Conventional and molecular cytogenetics of human non-medullary thyroid carcinoma: characterization of eight cell line models and review of the literature on clinical samples

<p>Abstract</p> <p>Background</p> <p>Cell lines are often poorly characterized from a genetic point of view, reducing their usefulness as tumor models. Our purpose was to assess the genetic background of eight commonly used human thyroid carcinoma models and to compare the findings with those reported for primary tumors of the gland.</p> <p>Methods</p> <p>We used chromosome banding analysis and comparative genomic hybridization to profile eight non-medullary thyroid carcinoma cell lines of papillary (TPC-1, FB2, K1 and B-CPAP), follicular (XTC-1) or anaplastic origin (8505C, C643 and HTH74). To assess the representativeness of the findings, we additionally performed a thorough review of cytogenetic (n = 125) and DNA copy number information (n = 270) available in the literature on clinical samples of thyroid carcinoma.</p> <p>Results</p> <p>The detailed characterization of chromosomal markers specific for each cell line revealed two cases of mistaken identities: FB2 was shown to derive from TPC-1 cells, whereas K1 cells have their origin in cell line GLAG-66. All cellular models displayed genomic aberrations of varying complexity, and recurrent gains at 5p, 5q, 8q, and 20q (6/7 cell lines) and losses at 8p, 13q, 18q, and Xp (4/7 cell lines) were seen. Importantly, the genomic profiles were compatible with those of the respective primary tumors, as seen in the meta-analysis of the existing literature data.</p> <p>Conclusion</p> <p>We provide the genomic background of seven independent thyroid carcinoma models representative of the clinical tumors of the corresponding histotypes, and highlight regions of recurrent aberrations that may guide future studies aimed at identifying target genes. Our findings further support the importance of routinely performing cytogenetic studies on cell lines, to detect cross-contamination mishaps such as those identified here.</p

Search for NTRK1 proto-oncogene rearrangements in human thyroid tumours originated after therapeutic radiation

Rearrangements of NTRK1 proto-oncogene were detected in ‘spontaneous’ papillary thyroid carcinomas with a frequency varying from 5 to 25% in different studies. These rearrangements result in the formation of chimaeric genes composed of the tyrosine kinase domain of NTRK1 fused to 5′ sequences of different genes. To investigate if the NTRK1 gene plays a role in radiation-induced thyroid carcinogenesis, we looked for the presence of NTRK1 -activating rearrangements in 32 human thyroid tumours (16 follicular adenomas, 14 papillary carcinomas and two lymph-node metastases of papillary thyroid carcinomas) from patients who had received external radiation, using the reverse transcription polymerase chain reaction, Southern blot and direct sequencing techniques. These data were compared with those obtained in a series of 28 ‘spontaneous’ benign and malignant thyroid tumours, collected from patients without a history of radiation exposure and four in vitro culture cell lines derived from ‘spontaneous’ thyroid cancers. Our results concerning the radiation-associated tumours showed that only rearrangements between NTRK1 and TPM3 genes (TRK oncogene) were detected in 2/14 papillary carcinomas and in one lymph-node metastasis of one of these papillary thyroid carcinomas. All the radiation-associated adenomas were negative. In the ‘spontaneous’ tumours, only one of the 14 papillary carcinomas and one of the four in vitro culture cell lines, derived from a papillary carcinoma, presented a NTRK1 rearrangement also with the TPM3 gene. Twenty-five of this series of radiation-associated tumours were previously studied for the ras and RET/PTC oncogenes. In conclusion, our data: (a) show that the overall frequency of NTRK1 rearrangements is similar between radiation-associated (2/31: 6%) and ‘spontaneous’ epithelial thyroid tumours (2/32: 6%). The frequency, if we consider exclusively the papillary carcinomas, is in both cases 12%; (b) show that the TRK oncogene plays a role in the development of a minority of radiation-associated papillary thyroid carcinomas but not in adenomas; and (c) confirm that RET/PTC rearrangements are the major genetic alteration associated with ionizing radiation-induced thyroid tumorigenesis. © 2000 Cancer Research Campaig

Gene rearrangement and Chernobyl related thyroid cancers

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10–15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the RET oncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant. © 2000 Cancer Research Campaig

Assessment of radon-induced health risk for occupants of a house built on uranium ore residue

National audiencePosition du problèmeÀ la demande des pouvoirs publics français, l’institut de radioprotection et de sûreté nucléaire a évalué la situation radiologique d’une maison construite sur des résidus de minerais d’uranium en Haute-Vienne, ainsi que les risques sanitaires dus à l’exposition au radon pour l’ensemble des occupants. Le radon est une cause avérée de cancer du poumon en cas d’inhalation régulière et sur une longue durée, et le risque augmente avec l’exposition cumulée.Méthodes. L’exposition au radon a été reconstituée pour différents profils-types d’occupation de la maison. Un modèle de risque dérivé d’une étude épidémiologique européenne a été utilisé pour calculer les probabilités vie entière de décès par cancer du poumon selon les profils-types considérés.Résultats.L’évaluation des risques des occupants de la maison a mis en évidence les principaux résultats suivants. Pour un enfant résident scolarisé, ayant été exposé au radon de la naissance jusque l’âge de 7 ans, le risque relatif vie entière (RVE) est estimé à 5. Pour les derniers résidents adultes et jeunes adultes, ayant été exposés pendant plus de 10 ans dans la maison, la probabilité de décès par cancer du poumon est comparable à celle d’un fumeur régulier de cigarettes, avec un RVE compris entre 10 et 13 et une probabilité vie entière de décès par cancer du poumon comprise entre 3 et 4 %. Si ces personnes exposées au radon fumaient régulièrement, cette probabilité se situerait entre 6 et 32 % (en supposant une interaction additive ou multiplicative).Conclusion. Pour les anciens occupants (non-fumeurs) ayant été exposés 10 ans durant leur enfance, le RVE est deux fois plus faible. Pour les enfants ayant été en garde ou en nourrice dans la maison, l’augmentation de la probabilité de décès par cancer du poumon est faible, avec un RVE inférieur à 2. Sous l’hypothèse, comme pour l’adulte, d’une décroissance du risque au-delà de 30 ans après la fin de l’exposition, l’augmentation de risque est quasi-nulle pour les anciens occupants exposés durant l’enfance et les enfants en garde, avec un RVE proche de 1.Background At the request of French public authorities, the Institute of Radiological Protection and Nuclear Safety has assessed the radiological situation of a house built on uranium ore residues in Haute-Vienne and the health risks induced from exposure to radon for all occupants. Classified as a lung carcinogen by the World Health Organization, radon is a proven cause of lung cancer in case of regular inhalation over a long period, and the risk increases with cumulative exposure. Methods Radon exposure was reconstructed for various standard profiles of house occupancy. A risk model derived from a European epidemiological study was used to calculate the lifetime probability of death from lung cancer according to these standard profiles. Results Risk assessment of the occupants of the house highlighted the following main findings. For a resident school child having been exposed to radon from birth to the age of 7, the lifetime relative risk (LRR) was estimated at 5. For last adult and young adult residents having lived more than 10 years in the house, the probability of death from lung cancer was in the same order of magnitude as that of a regular cigarette smoker, with a LRR from 10 to 13 and a lifetime probability of death from lung cancer between 3 and 4%. If these individuals smoked regularly, in addition to being exposed to radon, this probability would be between 6 and 32% (supposing an additive or multiplicative interaction). Conclusion For former occupants (non-smokers) having been exposed 10 years during childhood, the LRR was two-fold lower. For children having been in day care in the house, the increased probability of death from lung cancer was low, with a LRR lower than 2. Supposing, as in adults, that the risk decreases beyond 30 years after the end of radon exposure, the increase was almost zero for former occupants exposed during childhood and during day care, with a LRR close to 1. © 2016 Elsevier Masson SASBackground At the request of French public authorities, the Institute of Radiological Protection and Nuclear Safety has assessed the radiological situation of a house built on uranium ore residues in Haute-Vienne and the health risks induced from exposure to radon for all occupants. Classified as a lung carcinogen by the World Health Organization, radon is a proven cause of lung cancer in case of regular inhalation over a long period, and the risk increases with cumulative exposure. Methods Radon exposure was reconstructed for various standard profiles of house occupancy. A risk model derived from a European epidemiological study was used to calculate the lifetime probability of death from lung cancer according to these standard profiles. Results Risk assessment of the occupants of the house highlighted the following main findings. For a resident school child having been exposed to radon from birth to the age of 7, the lifetime relative risk (LRR) was estimated at 5. For last adult and young adult residents having lived more than 10 years in the house, the probability of death from lung cancer was in the same order of magnitude as that of a regular cigarette smoker, with a LRR from 10 to 13 and a lifetime probability of death from lung cancer between 3 and 4%. If these individuals smoked regularly, in addition to being exposed to radon, this probability would be between 6 and 32% (supposing an additive or multiplicative interaction). Conclusion For former occupants (non-smokers) having been exposed 10 years during childhood, the LRR was two-fold lower. For children having been in day care in the house, the increased probability of death from lung cancer was low, with a LRR lower than 2. Supposing, as in adults, that the risk decreases beyond 30 years after the end of radon exposure, the increase was almost zero for former occupants exposed during childhood and during day care, with a LRR close to 1. © 2016 Elsevier Masson SA

Development of two mobile laboratories for a routine and accident monitoring of internal contamination

International audienceTo provide medical surveillance of workers exposed to risk of internal contamination, IRSN (French Institute for Radiological Protection and Nuclear Safety) has developed two mobile laboratories for on-site monitoring. The laboratories are unique in Europe. They meet the new radiation protection requirements for nuclear medicine departments and radiological emergency response. Details of the design, calibration procedures and performance characteristics of these systems in measurements of various types of organs (thyroid, lung and whole body) are described. The sensitivity of the measurements is very close to that achieved in a heavily shielded stationary laboratory. © 2012 Elsevier Ltd

Estimation personnalisée de la dose après totalisation isotopique par l'131I chez un patient présentant un goitre endothoracique résiduel

National audienceA patient treated with 3.7 GBq of 131I after thyroidectomy for a papillary carcinoma presented, three days after iodine administration, an unusually elevated dose rate at 1 m. Scintigraphy and Single Photon Emission Computed Tomography coupled with Computed Tomography (SPECT/CT) were performed and showed a significant iodine uptake at the anterior mediastinal level due to the presence of a residual intrathoracic goitre. The proximity between this iodofixant goitre and the surrounding tissues prompted dose estimations to local organs at risk, in particular the heart. Dosimetric estimations were initially performed with OLINDA/EXM software, commonly used in nuclear medicine. More personalised doses were then calculated using the OEDIPE software associated with the Monte Carlo code MCNPX. Calculations with the OLINDA/EXM software enabled a first assessment of the mean absorbed dose to the heart, estimated at about 2 Gy for an uptake of 56% of the administered activity. In a second step, the use of the OEDIPE software allowed us to take into account the specific geometry of the patient as well as the distribution of iodine uptake at a mediastinal level and to determine a mean absorbed dose of approximately 1 Gy to the heart. Thus, the use of a voxelised phantom based on CT images of the patient, associated with direct Monte Carlo calculations, enabled us to improve the calculation of the absorbed doses to the heart compared with the use of a standard anthropomorphic phantom. © EDP Sciences 2015Chez un patient ayant reçu 3,7 GBq d’131I après thyroïdectomie totale pour un carcinomepapillaire, la mesure du débit de dose à 1 m, réalisée de façon systématique 3 jours aprèsle traitement, a montré une valeur anormalement élevée. Une scintigraphie et uneTomographie d’Émission MonoPhotonique associée à une Tomodensitométrie (TEMP/TDM) ontalors été réalisées et ont montré une fixation importante de l’iode au niveau médiastinalantérieur due à la présence d’un goitre endothoracique résiduel. Compte tenu de laproximité entre ce goitre iodofixant et les tissus avoisinants, les doses reçues par lesorganes à risque les plus proches, notamment le cœur, ont été évaluées. Cette évaluation aété réalisée, dans un premier temps, avec le logiciel OLINDA/EXM, couramment utilisé enmédecine nucléaire. Des doses plus personnalisées ont ensuite été calculées à l’aide dulogiciel OEDIPE associé au code Monte Carlo MCNPX. Les calculs effectués avec le logicielOLINDA/EXM ont permis d’évaluer la dose moyenne absorbée au cœur à environ 2 Gy avec unefixation de 56 % de l’activité administrée. Dans un second temps, l’utilisation dulogiciel OEDIPE a permis de prendre en compte la géométrie spécifique du patient ainsi que la répartition de la fixation d’iode au niveau médiastinal et de déterminer une doseabsorbée moyenne d’environ 1 Gy au cœur. Ainsi, l’utilisation d’un fantôme voxelisé, basésur les images TDM du patient, associé à un calcul Monte Carlo direct a permis d’optimiserle calcul des doses absorbées au cœur par rapport à l’utilisation d’un fantômeanthropomorphe standard

Review of standards of protection for pregnant workers and their offspring

The recommendations of the International Commission on Radiological Protection and the IAEA Basic Safety Standards (BSS) make clear that the embryo and fetus should be regarded as a member of the public when considering the protection of female workers who are or may be pregnant. The BSS note that the embryo and fetus should be 'afforded the same broad level of protection as required for members of the public'. Similar guidance is included in national legislation in a number of countries. On the basis of a review of such guidance, it was concluded that although the recommendations provided in the BSS are in general agreement with the international consensus on approaches to the protection of pregnant workers and their offspring, more specific supporting guidance is needed. The IAEA is preparing a technical document that extends and clarifies previous advice and considers the practical application of the advice for workers in different types of workplace, for which important potential routes of exposure for the pregnant worker have been identified. This action is being carried out under the framework of the International Action Plan for Occupational Radiation Protection. © The Author 2007. Published by Oxford University Press. All rights reserved

Long term retention and excretion of 201Tl in a patient after myocardial perfusion imaging

201Tl is widely used in nuclear medicine to carry out myocardial perfusion imaging (MPI). However, very limited data is available on long-term distribution in the body, excretion and corresponding dose. In this study we performed a 2 month follow-up of a patient who underwent MPI, by urine analysis and in vivo measurements. The biological half-life of thallium was consequently estimated to be 11.6-27 d, which is in partial agreement with previous studies. We also estimated excretion and retention of 200Tl, 201Tl and 202Tl isotopes using the biokinetic parameters from ICRP publication 53 and compared the forecast result with actual measurements. The latter demonstrated a higher urinary excretion and a higher body retention than what was expected. Our results therefore suggest that the long-term retention and consequently the effective dose coefficient for 201Tl considered in ICRP publications 53 and 80 may be slightly underestimated. © The Author 2005. Published by Oxford University Press. All rights reserved