

BRAF exon 15 mutations are the most common molecular alterations found in papillary thyroid carcinoma (PTC). To date, there is no information regarding BRAF alterations in the thyroid parenchyma surrounding the tumor. To explore the early events associated with the development of PTC, we used massively parallel sequencing to investigate BRAF exon 15 in 30 PTCs and in 100 samples from the thyroid parenchyma surrounding the tumor. BRAF p.V600E was identified in 19/30 PTCs (63.3%). BRAF p.V600E mutations were identified in the tissue adjacent the PTC only in samples containing psammoma bodies. The other samples were either BRAF wild type (WT) or carried BRAF non p.V600E mutations. Specifically, BRAF p.G593D, -p.A598T, -p.V600M, -p.R603Q, -p.S607F, and -p.S607P were identified in 4 of 36 (11.1%) samples with follicular cell atypia, in 2 of 16 (12.5%) with follicular cell hyperplasia, and in 1 of 33 (3.0%) histologically normal samples—Only in tissue surrounding BRAF p.V600E mutated PTCs. These mutations are predicted to affect protein function in silico but, in vitro, have kinase activity and BRAF phosphorylation levels similar to BRAF WT. No BRAF exon 15 mutations were identified in samples adjacent to PTCs that were BRAF WT. A mutagenic process affecting BRAF exon 15 occurs in a subset of thyroid glands that develop BRAF p.V600E mutated PTCs.

Highlights

Papillary thyroid carcinoma (PTC) is the most common malignancy of the endocrine system [1], and its incidence has been increasing in the recent past, mostly due to the early detection of small asymptomatic tumors [1,2,3]
One case was classified as infiltrative follicular variant PTC, a type of PTC that is known to have a BRAF p.V600E-like profile [2]
Two cases were classified as encapsulated follicular variant papillary carcinoma, a type of PTC known to have an RAS-like molecular profile [2,4,6,7], and both had invasion of the tumor capsule

Summary

Introduction

Papillary thyroid carcinoma (PTC) is the most common malignancy of the endocrine system [1], and its incidence has been increasing in the recent past, mostly due to the early detection of small asymptomatic tumors [1,2,3]. The work of the Cancer Genome Atlas classification of PTC [4] has identified two molecular signatures: (i) BRAF p.V600E-like typical of classic/conventional. PTC and (ii) RAS-like typical of the encapsulated follicular variant PTC, a tumor type with features that overlaps with other follicular patterned tumors, such as follicular thyroid adenoma and carcinoma [2,4,5]. Other far less common BRAF alterations include nucleotide changes associated with follicular patterned tumors (follicular adenoma, follicular carcinoma, and encapsulated follicular variant papillary carcinoma) and rearrangements associated with radiation-induced PTCs [2]

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Conclusion