Cargando…

Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma

SIMPLE SUMMARY: The BRAF(V600E) point mutation is the most common driver mutation in papillary thyroid carcinoma (PTC) and is known to be associated with aggressive clinical features. However, the negative prognostic impact of BRAF(V600E) on PTC mostly depends on tumor characteristics, not on itself...

Descripción completa

Detalles Bibliográficos
Autores principales: Song, Eyun, Jin, Meihua, Jang, Ahreum, Jeon, Min Ji, Song, Dong Eun, Yoo, Hye Jin, Kim, Won Bae, Shong, Young Kee, Kim, Won Gu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616313/
https://www.ncbi.nlm.nih.gov/pubmed/34831001
http://dx.doi.org/10.3390/cancers13225846
_version_ 1784604317171318784
author Song, Eyun
Jin, Meihua
Jang, Ahreum
Jeon, Min Ji
Song, Dong Eun
Yoo, Hye Jin
Kim, Won Bae
Shong, Young Kee
Kim, Won Gu
author_facet Song, Eyun
Jin, Meihua
Jang, Ahreum
Jeon, Min Ji
Song, Dong Eun
Yoo, Hye Jin
Kim, Won Bae
Shong, Young Kee
Kim, Won Gu
author_sort Song, Eyun
collection PubMed
description SIMPLE SUMMARY: The BRAF(V600E) point mutation is the most common driver mutation in papillary thyroid carcinoma (PTC) and is known to be associated with aggressive clinical features. However, the negative prognostic impact of BRAF(V600E) on PTC mostly depends on tumor characteristics, not on itself. Moreover, the prognosis of BRAF(V600E)-mutant PTCs varies widely implying the genetic diversity of this subtype. Additional genetic alterations other than BRAF(V600E) may be responsible for the aggressiveness of this group but to date, no mutations other than TERT promoter mutation have been identified. This study aimed to investigate the effect of additional genetic alterations, focusing on the mutations in genes encoding functional groups on survival in BRAF(V600E)-mutant PTCs. We observed that coexistence of mutations in BRAF(V600E) and the three functional groups had the worst survival in patients with PTCs compared with mutations in BRAF(V600E) and genes other than those associated with functional groups or mutations in only BRAF(V600E). ABSTRACT: The prognosis of BRAF(V600E)-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAF(V600E)-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAF(V600E)-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAF(V600E)-mutation (group 1), 22 had BRAF(V600E) and mutation other than FGs (group 2), and 13 had BRAF(V600E) and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39–97.58, p = 0.024). Coexistence of mutations in BRAF(V600E) and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAF(V600E)-mutant PTCs may be valuable in risk stratifying this subtype.
format Online
Article
Text
id pubmed-8616313
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-86163132021-11-26 Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma Song, Eyun Jin, Meihua Jang, Ahreum Jeon, Min Ji Song, Dong Eun Yoo, Hye Jin Kim, Won Bae Shong, Young Kee Kim, Won Gu Cancers (Basel) Article SIMPLE SUMMARY: The BRAF(V600E) point mutation is the most common driver mutation in papillary thyroid carcinoma (PTC) and is known to be associated with aggressive clinical features. However, the negative prognostic impact of BRAF(V600E) on PTC mostly depends on tumor characteristics, not on itself. Moreover, the prognosis of BRAF(V600E)-mutant PTCs varies widely implying the genetic diversity of this subtype. Additional genetic alterations other than BRAF(V600E) may be responsible for the aggressiveness of this group but to date, no mutations other than TERT promoter mutation have been identified. This study aimed to investigate the effect of additional genetic alterations, focusing on the mutations in genes encoding functional groups on survival in BRAF(V600E)-mutant PTCs. We observed that coexistence of mutations in BRAF(V600E) and the three functional groups had the worst survival in patients with PTCs compared with mutations in BRAF(V600E) and genes other than those associated with functional groups or mutations in only BRAF(V600E). ABSTRACT: The prognosis of BRAF(V600E)-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAF(V600E)-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAF(V600E)-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAF(V600E)-mutation (group 1), 22 had BRAF(V600E) and mutation other than FGs (group 2), and 13 had BRAF(V600E) and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39–97.58, p = 0.024). Coexistence of mutations in BRAF(V600E) and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAF(V600E)-mutant PTCs may be valuable in risk stratifying this subtype. MDPI 2021-11-22 /pmc/articles/PMC8616313/ /pubmed/34831001 http://dx.doi.org/10.3390/cancers13225846 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Song, Eyun
Jin, Meihua
Jang, Ahreum
Jeon, Min Ji
Song, Dong Eun
Yoo, Hye Jin
Kim, Won Bae
Shong, Young Kee
Kim, Won Gu
Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma
title Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma
title_full Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma
title_fullStr Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma
title_full_unstemmed Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma
title_short Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF(V600E)-Mutant Advanced Papillary Thyroid Carcinoma
title_sort mutation in genes encoding key functional groups additively increase mortality in patients with braf(v600e)-mutant advanced papillary thyroid carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616313/
https://www.ncbi.nlm.nih.gov/pubmed/34831001
http://dx.doi.org/10.3390/cancers13225846
work_keys_str_mv AT songeyun mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT jinmeihua mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT jangahreum mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT jeonminji mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT songdongeun mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT yoohyejin mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT kimwonbae mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT shongyoungkee mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma
AT kimwongu mutationingenesencodingkeyfunctionalgroupsadditivelyincreasemortalityinpatientswithbrafv600emutantadvancedpapillarythyroidcarcinoma