The Role of Fragile Sites in Sporadic Papillary Thyroid Carcinoma

Dillon, Laura W.; Lehman, Christine E.; Wang, Yuh‐Hwa

doi:10.1155/2012/927683

Cited by 8 publications

(9 citation statements)

References 107 publications

(104 reference statements)

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“…However, exposure to low doses of radiation in routine diagnostic X-ray does not increase the risk of development of thyroid cancer (6,15), which suggests that radiation exposure is not the sole risk factor.…”

Section: Introductionmentioning

confidence: 99%

“…When diagnosed early, they are curable and can occur at any age, most often between 30 and 40 years old (4). Generally, the cases have good prognosis and long survival, similar to people who never had cancer in over 80% of cases (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…The cases of thyroid cancer have increased steadily in the United States and other countries over the years, with three times the incidence of the 1970s (6). According to estimates from the National Cancer Institute, in Brazil in 2012, 10,590 new cases are expected, with an estimated risk of 11 cases per 100,000 women (7).…”

Section: Introductionmentioning

confidence: 99%

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Evolution of thyroid cancer mortality in adults in Brazil

Guimarães

Muzi

Parreira

et al. 2013

Arq Bras Endocrinol Metab

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RESUMOObjetivo: Avaliar a tendência da mortalidade por câncer de tireoide no Brasil entre 1980 e 2010. Materiais e métodos: Estudo ecológico, de séries temporais. As taxas de mortalidade por câncer de tireoide ajustadas por idade segundo sexo foram calculadas entre 1980 e 2010. Os dados foram analisados por três estratégias distintas: regressão polinomial, joinpoint analysis e médias móveis. Resultados:Mais de 70% das mortes ocorrem nos idosos, independente do sexo. Entre adultos jovens, a mortalidade é baixa, sem diferença entre homens e mulheres. Entre adultos maduros e idosos a mortalidade é crescente e com aumento expressivo para mulheres. Há uma tendência de mortalidade decrescente no sexo feminino para adultos e global; e no sexo masculino para 40-59 anos e global, ambos excluindo os idosos, com significância estatística. Conclusão: O conhecimento sobre a tendência permite estabelecer prioridades e alocar recursos de forma direcionada para a modificação positiva desse cenário na população brasileira. Arq Bras Endocrinol Metab. 2013;57(7):538-44 Descritores Câncer de tireoide; mortalidade; série histórica; epidemiologia ABSTRACT Objective: To assess the trend of thyroid cancer mortality in Brazil between 1980 and 2010. Materials and methods: An ecological study of time series. Mortality rates for thyroid cancer adjusted by age according to gender were calculated between 1980 and 2010. Data were analyzed by three distinct strategies: polynomial regression, joinpoint analysis, and moving averages. Results: Over 70% of deaths occur in the elderly, regardless of sex. Among young adults, the mortality rate is low, with no difference between men and women. Among mature adults and elderly, mortality is increasing, and significantly, for women. There is a trend of decreasing mortality in all female adults and overall population, and in males and 40-59 years and overall population, both excluding the elderly, with statistical significance. Conclusion: Knowledge about trends allows setting priorities and allocating resources toward positive changes in this scenario in the Brazilian population. Arq Bras Endocrinol Metab.2013;57(7):538-44

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evolution of thyroid cancer mortality in adults in Brazil

Guimarães

Muzi

Parreira

et al. 2013

Arq Bras Endocrinol Metab

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“…1 and 3 ). In addition to the chemicals that we used here, fragile sites are sensitive to a range of environmental and dietary agents, and chemotherapeutic drugs [ 5 ]. Therefore, our study points to the importance of investigating these chemicals and their role in inducing DNA breakage in leukemia-associated genes, and possibly in leading to disease-causing gene rearrangements.…”

Section: Discussionmentioning

confidence: 99%

“…Low-dose APH exposure leads to expression of over 230 fragile sites in human cells [ 4 ]. In addition to APH, fragile sites are prone to break following exposure to many chemicals, including environmental and chemotherapeutic agents (reviewed in [ 5 ]). Therefore, understanding both the mechanism for, and consequences of, fragile site breakage following exposure to such chemicals will be important in guiding treatment decisions and preventing exposures that may cause human disease.…”

Section: Introductionmentioning

confidence: 99%

Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

Thys

Lehman

Pierce

et al. 2015

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Hematopoietic stem and progenitor cells (HSPCs) give rise to all of the cells that make up the hematopoietic system in the human body, making their stability and resilience especially important. Damage to these cells can severely impact cell development and has the potential to cause diseases, such as leukemia. Leukemia-causing chromosomal rearrangements have largely been studied in the context of radiation exposure and are formed by a multi-step process, including an initial DNA breakage and fusion of the free DNA ends. However, the mechanism for DNA breakage in patients without previous radiation exposure is unclear. Here, we investigate the role of non-cytotoxic levels of environmental factors, benzene, and diethylnitrosamine (DEN), and chemotherapeutic agents, etoposide, and doxorubicin, in generating DNA breakage at the patient breakpoint hotspots of the MLL and CBFB genes in human HSPCs. These conditions represent exposure to chemicals encountered daily or residual doses from chemotherapeutic drugs. Exposure of HSPCs to non-cytotoxic levels of environmental chemicals or chemotherapeutic agents causes DNA breakage at preferential sites in the human genome, including the leukemia-related genes MLL and CBFB. Though benzene, etoposide, and doxorubicin have previously been linked to leukemia formation, this is the first study to demonstrate a role for DEN in the generation of DNA breakage at leukemia-specific sites. These chemical-induced DNA breakpoints coincide with sites of predicted topoisomerase II cleavage. The distribution of breakpoints by exposure to non-cytotoxic levels of chemicals showed a similar pattern to fusion breakpoints in leukemia patients. Our findings demonstrate that HSPCs exposed to non-cytotoxic levels of environmental chemicals and chemotherapeutic agents are prone to topoisomerase II-mediated DNA damage at the leukemia-associated genes MLL and CBFB. These data suggest a role for long-term environmental chemical or residual chemotherapeutic drug exposure in generation of DNA breakage at sites with a propensity to form leukemia-causing gene rearrangements.

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DNA Fragile Site Breakage as a Measure of Chemical Exposure and Predictor of Individual Susceptibility to Form Oncogenic Rearrangements

Lehman

Dillon

Nikiforov

et al. 2017

CARCIN

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Chromosomal rearrangements induced by non-radiation causes contribution to the majority of oncogenic fusions found in cancer. Treatment of human thyroid cells with fragile site-inducing laboratory chemicals can cause preferential DNA breakage at the RET gene and generate the RET/PTC1 rearrangement, a common driver mutation in papillary thyroid carcinomas (PTC). Here, we demonstrate that treatment with non-cytotoxic levels of environmental chemicals (benzene and diethylnitrosamine) or chemotherapeutic agents (etoposide and doxorubicin) generates significant DNA breakage within RET at levels similar to those generated by fragile site-inducing laboratory chemicals. This suggests that chronic exposure to these chemicals plays a role in the formation of non-radiation associated RET/PTC rearrangements. We also investigated whether the sensitivity of the fragile RET region could predict the likelihood of rearrangement formation using normal thyroid tissues from patients with and without RET/PTC rearrangements. We found that normal cells of patients with thyroid cancer driven by RET/PTC rearrangements have significantly higher blunt-ended, double-stranded DNA breaks at RET than those of patients without RET/PTC rearrangements. This sensitivity of a cancer driver gene suggests for the first time that a DNA breakage test at the RET region could be utilized to evaluate susceptibility to RET/PTC formation. Further, the significant increase of blunt-ended, double-stranded DNA breaks, but not other types of DNA breaks, in normal cells from patients with RET/PTC-driven tumors suggests that blunt-ended double-stranded DNA breaks are a preferred substrate for rearrangement formation, and implicate involvement of the non-homologous end joining pathway in the formation of RET/PTC rearrangements.

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The Role of Fragile Sites in Sporadic Papillary Thyroid Carcinoma

Cited by 8 publications

References 107 publications

Evolution of thyroid cancer mortality in adults in Brazil

Evolution of thyroid cancer mortality in adults in Brazil

Environmental and chemotherapeutic agents induce breakage at genes involved in leukemia-causing gene rearrangements in human hematopoietic stem/progenitor cells

DNA Fragile Site Breakage as a Measure of Chemical Exposure and Predictor of Individual Susceptibility to Form Oncogenic Rearrangements

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