Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features

Durand, Stéphanie; Ferraro‐Peyret, Carole; Joufre, Mireille; Chave, Annie; Borson‐Chazot, Françoise; Selmi-Ruby, Samia; Rousset, Bernard

doi:10.1677/erc-08-0081

Cited by 16 publications

(7 citation statements)

References 45 publications

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“…Although this result was not the main focus of our study, it is noteworthy in the context of the molecular PTC background and recent studies. A similar distribution of asymptomatic thyroids and PTCs harboring BRAF , RET , and RAS alterations was observed also by Durand et al [ 45 ], who performed hierarchical clustering exclusively on the published Giordano PTC samples using 51 genes differentially expressed between their BRAF / RET (+) PTCs and PTC(−). We confirmed that the observed clustering of PTCs with distinct molecular events was not an artifact of the Giordano et al data, but rather an inherent feature of PTC.…”

Section: Discussionsupporting

confidence: 74%

BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma

et al. 2015

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BackgroundThe molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation–its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior.MethodsIn order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset.ResultsMost of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(−) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project.ConclusionThe study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.

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Section: Discussionsupporting

confidence: 74%

BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma

et al. 2015

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“…In rat thyroid PCCL3 cells conditionally expressing oncogenic BRAF, increased invasion into Matrigel was observed compared with cells expressing RET/PTC3 in vitro, which was consistent with the biological behavior of human PTC (5). In addition, PTC without the BRAF V600E mutation mainly corresponded to FV-PTC, and maintained a thyroid differentiation expression level close to that of normal tissue and thus had a better prognosis than PTC with the gene alteration (6). Furthermore, the BRAF V600E mutation may induce genetic instability in PTC, facilitating secondary genetic alternation of members of the PI3k/Akt pathway that may induce PTC progression to a more aggressive thyroid cancer (7).…”

Section: Introductionsupporting

confidence: 72%

“…Numerous studies have demonstrated an association between the BRAF V600E mutation with aggressive clinicopathological characteristics of PTC, including extrathyroidal invasion, LNM, advanced tumor-node-metastasis stage, loss of radioiodine avidity and disease recurrence (5)(6)(7). BRAF mutation presents a low positive predictive value (28%) and a high negative predictive value (87%) for PTC recurrence, suggesting that BRAF mutational status in clinical management of PTC should be used with caution.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

Oncology Letters

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Abstract. The aim of the present study was to investigate the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) patients from eastern coastal China and to determine whether it is correlated with the clinicopathological features of PTCs with or without current Hashimoto thyroiditis (HT). The BRAF V600E mutation status was analyzed in 206 thyroid nodules of 154 patients undergoing thyroidectomy using polymerase chain reaction and bi-directional sequencing. Multivariate analysis was performed to investigate the association of the BRAF V600E mutation with clinicopathological features. Thyroid nodules were classified as PTC, nodular goiter (NG), adenomatoid nodule, adenoma and HT. The BRAF V600E mutation was observed in 61.5% of PTCs analyzed; it was also detected in one normal tissue adjacent to PTC and one NG. One patient exhibited double mutations in the BRAF gene; the BRAF V600E mutation in the PTC lesion and the BRAF K601E mutation in the contralateral NG lesion. Patients harboring the BRAF V600E mutation had higher thyroid stimulating hormone levels (2.453±1.464 vs. 1.966±1.296 mIU/l), a reduced occurrence of papillary thyroid microcarcinoma (55.0 vs. 88%), and a higher occurrence of lymph node metastasis (LNM; 42.5 vs. 16.0%) compared with those with wild-type BRAF (all P<0.05). Binary logistic regression analysis revealed that the BRAF V600E mutation was associated with LNM of PTC (hazard ratio, 5.051; 95% confidence interval, 1.068-23.893; P= 0.041). Conversely, no association was identified between the BRAF V600E mutation and HT (38.5 vs. 67.3%, χ 2 =3.656, P=0.056). Thus, in regional PTCs, the BRAF V600E mutation was prevalent, suggesting that it may be an early and phenotypically defining molecular event in PTC, and may represent an independent factor that predicts LNM.

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“…They also showed that mutational status was more highly correlated to gene expression than morphology, confirming the previous observation (Fagin 2004) of BRAF and RET/PTC mutations as dominant alternative molecular events in PTC. The distinct differences in gene profile between PTC without BRAF mutations or RET/PTC rearrangements when compared to PTC with this mutations, were confirmed by others (Durand et al 2009). However, similarities were also obvious: it was shown that BRAF mutations and RET/PTC rearrangements resulted in similar gene expression profile and led to decreased expression of genes related to thyroid differentiation (e.g.…”

Section: Papillary Thyroid Cancersupporting

confidence: 59%

Gene Expression Analysis by DNA Microarray in Papillary and Follicular Differentiated Thyroid Cancer

Jarząb

Handkiewicz-Junak

2012

Therapeutic Nuclear Medicine

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Molecular characteristics of papillary thyroid carcinomas without BRAF mutation or RET/PTC rearrangement: relationship with clinico-pathological features

Abstract: About 60-70% of papillary thyroid carcinomas (PTC) present a BRAF

Cited by 16 publications

References 45 publications

BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma

BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma

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

Gene Expression Analysis by DNA Microarray in Papillary and Follicular Differentiated Thyroid Cancer

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