Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas

doi:10.1016/j.canlet.2003.12.004

Cancer Letters

Volume 209, Issue 1, June 2004, Pages 1-6

https://doi.org/10.1016/j.canlet.2003.12.004 Get rights and content

Abstract

Point mutations of the BRAF gene have been recently described with high prevalence in papillary thyroid carcinomas. However, this molecular alteration has not been studied in radiation-induced thyroid tumors. We analyzed the prevalence of BRAF point mutations and RET/PTC rearrangements in 55 post-Chernobyl papillary carcinomas, compared with 82 sporadic papillary carcinomas. Radiation-induced tumors demonstrated a low prevalence (4%) of BRAF point mutations and high prevalence (58%) of RET/PTC rearrangements. Sporadic papillary carcinomas revealed a clearly distinct pattern, with 37% of tumors harboring BRAF mutations and 20% RET/PTC rearrangements. These results demonstrate a significant difference in the molecular genetic profile of sporadic and radiation-induced thyroid tumors.

Introduction

Activating point mutation of the serine/threonine kinase BRAF have been recently described in papillary thyroid carcinomas with the prevalence ranging from 29 to 69% [1], [2], [3], [4], [5], [6]. All mutations identified so far affect nucleotide 1796 in exon 15, resulting in a thymine-to-adenine transversion, which translates into a valine-to-glutamate substitution at residue 599 (V599E).

Exposure to ionizing radiation is a well known risk factor for thyroid cancer, particularly for papillary carcinoma. In April 1986, an accident at the Chernobyl Nuclear Power Station in the former USSR led to a dramatic increase in the incidence of childhood thyroid cancer in contaminated areas of Belarus, Ukraine, and western Russia [7], [8], [9]. Because of the low prevalence of thyroid tumors in children and young adults, this tragic disaster has created one of the richest paradigms of radiation-induced thyroid neoplasms. Most post-Chernobyl tumors were papillary carcinomas and had an unusually high prevalence of RET/PTC rearrangements, which were found in 67–87% of tumors removed 5–8 years after exposure and in 49–65% of those removed 7–11 years after the accident [10], [11], [12], [13], [14], [15].

The prevalence of BRAF mutations has not been studied in radiation-induced tumors. In this study, we determined the prevalence of BRAF mutations as well as RET/PTC rearrangements in a large series of post-Chernobyl papillary carcinomas, and compared those with sporadic papillary carcinomas.

Section snippets

Tumor samples and nucleic acid extraction

We analyzed a series of 55 post-Chernobyl papillary carcinomas, which included 34 tumors operated in 1991–1992 in Minsk, Belarus and 21 tumors removed in 1995–1998 in the Institute of Endocrinology and Metabolism in Kiev, Ukraine. A control group was composed of 82 cases of sporadic papillary carcinomas, i.e. tumors from patients without radiation history. Among radiation-induced tumors from Belarus, the age of patients at surgery ranged from 6 to 20 years. These patients were between one month

Prevalence of BRAF mutations

In the group of 55 radiation-associated papillary carcinomas, two (4%) BRAF mutations were identified. Both cases were papillary carcinomas from Ukraine, and revealed T-to-A transversion at nucleotide 1796 (Fig. 1). No other mutations in the BRAF gene were found in exons 11 and 15 of BRAF in tumors from Ukraine by sequencing of cDNA, and in tumors from Belarus by LightCycler PCR and FMCA (Fig. 2). The tumors samples with BRAF mutations were from patients that were 12 and 25 years old at the

Discussion

Previous studies of thyroid carcinomas in children and young adults exposed to radiation after the Chernobyl accident have established that these radiation-associated tumors have a significantly higher prevalence of RET/PTC rearrangement, especially of the RET/PTC3 type [10], [11], [12], [13], [14], [15]. In this study, we confirm this association, and demonstrate that by contrast, the most common genetic change associated with sporadic papillary carcinomas, BRAF point mutations, is present

Acknowledgements

This study was supported in part by the American Cancer Society grants RSG-03-027-01-CCE (to Y.E.N.), NIH grant CA50706 (to J.A.F.), EC Nuclear Safety program, contract no. FIGH-CT-1999-00004, and by the Italian Association for Cancer Research (AIRC). Ukrainian tissues were obtained from the Chernobyl Tissue Bank (www.chernobyltissuebank.com). Tissue samples were collected in part using a support by grant from the NIH (PHS M01 RR08084-the Children's Hospital-University of Cincinnati General

References (19)

R.M Tuttle et al.
The Chernobyl accident and its consequences: update at the millennium
Semin. Nucl. Med.
(2000)
F Basolo et al.
Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma
Am. J. Pathol.
(2002)
E.T Kimura et al.
High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma
Cancer Res.
(2003)
P Soares et al.
Sobrinho-Simoes, BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC
Oncogene
(2003)
Y Cohen et al.
BRAF Mutation in Papillary Thyroid Carcinoma
J. Natl. Cancer Inst.
(2003)
X Xu et al.
High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines
Cancer Res.
(2003)
H Namba et al.
Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers
J. Clin. Endocrinol. Metab.
(2003)
T Fukushima et al.
BRAF mutaions in papillary carcinomas of the thyroid
Oncogene
(2003)
V.S Kazakov et al.
Thyroid cancer after Chernobyl
Nature
(1992)

There are more references available in the full text version of this article.

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Low prevalence of BRAF mutations in radiation-induced thyroid tumors in contrast to sporadic papillary carcinomas

Abstract

Introduction

Section snippets

Tumor samples and nucleic acid extraction

Prevalence of BRAF mutations

Discussion

Acknowledgements

Semin. Nucl. Med.

Am. J. Pathol.

High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma

Cancer Res.

Sobrinho-Simoes, BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC

Oncogene

BRAF Mutation in Papillary Thyroid Carcinoma

J. Natl. Cancer Inst.

High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines

Cancer Res.

Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers

J. Clin. Endocrinol. Metab.

BRAF mutaions in papillary carcinomas of the thyroid

Oncogene

Thyroid cancer after Chernobyl

Nature