BRAF mutations in thyroid tumors from an ethnically diverse group

Abstract

BackgroundThe molecular etiology of thyroid carcinoma (TC) and other thyroid diseases which may present malignant precursor lesions is not fully explored yet. The purpose of this study was to estimate frequency, type and clinicopathological value of BRAF exon 15 mutations in different types of cancerous and non-cancerous thyroid lesions originating in an ethnically diverse population.MethodsBRAF exon 15 was sequenced in 381 cases of thyroid lesions including Hashimoto´s thyroiditis, nodular goiters, hyperplastic nodules, follicular adenomas (FA), papillary TC (PTC), follicular variant PTC (FVPTC), microcarcinomas of PTC (micro PTC; tumor size ≤ 1 cm), follicular TC (FTC), and non-well differentiated TC (non-WDTC).ResultsWe identified BRAF mutations in one of 69 FA, 72 of 115 (63%) PTC, seven of 42 (17%) FVPTC, 10 of 56 (18%) micro PTC, one of 17 (6%) FTC, and one of eight (13%) non-WDTC. Most of the cases showed the common V600E mutation. One case each of PTC, FVPTC, and FTC harbored a K601E mutation. A novel BRAF mutation was identified in a FA leading to deletion of threonine at codon 599 (p.T599del). A rare 3-base pair insertion was detected in a stage III PTC resulting in duplication of threonine at codon 599 (p.T599dup). Patients with PTC harboring no BRAF mutation (BRAFwt) were on average younger than those with a BRAF mutation (BRAFmut) in the PTC (36.6 years vs. 43.8 years). Older age (≥ 45 years) in patients with PTC was significantly associated with tumor size ≥ 4 cm (P = 0.018), vessel invasion (P = 0.004), and distant metastasis (P = 0.001). Lymph node (LN) involvement in PTC significantly correlated with tumor size (P = 0.044), and vessel invasion (P = 0.013). Of notice, taken the whole TC group, family history of thyroid disease positively correlated with capsular invasion (P = 0.025).ConclusionsOlder age is manifold associated with unfavorable tumor markers in our series. The K601E identified in a PTC, FVPTC, and FTC seems to be more distributed among different histological types of TC than previously thought. The T599del is a yet undescribed mutation and the rare T599dup has not been reported as a mutation in PTC so far.

Uncommon BRAF mutations in the follicular variant of thyroid papillary carcinoma: New insights

“…Not only does this latter histotype exhibit a mixed pattern, including PTC nuclei and follicular growth without papillae patterned as diffuse or encapsulated variants, but the molecular profile appears to be somewhere in between the profiles of PTC and follicular carcinoma (FTC). Detection of the BRAF lysine (K) to glutamic acid (E) substitution at codon 601 ( BRAF K601E ) mutation and of the subset of complex and less common BRAF mutations has been documented in FVPCs and has been correlated with less tumorigenic potential than that of the BRAF V600E mutation, as described in the limited literature . In this report, we retrospectively focus on morphologic and molecular findings in 106 cytologic thyroid lesions that were diagnosed as PTC and FVPC on histology.…”

Novel BRAF mutation in melanoma: A case report

“…BRAF mutational status of the primary lesion was assessed by both Sanger sequencing and pyrosequencing, using the Anti-EGFR MoAb response BRAF Status kit (Diatech S.p.A., Jesi, Italy). Genetic analysis showed a rare aminoacidic insertion in codon 599 of the BRAF gene (1797_1798insACA, T599insT: Although in this study and in cited reports (8,(10)(11)(12)(13)(14) all mutations lead to the same T599dup alteration at amino acid level, at DNA level they are described as an ACA duplication (11,12), and as an insertion of TAC between C and A in the other studies. In silico analysis, performed on BRAFV599ins and BRAFT599insT (9,12), indicates that mutations involving the P-loop make the active geometrical conformation more stable than the wild-type counterpart, causing an highly productive catalytic state.…”

“…Less frequent BRAF mutations (5,6) with alterations in the same crucial site, such as Threonine599 and Serine601 (7), have been described. Herein, we report a single case of primary cutaneous melanoma showing a mutation occurring in the P-loop activating site (c.1797_1798insACA, T599insT), which was not previously described in melanomas, but only rarely found in Pilocytic Astrocytoma (PA), Papillary Thyroid Carcinoma (PTC) and Anaplastic Thyroid Carcinoma (ATC) (8)(9)(10)(11). In silico and in vitro data indicate that rare and/or complex mutations in codons 599-601 increase kinase activity similarly to the typical V600E (8,9,12,13).…”

Clinical significance of BRAF V600E mutation in 154 patients with thyroid nodules

“…An A→G transversion at exon 15 nucleotide 1801 (A1801G) of the BRAF gene resulted in the replacement of lysine with glutamic acid at position 601 (BRAF K601E), which was also a heterozygous mutation in this patient. Trovisco et al (14) first reported the BRAF K601E mutation in a PTC patient in 2005, and 18 additional cases have been subsequently described (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Meta-analysis demonstrated that the BRAF K601E mutation was predominantly identified in FV-PTC, followed by FTC and PTC, and only one case of TA had the BRAF K601E mutation.…”

“…Meta-analysis demonstrated that the BRAF K601E mutation was predominantly identified in FV-PTC, followed by FTC and PTC, and only one case of TA had the BRAF K601E mutation. Although it may affect the PI3k/Akt pathway, this mutation exhibited relatively inactive biological characteristics in the pathogenesis of TC compared with the BRAF V600E mutation (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Moreover, in multifocal papillary thyroid carcinoma (mPTC), individual tumor foci may be identical and are frequently composed of various histological types, and individual tumor foci also harbor different mutations.…”