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• W1704572801 abstract "In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of nonsilent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion’s histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors. In an attempt to progress in the understanding of the relationship of mitochondrial DNA (mtDNA) alterations and thyroid tumorigenesis, we studied the mtDNA in 79 benign and malignant tumors (43 Hürthle and 36 non-Hürthle cell neoplasms) and respective normal parenchyma. The mtDNA common deletion (CD) was evaluated by semiquantitative polymerase chain reaction. Somatic point mutations and sequence variants of mtDNA were searched for in 66 tumors (59 patients) and adjacent parenchyma by direct sequencing of 70% of the mitochondrial genome (including all of the 13 OXPHOS system genes). We detected 57 somatic mutations, mostly transitions, in 34 tumors and 253 sequence variants in 59 patients. Follicular and papillary carcinomas carried a significantly higher prevalence of nonsilent point mutations of complex I genes than adenomas. We also detected a significantly higher prevalence of complex I and complex IV sequence variants in the normal parenchyma adjacent to the malignant tumors. Every Hürthle cell tumor displayed a relatively high percentage (up to 16%) of mtDNA CD independently of the lesion’s histotype. The percentage of deleted mtDNA molecules was significantly higher in tumors with D-loop mutations than in mtDNA stable tumors. Sequence variants of the ATPase 6 gene, one of the complex V genes thought to play a role in mtDNA maintenance and integrity in yeast, were significantly more prevalent in patients with Hürthle cell tumors than in patients with non-Hürthle cell neoplasms. We conclude that mtDNA variants and mtDNA somatic mutations of complex I and complex IV genes seem to be involved in thyroid tumorigenesis. Germline polymorphisms of the ATPase 6 gene are associated with the occurrence of mtDNA CD, the hallmark of Hürthle cell tumors. Hürthle (oxyphil) cells are found in a minority of thyroid tumors, either benign (Hürthle cell adenoma) or malignant (Hürthle cell variants of follicular and papillary carcinoma), as well as in other types of thyroid tumors and several nonneoplastic thyroid disorders.1Müller-Höcker J Jacob U Seibel P Hashimoto thyroiditis is associated with defects of cytochrome-c oxidase in oxyphil Askanazy cells and with the common deletion (4,977) of mitochondrial DNA.Ultrastruct Pathol. 1998; 22: 91-100Crossref PubMed Scopus (51) Google Scholar, 2Máximo V Sobrinho-Simões M Hurthle cell tumours of the thyroid. A review with emphasis on mitochondrial abnormalities with clinical relevance.Virchows Arch. 2000; 437: 107-115Crossref PubMed Scopus (113) Google Scholar Hürthle cells are characterized by a large, granular, eosinophilic cytoplasm, which is filled with abnormal mitochondria. Most Hürthle cell tumors are sporadic and frequently occur in association with autoimmune thyroiditis, but their occurrence in a familial setting has also been reported.3Katoh R Harach HR Williams ED Solitary, multiple, and familial oxyphil tumours of the thyroid gland.J Pathol. 1998; 186: 292-299Crossref PubMed Scopus (46) Google Scholar, 4Canzian F Amati P Harach HR Kraimps JL Lesueur F Barbier J Levillain P Romeo G Bonneau D A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2.Am J Hum Genet. 1998; 63: 1743-1748Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar The abundance of abnormal mitochondria makes Hürthle cell tumors a good model to study mtDNA abnormalities in human cancer. Mitochondrial DNA (mtDNA) is thought to be more susceptible than nuclear DNA to mutagen-induced damage for several reasons: mtDNA polymerase γ replicates the DNA with poor fidelity,5Kunkel TA Loeb LA Fidelity of mammalian DNA polymerases.Science. 1981; 213: 765-767Crossref PubMed Scopus (127) Google Scholar mtDNA is a naked (without histones) molecule to which chemical carcinogens can easily bind,6Backer JM Weinstein IB Mitochondrial DNA is a major cellular target for a dihydrodiol-epoxide derivative of benzo[a]pyrene.Science. 1980; 209: 297-299Crossref PubMed Scopus (218) Google Scholar, 7Allen JA Coombs MM Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA.Nature. 1980; 287: 244-245Crossref PubMed Scopus (184) Google Scholar and mtDNA is particularly susceptible to the high concentration of reactive oxygen species in mitochondria.8Oberley LW Buettner GR Role of superoxide dismutase in cancer: a review.Cancer Res. 1979; 39: 1141-1149PubMed Google Scholar Nuclear microsatellite instability (nMSI) is related to functional loss of mismatch repair genes, including the hMSH2, hMLH1, hPMS1, and hPMS2 genes.9Parsons R Li GM Longley MJ Fang WH Papadopoulos N Jen J de la Chapelle A Kinzler KW Vogelstein B Modrich P Hypermutability and mismatch repair deficiency in RER+ tumor cells.Cell. 1993; 75: 1227-1236Abstract Full Text PDF PubMed Scopus (957) Google Scholar, 10Boyer JC Umar A Risinger JI Lipford JR Kane M Yin S Barrett JC Kolodner RD Kunkel TA Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines.Cancer Res. 1995; 55: 6063-6070PubMed Google Scholar In the mitochondrial genome, the mismatch repair system has been found only in yeast strains in which MSH1 and MSH2 are separately involved in mitochondrial and nuclear DNA repair systems, respectively.11Reenan RA Kolodner RD Characterization of insertion mutations in the Saccharomyces cerevisiae MSH1 and MSH2 genes: evidence for separate mitochondrial and nuclear functions.Genetics. 1992; 132: 975-985Crossref PubMed Google Scholar No MSH1 homologue has been found in mammalian cells and it remains uncertain whether a mismatch repair system plays a role in the maintenance of the mammalian mitochondrial genome. The term mitochondrial microsatellite instability (mtMSI) was introduced by Habano and colleagues,12Habano W Nakamura S Sugai T Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome.Oncogene. 1998; 17: 1931-1937Crossref PubMed Scopus (147) Google Scholar in a study on colorectal tumors, to describe alterations in repetitive regions of mtDNA. For the evaluation of mtMSI, Habano and colleagues12Habano W Nakamura S Sugai T Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome.Oncogene. 1998; 17: 1931-1937Crossref PubMed Scopus (147) Google Scholar quantified the alterations in two simple repeat sequences in a noncoding displacement-loop (D-loop) region in mtDNA. Additional studies have addressed the issue of mtMSI in human cancers13Tamura G Nishizuka S Maesawa C Suzuki Y Iwaya T Sakata K Endoh Y Motoyama T Mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 316-319Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 14Habano W Sugai T Nakamura SI Uesugi N Yoshida T Sasou S Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinoma.Gastroenterology. 2000; 118: 835-841Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 15Richard SM Bailliet G Paez GL Bianchi MS Peltomaki P Bianchi NO Nuclear and mitochondrial genome instability in human breast cancer.Cancer Res. 2000; 60: 4231-4237PubMed Google Scholar, 16Máximo V Soares P Seruca R Sobrinho-Simoe˜s M Comments on mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 1407-1408Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 17Máximo V Soares P Seruca R Rocha AS Castro P Sobrinho-Simões M Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma.Genes Chromosom Cancer. 2001; 32: 136-143Crossref PubMed Scopus (105) Google Scholar without reaching concordant conclusions about the relationship between the instability of nuclear and mitochondrial genomes.12Habano W Nakamura S Sugai T Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome.Oncogene. 1998; 17: 1931-1937Crossref PubMed Scopus (147) Google Scholar, 13Tamura G Nishizuka S Maesawa C Suzuki Y Iwaya T Sakata K Endoh Y Motoyama T Mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 316-319Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 14Habano W Sugai T Nakamura SI Uesugi N Yoshida T Sasou S Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinoma.Gastroenterology. 2000; 118: 835-841Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 15Richard SM Bailliet G Paez GL Bianchi MS Peltomaki P Bianchi NO Nuclear and mitochondrial genome instability in human breast cancer.Cancer Res. 2000; 60: 4231-4237PubMed Google Scholar, 16Máximo V Soares P Seruca R Sobrinho-Simoe˜s M Comments on mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 1407-1408Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 17Máximo V Soares P Seruca R Rocha AS Castro P Sobrinho-Simões M Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma.Genes Chromosom Cancer. 2001; 32: 136-143Crossref PubMed Scopus (105) Google Scholar Alterations of mtDNA have been demonstrated in various types of human cancer and include large deletions, missense mutations, frameshift mutations, and small deletions/insertions.1Müller-Höcker J Jacob U Seibel P Hashimoto thyroiditis is associated with defects of cytochrome-c oxidase in oxyphil Askanazy cells and with the common deletion (4,977) of mitochondrial DNA.Ultrastruct Pathol. 1998; 22: 91-100Crossref PubMed Scopus (51) Google Scholar, 12Habano W Nakamura S Sugai T Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome.Oncogene. 1998; 17: 1931-1937Crossref PubMed Scopus (147) Google Scholar, 13Tamura G Nishizuka S Maesawa C Suzuki Y Iwaya T Sakata K Endoh Y Motoyama T Mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 316-319Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 14Habano W Sugai T Nakamura SI Uesugi N Yoshida T Sasou S Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinoma.Gastroenterology. 2000; 118: 835-841Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 15Richard SM Bailliet G Paez GL Bianchi MS Peltomaki P Bianchi NO Nuclear and mitochondrial genome instability in human breast cancer.Cancer Res. 2000; 60: 4231-4237PubMed Google Scholar, 16Máximo V Soares P Seruca R Sobrinho-Simoe˜s M Comments on mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 1407-1408Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 17Máximo V Soares P Seruca R Rocha AS Castro P Sobrinho-Simões M Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma.Genes Chromosom Cancer. 2001; 32: 136-143Crossref PubMed Scopus (105) Google Scholar, 18Máximo V Soares P Rocha AS Sobrinho-Simões M The common deletion of mitochondrial DNA is found in goitres and thyroid tumors with and without oxyphil cell change.Ultrastruct Pathol. 1998; 22: 271-273Crossref PubMed Scopus (33) Google Scholar, 19Burgart LJ Zheng J Shu Q Strickler JG Shibata D Somatic mitochondrial mutation in gastric cancer.Am J Pathol. 1995; 147: 1105-1111PubMed Google Scholar, 20Habano W Sugai T Yoshida T Nakamura S Mitochondrial gene mutation, but not large-scale deletion, is a feature of colorectal carcinomas with mitochondrial microsatellite instability.Int J Cancer. 1999; 83: 625-629Crossref PubMed Scopus (105) Google Scholar, 21Polyak K Li Y Zhu H Lengauer C Willson JK Markowitz SD Trush MA Kinzler KW Vogelstein B Somatic mutations of the mitochondrial genome in human colorectal tumours.Nat Genet. 1998; 20: 291-293Crossref PubMed Scopus (730) Google Scholar, 22Fliss MS Usadel H Caballero OL Wu L Buta MR Eleff SM Jen J Sidransky D Facile detection of mitochondrial DNA mutations in tumors and bodily fluids.Science. 2000; 287: 2017-2019Crossref PubMed Scopus (694) Google Scholar, 23Yeh JJ Lunetta KL van Orsouw NJ Moore FD Mutter GL Vijg J Dahia PL Eng C Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours.Oncogene. 2000; 19: 2060-2066Crossref PubMed Scopus (149) Google Scholar, 24Máximo V Sobrinho-Simões M Mitochondrial DNA ‘common’ deletion in Hurthle cell lesions of the thyroid.J Pathol. 2000; 192: 561-562Crossref PubMed Scopus (44) Google Scholar, 25Lewis PD Baxter P Paul Griffiths A Parry JM Skibinski DO Detection of damage to the mitochondrial genome in the oncocytic cells of Warthin's tumour.J Pathol. 2000; 191: 274-281Crossref PubMed Scopus (73) Google Scholar, 26Tallini G Ladanyi M Rosai J Jhanwar SC Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumors.Cytogenet Cell Genet. 1994; 66: 253-259Crossref PubMed Scopus (79) Google Scholar mtDNA is a hot spot for mutations in cancer as it is preferentially damaged by many carcinogens.6Backer JM Weinstein IB Mitochondrial DNA is a major cellular target for a dihydrodiol-epoxide derivative of benzo[a]pyrene.Science. 1980; 209: 297-299Crossref PubMed Scopus (218) Google Scholar, 7Allen JA Coombs MM Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA.Nature. 1980; 287: 244-245Crossref PubMed Scopus (184) Google Scholar The role of mtDNA somatic mutations in this setting is not yet understood.14Habano W Sugai T Nakamura SI Uesugi N Yoshida T Sasou S Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinoma.Gastroenterology. 2000; 118: 835-841Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 21Polyak K Li Y Zhu H Lengauer C Willson JK Markowitz SD Trush MA Kinzler KW Vogelstein B Somatic mutations of the mitochondrial genome in human colorectal tumours.Nat Genet. 1998; 20: 291-293Crossref PubMed Scopus (730) Google Scholar, 22Fliss MS Usadel H Caballero OL Wu L Buta MR Eleff SM Jen J Sidransky D Facile detection of mitochondrial DNA mutations in tumors and bodily fluids.Science. 2000; 287: 2017-2019Crossref PubMed Scopus (694) Google Scholar, 23Yeh JJ Lunetta KL van Orsouw NJ Moore FD Mutter GL Vijg J Dahia PL Eng C Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours.Oncogene. 2000; 19: 2060-2066Crossref PubMed Scopus (149) Google Scholar We have previously detected the mitochondrial common deletion (mtDNA CD) in a small series of thyroid tumors composed of Hürthle (oxyphil) cells, as well as in some nonneoplastic thyroid lesions with incipient Hürthle cell changes.18Máximo V Soares P Rocha AS Sobrinho-Simões M The common deletion of mitochondrial DNA is found in goitres and thyroid tumors with and without oxyphil cell change.Ultrastruct Pathol. 1998; 22: 271-273Crossref PubMed Scopus (33) Google Scholar, 24Máximo V Sobrinho-Simões M Mitochondrial DNA ‘common’ deletion in Hurthle cell lesions of the thyroid.J Pathol. 2000; 192: 561-562Crossref PubMed Scopus (44) Google Scholar The mtDNA CD has also been detected in Hashimoto’s thyroiditis displaying oxyphilic cells.1Müller-Höcker J Jacob U Seibel P Hashimoto thyroiditis is associated with defects of cytochrome-c oxidase in oxyphil Askanazy cells and with the common deletion (4,977) of mitochondrial DNA.Ultrastruct Pathol. 1998; 22: 91-100Crossref PubMed Scopus (51) Google Scholar Very few studies analyzing mtDNA mutations in thyroid have been published to date.1Müller-Höcker J Jacob U Seibel P Hashimoto thyroiditis is associated with defects of cytochrome-c oxidase in oxyphil Askanazy cells and with the common deletion (4,977) of mitochondrial DNA.Ultrastruct Pathol. 1998; 22: 91-100Crossref PubMed Scopus (51) Google Scholar, 18Máximo V Soares P Rocha AS Sobrinho-Simões M The common deletion of mitochondrial DNA is found in goitres and thyroid tumors with and without oxyphil cell change.Ultrastruct Pathol. 1998; 22: 271-273Crossref PubMed Scopus (33) Google Scholar, 23Yeh JJ Lunetta KL van Orsouw NJ Moore FD Mutter GL Vijg J Dahia PL Eng C Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours.Oncogene. 2000; 19: 2060-2066Crossref PubMed Scopus (149) Google Scholar, 24Máximo V Sobrinho-Simões M Mitochondrial DNA ‘common’ deletion in Hurthle cell lesions of the thyroid.J Pathol. 2000; 192: 561-562Crossref PubMed Scopus (44) Google Scholar, 26Tallini G Ladanyi M Rosai J Jhanwar SC Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumors.Cytogenet Cell Genet. 1994; 66: 253-259Crossref PubMed Scopus (79) Google Scholar, 27Ebner D Rodel G Pavenstaedt I Haferkamp O Functional and molecular analysis of mitochondria in thyroid oncocytoma.Virchows Arch. 1991; 60: 139-144Crossref Scopus (43) Google Scholar Such studies were limited by the small size of the samples and the small percentage of mtDNA analyzed per case.1Müller-Höcker J Jacob U Seibel P Hashimoto thyroiditis is associated with defects of cytochrome-c oxidase in oxyphil Askanazy cells and with the common deletion (4,977) of mitochondrial DNA.Ultrastruct Pathol. 1998; 22: 91-100Crossref PubMed Scopus (51) Google Scholar, 18Máximo V Soares P Rocha AS Sobrinho-Simões M The common deletion of mitochondrial DNA is found in goitres and thyroid tumors with and without oxyphil cell change.Ultrastruct Pathol. 1998; 22: 271-273Crossref PubMed Scopus (33) Google Scholar, 23Yeh JJ Lunetta KL van Orsouw NJ Moore FD Mutter GL Vijg J Dahia PL Eng C Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours.Oncogene. 2000; 19: 2060-2066Crossref PubMed Scopus (149) Google Scholar, 24Máximo V Sobrinho-Simões M Mitochondrial DNA ‘common’ deletion in Hurthle cell lesions of the thyroid.J Pathol. 2000; 192: 561-562Crossref PubMed Scopus (44) Google Scholar, 26Tallini G Ladanyi M Rosai J Jhanwar SC Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumors.Cytogenet Cell Genet. 1994; 66: 253-259Crossref PubMed Scopus (79) Google Scholar, 27Ebner D Rodel G Pavenstaedt I Haferkamp O Functional and molecular analysis of mitochondria in thyroid oncocytoma.Virchows Arch. 1991; 60: 139-144Crossref Scopus (43) Google Scholar In an attempt to progress in the understanding of the putative relationship between mtDNA alterations in thyroid tumors in general, and Hürthle cell tumors in particular, we searched for mtDNA alterations in a large series of thyroid tumors, including both benign and malignant lesions, paying a special attention to the different histotypes of Hürthle cell neoplasms. In each case we have also analyzed the mtDNA of normal adjacent parenchyma in an attempt to find sequence variants of mtDNA putatively associated with the occurrence of Hürthle cell tumors. Seventy-nine thyroid tumors from 68 patients were studied. In 11 patients there were two distinct lesions that were separately studied. The 79 lesions were classified according to Hedinger and colleagues28Hedinger CE Williams ED Sobin LH Histological typing of thyroid tumors.in: Hedinger CE International Histological Classification of Tumours. vol 11. Springer-Verlag, Berlin1988Crossref Google Scholar and Rosai and colleagues29Rosai J Carcangiu ML DeLellis RA Tumors of the thyroid gland.Atlas of Tumor Pathology, 3rd series. Armed Forces Institute of Pathology, Washington1992Google Scholar as follicular adenoma (n = 15), follicular Hürthle cell adenoma (n = 20), follicular carcinoma (n = 5), follicular Hürthle cell carcinoma (n = 13), papillary carcinoma (n = 16), and papillary Hürthle cell carcinoma (n = 10). Samples from 32 lesions were obtained at the time of surgery, together with the corresponding normal adjacent tissues; these samples were carefully dissected by expert pathologists and snap-frozen. In 47 cases, microdissected paraffin-embedded material was used for the screening of mtDNA mutations because of the absence of representative tumor tissue in the frozen samples. DNA was extracted from microdissected frozen and/or paraffin-embedded pathological and normal thyroid tissue pairs using the NucleoSpin Tissue Kit (Macherey-Nagel, Düren, Germany). The detection of mtDNA CD was performed using two sets of primers: Mitout-F and Mitout-R (outside the deletion region) and Mitin-F and Mitin-R (within the deletion region).16Máximo V Soares P Seruca R Sobrinho-Simoe˜s M Comments on mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 1407-1408Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 18Máximo V Soares P Rocha AS Sobrinho-Simões M The common deletion of mitochondrial DNA is found in goitres and thyroid tumors with and without oxyphil cell change.Ultrastruct Pathol. 1998; 22: 271-273Crossref PubMed Scopus (33) Google Scholar In the wild-type mtDNA only the Mitin primer set gives a PCR product with 142 bp. In cases with the mtDNA CD, Mitin primers amplify a 142-bp target sequence and Mitout primers an aberrant PCR product with 214 bp.16Máximo V Soares P Seruca R Sobrinho-Simoe˜s M Comments on mutations in mitochondrial control region DNA in gastric tumours of Japanese patients.Eur J Cancer. 1999; 35: 1407-1408Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar PCR amplifications were performed in a 25-μl volume containing 200 μmol/L of each dNTP, 12.5 pmol of each of the forward and reverse primers, 50 mmol/L KCl, 10 mmol/L Tris-HCl, (pH 9.0), 1.5 mmol/L MgCl2, and 1 U of Taq DNA polymerase (Amersham Biosciences, Lda, Buckinghamshire, England). Cycling conditions were a single predenaturation step at 94°C for 5 minutes followed by 35 cycles of denaturation at 94°C for 20 seconds, annealing at 60°C for 20 seconds, and elongation at 72°C for 20 seconds, and a final incubation at 72°C for 2 minutes. PCR products were inspected by electrophoresis on 2% agarose gels. For the quantitation of the percentage of mtDNA molecules deleted in each sample, PCR co-amplification of two fragments of mtDNA (one within and the other outside the deletion region) were performed. PCR co-amplifications were performed in a 25-μl volume containing 200 μmol/L of each dNTP, 12.5 pmol of each of the forward and reverse of both sets of primers, 50 mmol/L KCl, 10 mmol/L Tris-HCl, (pH 9.0), 1.5 mmol/L MgCl2, and 1 U of Taq DNA polymerase (Amersham Biosciences, Lda). Cycling conditions were a single predenaturation step at 94°C for 5 minutes followed by 18 cycles of denaturation at 94°C for 20 seconds, annealing at 62°C for 20 seconds, and elongation at 72°C for 20 seconds, and a final incubation at 72°C for 2 minutes. PCR products were inspected by electrophoresis on 2% agarose gels. The optimal number of cycles of amplification to allow quantitation of the two PCR products was determined using three samples of normal thyroid. Two hundred ng of each DNA sample were subjected to a number of amplification cycles ranging from 10 to 25 cycles. PCR products were separated on a 2% agarose gel and stained with ethidium bromide. The intensity of the fluorescence was automatically measured and integrated with the genescan software Image Master (Amersham Biosciences, Lda). A close to exponential increase in the amount of PCR product was obtained between 15 and 23 cycles for both fragment products. In every semiquantitative PCR experiment 18 cycles were used. The determination of the optimal annealing temperature of the two sets of primers was performed using the same three samples of DNA of normal thyroid samples used in the determination of the optimal number of cycles for amplification. PCR triplicates of 200 ng of DNA of each sample were used for co-amplification of both fragments. Cycling conditions were a single predenaturation step at 94°C for 5 minutes followed by 18 cycles of denaturation at 94°C for 20 seconds, annealing varying between 54°C and 65°C for 20 seconds, and elongation at 72°C for 20 seconds, and a final incubation at 72°C for 2 minutes. PCR products were inspected by electrophoresis on 2% agarose gels. At 62°C the amount of PCR products of both fragments was similar. In all quantitation analyses, 18 cycles of PCR amplification and an annealing temperature of 62°C were used. By PCR/direct sequencing we analyzed 66 thyroid tumors and the respective adjacent normal thyroid tissue, surgically excised from 59 patients. In the remaining 13 tumors the study could not be performed for technical reasons. In seven cases (patients 52 to 58) blood samples were also analyzed. Using fragments varying from 0.6 to 1.4 kb we have screened 70% of the mitochondrial genome: all mtDNA coding genes, 46% of tRNA genes (tRNAPhe, Gly, Lys, Asp, Leu1, Ser1, His, Leu2, Ile, Ser2, Glu, Arg) and 52% of D-loop region. Details of PCR primers and sequencing primers are available on request from the authors. All PCR amplifications were performed in a 25-μl volume containing 200 μmol/L of each dNTP, 12.5 pmol of each of the forward and reverse primers, 50 mmol/L KCl, 10 mmol/L Tris-HCl, (pH 9.0), 1.5 mmol/L MgCl2, and 1 U of Taq DNA polymerase (Amersham Biosciences Lda). Cycling conditions were a single predenaturation step at 94°C for 5 minutes followed by 35 cycles of denaturation at 94°C for 30 seconds, annealing at 58°C for 20 seconds, and elongation at 72°C for 1 minute, and a final incubation at 72°C for 5 minutes. PCR products were separated by electrophoresis on 2% agarose gels and purified using the NucleoSpin Extract Kit (Macherey-Nagel, Düren, Germany). Sequencing analysis was then performed on purified products using the ABI Prism dGTP BigDye Terminator Ready Reaction Kit (Perkin-Elmer, Foster City, CA) and an ABI Prism 377 DNA sequencer (Perkin-Elmer). Both strands were screened using the original primers. Sequences were compared against a comprehensive mitochondrial databank (MITOMAP: A Human Mitochondrial Genome Database. Center for Molecular Medicine, Emory University, Atlanta, GA. http://www.gen.emory.edu/mitomap.html, 2000). All mtDNA-altered samples were subjected to an additional complete analysis. The statistical analysis of the results was performed using the chi-square test with the Yates correction, Fisher’s exact test, and Student’s t-test. A nonparametric test (Mann-Whitney) was also used whenever appropriate. A P value <0.05 was considered statistically significant. The overall results are summarized in Table 1. The mtDNA CD was found in all Hürthle cell tumors (100%, n = 43), in 5 of 15 (33.3%) adenomas, and in 3 of 16 (18.8%) papillary carcinomas without Hürthle cell features. The occurrence of mtDNA CD was significantly associated (P < 0.001) with Hürthle cell tumors. The mtDNA CD was also detected at very low levels in the normal adjacent thyroid tissue of some cases (Table 1). The histological study of the specimens in which mtDNA CD was observed, including the positive peritumoral tissues, revealed either typical Hürthle cells or follicular cells with relatively abundant, granular, oxyphilic cytoplasm of a kind we have previously designated as incipient Hürthle cell transformation.2Máximo V Sobrinho-Simões M Hurthle cell tumours of the thyroid. A review with emphasis on mitochondrial abnormalities with clinical relevance.Virchows Arch. 2000; 437: 107-115Crossref PubMed Scopus (113) Google Scholar, 18Máximo V Soares P Rocha AS Sobrinho-Simões M The common deletion of mitochondrial DNA is found in goitres and thyroid tumors with and without oxyphil cell change.Ultrastruct Pathol. 1998; 22:" @default.
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• W1704572801 title "Mitochondrial DNA Somatic Mutations (Point Mutations and Large Deletions) and Mitochondrial DNA Variants in Human Thyroid Pathology" @default.
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