Genetic Profiles of Aggressive Variants of Papillary Thyroid Carcinomas

Abstract

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.

Different Threshold of Malignancy for RAS-like Thyroid Tumors Causes Significant Differences in Thyroid Nodule Practice

“…The NIFTP (10-20%) alone lowered the BRAF prevalence in the Western practice significantly as they were RAS-like PTCs in Western practice. Furthermore, the prevalence of BRAFV600E was consistently high in Western countries [4,[65][66][67][68], similar to Eastern countries [69], when limited to classic and tall cell variant PTC. (Table 1).…”

Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAFV600E-Mutant Advanced Papillary Thyroid Carcinoma

“…The same study group explored the FG mutations in their subsequent work, which included 22 well-differentiated thyroid carcinomas as well as 35 PDTC, and provided the feasibility to apply the FG mutation in different subtypes of thyroid cancers including PTCs. We previously reported the frequency of mutations in these FGs, which were 43.7% in PTCs with distant metastasis [ 11 ] and 34% in PTCs with aggressive variants [ 12 ], whereas in the present study of only BRAF V600E -driven PTCs, the rate of mutations was 26% [13/50]. The mutational rate in classic PTC from the Cancer Genome Atlas is 20% [ 1 ], whereas the rates in advanced PTCs range between those in the classic PTC and ATC, a finding in line with the order of clinical prognosis.…”

“…The PIK3/AKT/mTOR pathway is one of the three key functional groups (FGs) presented by Landa et al in their study of extensive genetic characterization of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) [ 10 ]. Two other key FGs are the histone methyltransferases (HMTs) and the SWItch/Sucrose NonFermenting (SWI/SNF) chromatin remodeling complex, and mutations in these FGs are reported to be more frequent in advanced forms of thyroid cancers than in classic PTCs [ 11 , 12 ], albeit their clinical prognostic significance has not been established.…”

Mutação no gene BRAF em carcinoma diferenciado de tireoide avançado: um relato de caso

“…Geralmente, ele é clinicamente indolente, compatível com seu genoma simples, apresentando poucas alterações no número de cópias². Embora tenha uma alta incidência, apresenta taxas de sobrevida global excedendo a 90% 3,4,15 . Apesar de a maioria dos CPT ser bem diferenciada e com baixa taxa de invasão local, recidiva ou metástases (regionais ou distantes), existe em subgrupo de tumores que apresenta heterogeneidade genética associada com variantes histológicas de maior agressividade, podendo tornar o CDT mais invasivo e letal 5 As características clínicas e histológicas não predizem precisamente o comportamento biológico dos tumores de tireoide, sendo relevante identificar, por meio de exames Mutação no gene BRAF em carcinoma diferenciado de tireoide avançado: um relato de caso moleculares, os pacientes com maior risco de agressividade da doença, a fim de prevenir resultados desfavoráveis e implementar terapias mais personalizadas 6 .…”

“…A mutação somática de maior evidência no CDT encontra-se no gene BRAF, que resulta em uma transversão de timina para adenina no nucleotídeo 1799 (T1799A), levando a uma substituição de valina por ácido glutâmico no resíduo 600 da proteína (V600E) 7,9 . Mutação no gene BRAF tem uma associação significativa com estágios mais avançados do tumor, promovendo sua invasividade, metástase e recorrência, além de mostrar uma baixa resposta ao tratamento com radioiodo, sendo assim um importante fator prognóstico em CPT 2,10,12,15 .…”