Differential mutation frequency in mitochondrial DNA ...

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Dear Sir,. We read with interest the article on `Differential mutation frequency in mitochondrial DNA from thyroid tumours' recently published in Carcinogenesis ...
Carcinogenesis vol.24 no.6 pp.1155, 2003 DOI: 10.1093/carcin/bgg050

LETTER TO THE EDITOR

Re: Lohrer,H.D., Hieber,L. and Zitzelsberger,H. (2002) Differential mutation frequency in mitochondrial DNA from thyroid tumours. Carcinogenesis, 23, 1577±1582 Jorge Lima1,2, Valdemar M aximo1, Paula Soares1,2, 3 Dillwyn Williams , Tania Bogdanova4, Gerry A.Thomas5 and Manuel Sobrinho-Sim~ oes1,2,6,7

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To whom correspondence should be addressed Email: [email protected]

Dear Sir, We read with interest the article on `Differential mutation frequency in mitochondrial DNA from thyroid tumours' recently published in Carcinogenesis by Lohrer et al. (1). Lohrer et al. (1) compared the mitochondrial DNA (mtDNA) alterations in 126 post-Chernobyl thyroid tumours (samples from Belarus) and 40 sporadic thyroid tumours from patients with no known history of exposure to radiation (samples from Munich). In both sets of tumours, the authors analysed paired tumour and adjacent thyroid tissue. The region of mtDNA studied was the hypervariable region II (HVTII, positions 72±337; Cambridge notation accession no. NC_001807.2;2), a non-coding region which contains microsatellite-like sequences, particularly a C-mononucleotide track interrupted by a single thymidine at position 310 (1). Lohrer et al. (1) detected two sequence alterations in two patients from Belarus and eight sequence alterations in six patients from Munich. These alterations were found exclusively in the polycytidine sequence (positions 303±315 of the Cambridge notation) of HVTII. A number of polymorphisms were also detected in 37 patients (25 patients from Belarus and 12 from Munich) (1). Lohrer et al. (1) concluded that, although ionizing radiation could result in increased mtDNA mutations, a higher frequency of mtDNA mutations was found in the tumours from Munich compared with those from Belarus. Our group has been studying the mtDNA alterations in sporadic (non-irradiated) thyroid tumours (2±6). We would point out that Lohrer et al.'s study (1) included a comparison of tumour and non-neoplastic tissue. The thyroid in the children exposed to fallout from Chernobyl would have received over 1000 times the average whole body radiation dose, including the radiation to the bone marrow. We therefore consider that before accepting that radiation from Chernobyl did not cause mitochondrial mutations it is necessary to

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Acknowledgement This work was supported by a grant from FCT (POCTI/CBO/43944/2001).

References 1. Lohrer,H.D., Hieber,L. and Zitzelsberger,H. (2002) Differential mutation frequency in mitochondrial DNA from thyroid tumours. Carcinogenesis, 23, 1577±1582. 2. Maximo,V., Soares,P., Machado,J.C., Seruca,R. and Sobrinho-Sim~ oes,M. (2000) Mitochondrial DNA alteration in gastric cancer. Gastroenterology, 119, 1808±1809. 3. Maximo,V. and Sobrinho-Sim~ oes,M. (2000) Mitochondrial DNA `common' deletion in Hurthle cell lesions of the the thyroid. J. Pathol., 192, 561±562. 4. Maximo,V. and Sobrinho-Sim~ oes,M. (2000) Hurthle cell tumours of the thyroid. A review with emphasis on mitochondrial abnormalities with clinical relevance. Virchows Arch., 437, 107±115. 5. Maximo,V., Soares,P., Seruca,R., Rocha,A.S., Castro,P. and SobrinhoSim~ oes,M. (2001) Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma. Genes Chromosomes Cancer, 32, 136±143. 6. Maximo,V., Soares,P., Lima,J., Cameselle-Teijeiro,J. and SobrinhoSim~ oes,M. (2002) Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hurthle cell tumors. Am. J. Pathol., 160, 1857±1865.

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1 IPATIMUPÐInstitute of Molecular Pathology and Immunology of the University of Porto, Portugal, 2Medical Faculty of the University of Porto, Porto, Portugal, 3Strangeways Research Laboratory, University of Cambridge, Cambridge, UK, 4Institute of Endocrinology and Metabolism, Kiev, Ukraine, 5 South West Wales Cancer Institute, Swansea Clinical School, Singleton Hospital, Swansea, UK and 6Hospital S.Jo~ao, Porto, Portugal

compare both tumour and non-tumour findings in the thyroid with a relatively non-exposed tissue such as blood. We agree with the conclusion that there is no evidence that mitochondrial mutations were involved in the causation of those thyroid carcinomas that have arisen due to radiation exposure, but radiation could have caused mutations in the non-neoplastic thyroid, which by a combination of growth advantage and the natural growth of the thyroid in infancy could have expanded to detectable levels. Other possible routes to the generation of mitochondrial mutations could be through mutation in the genes maintaining mtDNA integrity or even through a mutation in mitochondria comparable to the genomic instability described in the nuclear genome after irradiation. These are speculations; but unless the opportunity that is provided by the occurrence of essentially organospecific irradiation after Chernobyl is taken, we will not know whether organospecific radiation leads to organospecific mitochondrial mutations. The study of Lohrer et al. (1) provides very interesting data, but it would have been greatly enhanced if they had been able to compare the frequency of mitochondrial mutations in irradiated and non-irradiated tissue, rather than assuming that the sequence changes in irradiated tissue were polymorphisms.