BRAF Mutations Are Not a Major Event in Post Chernobyl Childhood Thyroid Carcinomas (original) (raw)
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Cancer Letters, 2005
Our findings both support and extend those of Nikiforova et al. [M.N. Nikiforova, R. Ciampi, G. Salvatore, M. Santoro, M. Gandhi, J.A. Knauf, et al., Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas, Cancer Lett. 209 (2004) 1-6]: BRAF mutations are rare in childhood PTC, both in an irradiation setting and in sporadic tumors. q
The Journal of Clinical Endocrinology & Metabolism, 2004
Point mutations in BRAF are genetic hallmarks of papillary thyroid carcinoma (PTC). In this retrospective study, we examined thyroid aspirates and corresponding paraffin-embedded surgical samples for the presence of BRAF mutations. Altogether, we examined 96 cases, including 69 PTCs, 19 follicular adenomas, and eight nontoxic nodular goiters for BRAF; 60 of these samples were also examined for RET/PTC rearrangements. The results were correlated with the cytological diagnosis and the final histopathology. The BRAF mutation (V599E) was detected in 38% of the samples that were PTC on histopathology; RET/PTC was found in 18% of the PTC cases. In all the cases, the presence of the genetic alteration was confirmed in the surgically resected tumor. The identification of BRAF mutation and RET/PTC refined the diagnosis of PTC in five of 15 samples that were considered either indeterminate or insufficient at cytology. No mutation was found in aspirates of follicular adenomas and nontoxic nodular goiters. These results indicate that BRAF mutation and RET/PTC rearrangements are molecular markers of PTC that can be applied to FNA in adjunct to traditional cytology.
Modifications in the Papillary Thyroid Cancer Gene Profile Over the Last 15 Years
The Journal of Clinical Endocrinology & Metabolism, 2012
Background: Evidence for an increased prevalence of BRAF V600E mutations has been documented in recent decades. The aim of this study was to evaluate the prevalence of both RET/PTC rearrangements and BRAF V600E mutations in an Italian cohort of papillary thyroid carcinoma (PTC) patients followed at the Endocrine Units of Pisa, Milano, and Perugia from 1996 -2010. Patients and Methods: In total, 401 PTC patients were examined and grouped according to the time of surgery: group 1, 1996 -2000; group 2, 2001-2005; and group 3, 2006 -2010. Patients were analyzed for clinical, pathological, and molecular features. In parallel, the molecular characteristics of 459 PTC from Sicily were studied.
Scientific reports, 2015
After the accident at the Fukushima Daiichi Nuclear Power Plant, the thyroid ultrasound screening program for children aged 0-18 at the time of the accident was started from October 2011. The prevalence of thyroid carcinomas in that population has appeared to be very high (84 cases per 296,253). To clarify the pathogenesis, we investigated the presence of driver mutations in these tumours. 61 classic papillary thyroid carcinomas (PTCs), two follicular variant PTCs, four cribriform-morular variant PTCs and one poorly-differentiated thyroid carcinoma were analysed. We detected BRAF(V600E) in 43 cases (63.2%), RET/PTC1 in six (8.8%), RET/PTC3 in one (1.5%) and ETV6/NTRK3 in four (5.9%). Among classic and follicular variant PTCs, BRAF(V600E) was significantly associated with the smaller size. The genetic pattern was completely different from post-Chernobyl PTCs, suggesting non-radiogenic etiology of these cancers. This is the first study demonstrating the oncogene profile in the thyroid...
The Journal of Clinical Endocrinology & Metabolism, 2004
The nuclear disaster that occurred in Chernobyl in 1986 offered the unique opportunity to study the molecular genetics of one human tumor type, papillary carcinoma of the thyroid gland, associated with a specific etiology. We have analyzed RET rearrangements in post-Chernobyl papillary thyroid carcinomas (n ؍ 29), follicular thyroid adenomas (n ؍ 2), and follicular thyroid carcinoma (n ؍ 1) by interphase fluorescence in situ hybridization (FISH) analysis on paraffinembedded tissue sections. Paraffin sections were microdissected before use to ensure that only tumor was present. Cell nuclei were scored for the presence of a split FISH signal (separated red and green signal) in addition to an overlapping signal. Only cells with either two overlapping signals or one split and one overlapping signal were counted to ensure that only complete cell nuclei had been scored. In total, 23 of 32 cases (72%) showed RET rearrangements diagnosed by FISH interphase analysis. In all cases, the tumors were composed of a mixture of cells with and without ret rearrangement on FISH. In some cases, this distribution was clearly nonrandom because clustering of rearranged cells was detected within the same tumor nodule. Accordingly, only 31% of the cases positive for rearrangement on FISH also scored positive using RT-PCR. These findings suggest that because RET/PTC rearrangements are not present in a majority of tumor cells, either a fraction of post-Chernobyl papillary thyroid tumors are of multiclonal origin, or ret rearrangement is a later, subclonal event. (J Clin Endocrinol Metab 89: 4272-4279, 2004) Abbreviations: EC, Extracellular; FISH, fluorescence in situ hybridization; FITC, fluorescein isothiocyanate; LSM, laser scanning microscopy; PN, phosphate buffer with 0.1% nonidet P40; PTC, papillary thyroid carcinoma; TK, tyrosine kinase; YAC, yeast artificial chromosome. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
Gene signature of the post-Chernobyl papillary thyroid cancer
European Journal of Nuclear Medicine and Molecular Imaging, 2016
Purpose Following the nuclear accidents in Chernobyl and later in Fukushima, the nuclear community has been faced with important issues concerning how to search for and diagnose biological consequences of low-dose internal radiation contamination. Although after the Chernobyl accident an increase in childhood papillary thyroid cancer (PTC) was observed, it is still not clear whether the molecular biology of PTCs associated with low-dose radiation exposure differs from that of sporadic PTC. Methods We investigated tissue samples from 65 children/ young adults with PTC using DNA microarray (Affymetrix, Human Genome U133 2.0 Plus) with the aim of identifying molecular differences between radiation-induced (exposed to Chernobyl radiation, ECR) and sporadic PTC. All participants were resident in the same region so that confounding factors related to genetics or environment were minimized. Results There were small but significant differences in the gene expression profiles between ECR and non-ECR PTC (global test, p < 0.01), with 300 differently expressed probe sets (p < 0.001) corresponding to 239 genes. Multifactorial analysis of variance showed that besides radiation exposure history, the BRAF mutation exhibited independent effects on the PTC expression profile; the histological subset and patient Daria Handkiewicz-Junak and Michal Swierniak contributed equally to this work.
BRAF(V600E) mutation and the biology of papillary thyroid cancer
Endocrine Related Cancer, 2008
BRAF (V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF (V600E) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF (V600E) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF (V600E) were evaluated by both univariate and multivariate analyses. BRAF (V600E) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF (V600E) was associated with greater tumor size (PZ0.0048), extra-thyroid invasion (P!0.0001), and cervical lymph nodal metastases (PZ0.0001). Multivariate logistic regression analysis confirmed that BRAF (V600E) was an independent predictor of extra-thyroid invasion (PZ0.0001) and cervical lymph nodal metastasis (PZ0.0005). The association between BRAF (V600E) and extra-thyroid invasion was also found in micro-PTCs (PZ0.006). In 60 classical PTCs, BRAF (V600E) was positively correlated with matrix metalloproteinase-9 expression (PZ0.0047), suggesting a possible mechanism for BRAF (V600E) effect on PTC invasiveness. No association was found between BRAF (V600E) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P!0.0001 compared with Western Sicily). These results indicate that BRAF (V600E) mutation is a marker of aggressive disease in both micro-and macro-PTCs. Moreover, for the first time, a possible link between BRAF (V600E) mutation and environmental carcinogens is suggested. Endocrine
Journal of Endocrinological Investigation, 2010
Background: Activating point mutation of the BRAF gene, the most common genetic alteration reported in papillary thyroid carcinomas (PTC), has been associated with poor prognostic characteristics. Aim: Our objective was to determine the frequency of BRAF V600E mutation in PTC tumor tissues from the period 1960-2007 and to correlate it with clinicopathological parameters. Subjects and methods: DNAs were extracted from 242 PTCs, 23 sporadic medullary carcinomas, one anaplastic carcinoma and 6 poorly differentiated carcinomas. The presence of BRAF V600E mutation was determined using single strand conformation polymorphism method and verified by direct sequencing. Results: BRAF V600E mutation was detected in 81 of 242 PTCs (33.5%), in one of 6 poorly differentiated carcinomas (16.7%) and in anaplastic carcinoma. BRAF V600E mutation was much less frequent in the follicular variant compared to classical variant and mixed fol-licular-classical variant of PTCs (p=0.001). BRAF V600E mutation was significantly associated with presence of nodal metastasis (p=0.029), more advanced TNM stage (p=0.014) and recurrence of disease (p=0.008). The mutation correlated with a higher age at diagnosis (p=0.049) and with a greater tumor size (p=0.041). Multivariate analysis confirmed these findings. The prevalence of BRAF V600E mutation before 1986 was significantly lower than after it (p=0.008). Conclusions: Our data suggest that BRAF V600E mutation is associated with high-risk clinicopathological characteristics of PTC and worse prognosis of patients. The frequency of the mutation significantly varied during the observed period but rather because of the different age distribution of patients in particular periods than as a consequence of Chernobyl accident. (J. Endocrinol. Invest. 33: 318-324, 2010) © 2 0 1 0 , E d i t r i c e K u r t i s