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

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.

Clinical features and survival outcomes of ocular melanoma in a multi-ethnic Asian cohort

“… † Lies within protein kinase domain of the Braf protein but actual effect on protein function remains unknown 36 . ‡ Two point mutations at codon 558 (AAG to AAT) and codon 559 (GTT to ATT).…”

“…† Lies within protein kinase domain of the Braf protein but actual effect on protein function remains unknown 36 .…”

A juvenile case of epilepsy‐associated, isocitrate dehydrogenase wild‐type/histone 3 wild‐type diffuse glioma with a rare BRAFA598T mutation

“…The tumor was genetically IDH wild‐type/H3 wild‐type but harbored the rare BRAF A598T mutation. BRAF A598T mutation has been reported in lung adenocarcinoma 16 and thyroid tissue adjacent to the papillary thyroid carcinoma 17 but never previously in gliomas. BRAF is an important member of the MAPK pathway, and BRAF V600E is the most common cancer‐associated mutation.…”

“…BRAF V600E mutation is related to a gain‐of‐function effect of a protein and induces constitutive activation of the MAPK pathway, resulting in dysregulated cell proliferation and growth. In contrast, BRAF A598T mutation is predicted to induce a loss‐of‐function effect of a kinase (http://www.jax.org, 17,18 ). Tumorigenesis of a BRAF ‐inactivating mutation has recently been reported 19–22 .…”

What Is New in Thyroid Cancer: The Special Issue of the Journal Cancers

“…Interestingly, their data indicated that a mutagenic process affecting BRAF exon 15 takes place in a subset of thyroid glands that develop BRAF p.V600E mutated PTCs. While the carcinoma develops only if the p.V600E mutation occurs, its development is accompanied by other exon 15 mutations [ 2 ]. Fugazzola et al reviewed the data in favor of the occurrence of intratumoral heterogeneity in PTC and reasoned on its impact on prognosis and on the response to targeted therapy [ 3 ].…”