| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Institute of Molecular Pathology and Immunology,*the University of Porto, Porto, Portugal; the Department of Pathology,Medical Faculty of Porto, Porto, Portugal; the Department of Pathology,Hospital São João, Porto, Portugal; and the Department of Pathology,Hospital Clínico Universitario, Santiago de Compostela, Spain
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
Mitochondrial DNA (mtDNA) is thought to be more susceptible than nuclear DNA to mutagen-induced damage for several reasons: mtDNA polymerase 
replicates the DNA with poor fidelity,5
mtDNA is a naked (without histones) molecule to which chemical carcinogens can easily bind,6,7
and mtDNA is particularly susceptible to the high concentration of reactive oxygen species in mitochondria.8
Nuclear microsatellite instability (nMSI) is related to functional loss of mismatch repair genes, including the hMSH2, hMLH1, hPMS1, and hPMS2 genes.9,10
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.11
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,12 in a study on colorectal tumors, to describe alterations in repetitive regions of mtDNA. For the evaluation of mtMSI, Habano and colleagues12 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 cancers13-17 without reaching concordant conclusions about the relationship between the instability of nuclear and mitochondrial genomes.12-17
Alterations of mtDNA have been demonstrated in various types of human cancer and include large deletions, missense mutations, frameshift mutations, and small deletions/insertions.1,12-26 mtDNA is a hot spot for mutations in cancer as it is preferentially damaged by many carcinogens.6,7 The role of mtDNA somatic mutations in this setting is not yet understood.14,21-23
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.18,24 The mtDNA CD has also been detected in Hashimoto’s thyroiditis displaying oxyphilic cells.1
Very few studies analyzing mtDNA mutations in thyroid have been published to date.1,18,23,24,26,27 Such studies were limited by the small size of the samples and the small percentage of mtDNA analyzed per case.1,18,23,24,26,27 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.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
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 colleagues28 and Rosai and colleagues29 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 Extraction
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).
Screening of mtDNA CD by Polymerase Chain Reaction (PCR)
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).16,18 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.16 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.
Semiquantitative PCR
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.
Screening of mtDNA Somatic Mutations and mtDNA Variants by Direct Sequencing
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.
Statistical 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.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
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.2,18
|
The average percentage and the SD of mtDNA CD in the lesions of each group are summarized in Table 1
. The amount of mtDNA CD was significantly higher (P < 0.0001) in Hürthle cell tumors than in non-Hürthle cell tumors independently of the benignity or malignancy of the lesions. The percentage of mtDNA CD was significantly higher (P < 0.0001 and P = 0.0012, respectively) in Hürthle cell follicular carcinomas (7.4 ± 2.2%) than in Hürthle cell adenomas (4.3 ± 1.6%) and Hürthle cell papillary carcinomas (4.3 ± 1.6%) (Table 1)
.
MtDNA Somatic Point Mutations
D-Loop Region
The results of the screening of D-loop somatic mutations are summarized in Table 2
. Most of the mutations found in the D-loop region were located in repetitive regions. Following Habano and colleagues20
we classified the tumors displaying somatic mutations in repetitive regions (variations in the number of repetitive units) as lesions with mtDNA D-loop instability. MtDNA D-loop instability was detected in 32 of 66 (48.5%) tumors (Table 2)
. By tumor type, mtDNA D-loop instability was found in 3 of 10 (30.0%) adenomas, 12 of 20 (60.0%) Hürthle cell adenomas, 1 of 4 (25.0%) follicular carcinomas, 7 of 13 (53.9%) Hürthle cell follicular carcinomas, 5 of 12 (41.7%) papillary carcinomas, and in 4 of 7 (57.1%) Hürthle cell papillary carcinomas. The percentage of tumors with D-loop instability is similar (P = 0.822) in benign (50.0%, 15 of 30) and in malignant tumors (47.2%, 17 of 36). The percentage of Hürthle cell tumors with mtDNA D-loop instability (57.5%, 23 of 40) is higher, although not significantly (P = 0.069), than the percentage of non-Hürthle cell tumors with mtDNA D-loop instability (34.6%, 9 of 26).
|
The results of the screening of mtDNA somatic mutations in coding genes, including tRNAs genes, are summarized in Tables 3 4, and 5
. We detected 57 mtDNA somatic mutations in 34 of the 66 (51.5%) tumors (Table 3)
. These somatic mutations include three deletions [one of 15 bp in the CytB gene (patient 3) and two in the COII gene, one of 573 bp (patient 3) and another of 569 bp (patient 9)]; three tRNA somatic point mutations, one in the tRNASer2 (patient 14), another in the tRNAAla (patient 30), and another in tRNAIle (patient 41); and 51 point mutations in the OXPHOS system genes (Table 3)
. From these 51 point mutations, 25 (49.0%) were silent mutations and 26 (51.0%) were missense mutations (Table 3)
; 44 of the 54 (81.5%) somatic point mutations (3 in tRNAs and 51 in OXPHOS system genes) were transitions. The technique we have used (automated direct sequencing) does not allow to decide with certainty if the mtDNA somatic mutations are homoplasmic or not, because it is not as sensitive as the manual sequencing. It is likely, however, that most somatic mutations are homoplasmic or near homoplasmic, because we have detected only a single signal in all but five cases in which two signals could be individualized. The same is also true for almost all mtDNA variants (see below). The results of the automated sequencing were confirmed in some samples using manual sequencing. The comparison of the prevalence of mutations in coding genes of the OXPHOS system in benign and malignant tumors did not yield any significant difference, but for the higher prevalence (P = 0.015) of missense point mutations in genes of the complex I in carcinomas than in adenomas (Table 4)
; the aforementioned missense mutations were detected in six of the seven genes of complex I (ND1, ND3, ND4, ND4L, ND5, and ND6) without any apparent concentration in a single gene (Table 3)
. The comparison of the prevalence of mutations in coding genes of the OXPHOS system in non-Hürthle cell and Hürthle cell tumors did not yield any significant differences (Table 5)
. There was however a trend (P = 0.096) toward a higher prevalence of missense point mutations in complex V genes in Hürthle cell tumors (Table 5)
; all of the missense mutations detected in complex V (n = 4) involved ATPase 6 gene (Table 3)
.
|
|
|
The percentage of tumors with mtDNA CD was higher, although not significantly (P = 0.148), in the group of tumors with D-loop instability (78.1%, 25 of 32) than in the group without D-loop instability (61.8%, 21 of 34). The amount (mean ± SD) of mtDNA CD was significantly higher (P = 0.045) in tumors with D-loop instability (4.1 ± 3.2%) than in tumors without D-loop instability (2.6 ± 2.8%). The percentage of tumors with mtDNA somatic mutations was significantly higher (P = 0.026) in tumors with D-loop instability (65.6%, 21 of 32) than in tumors without D-loop instability (38.2%, 13 of 34).
MtDNA Variants
The results of the study of mtDNA variants in the adjacent parenchyma of the tumors are summarized in Table 6
. In the seven patients from whom blood samples were available the mtDNA variants detected in the normal adjacent parenchyma were also present in blood samples (data not shown); the mtDNA sequence variants detected in normal adjacent parenchyma were thus considered as germinal mtDNA variants.
|
The comparison of the prevalence of mtDNA variants in patients with benign and malignant tumors shows a significant higher prevalence (P = 0.001 and P = 0.005, respectively) of complex I and complex IV variants in patients with malignant tumors than in patients with benign tumors (Table 6)
. Complex V variants were significantly more frequent (P < 0.001) in patients with Hürthle cell tumors than in patients with tumors without Hürthle cell features (Table 6)
.
Almost all of the variants detected in complex V genes of patients with Hürthle cell tumors involved the ATPase 6 gene (91.9%, 34 of 37) and most of them were nonsilent (79.4%, 27 of 34). The same does not hold true regarding the variants detected in patients with non-Hürthle cell tumors [8 of 11 (72.7%) involved ATPase6; 2 (25.0%) were nonsilent and 6 (75.0%) were silent].
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The increased number of mitochondria and the mitochondrial structural abnormalities observed in Hürthle cell tumors mimic those detected in the cells of patients with several mitochondrial diseases and myopathies.32-36 There is oxyphilic transformation of epithelial cells of the choroid plexus in mitochondrial encephalopathies (because of mtDNA alterations),34 and oxyphilic changes associated to mtDNA alterations have been described in Leigh syndrome35 and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).36
It has been suggested that mtDNA large deletions may reflect a deletion-prone region of mtDNA that is thought to be structural.31,37 Such deletions would result in most instances from the action of reactive oxygen species over the mtDNA.6,7 This assumption is supported by the results of the present study: 81.5% of the mtDNA somatic point mutations were transitions. The presence of mtDNA deletions in normal thyroid tissue may be the result of an age-related accumulation effect of endogenous oxidative damage, aggression of lymphocytes in autoimmune thyroid diseases, or, as observed in some mitochondrial degenerative diseases, the result of alterations in a nuclear gene, or genes, affecting the mitochondrial biogenesis.3,38,39 The oxidative pressure that results from tumor development can also produce reactive oxygen species and mtDNA damage in some lesions.6-8,21
The cause of mitochondrial proliferation in Hürthle cell tumors associated with mtDNA damage is unknown, although there is evidence of a decline in oxidative phosphorylation, and a higher requirement by the mitochondria for cytosolic ATP because of OXPHOS deficiency, which is accompanied by an induction of nuclear and mtDNA OXPHOS system gene transcriptions.31 These findings suggest a defect in the energy production machinery of the cell and indicate that the increased mitochondrial content may be compensatory, putatively because of the involvement of nuclear genes controlling mitochondrial number through a sort of a feed-back mechanism.40 Recently, Savagner and colleagues41 showed that ATP production is deficient in a series of Hürthle cell tumors, mainly because of a coupling defect in mitochondria; this defect might be related to a twofold increase in UCP2 (uncoupling protein 2) expression.41 Savagner and colleagues41 suggested that mitochondrial proliferation could therefore be an adaptative response to the UCP2 overexpression or, alternatively, the UCP2 overexpression might be a response to the proliferation of mitochondria compensating for the decreased mitochondrial ATP synthesis because of OXPHOS abnormalities. The results we have obtained fit better with the latter hypothesis.
The trend to an association between D-loop instability and occurrence and amount of mtDNA CD may be a consequence of the mtDNA CD rather than its cause. Taking into consideration that the mtDNA CD leads to a higher replicative rate as a sort of compensatory effect,34,42 it is possible that the instability in mtDNA may result from the high rate of mtDNA replication. Alternatively, it has been suggested that D-loop instability indicates the existence of a deficient repair mechanism of mtDNA alterations;11,12,14 such deficiency might explain the concurrent existence of mtDNA point mutations and mtDNA large deletions in tumors with D-loop instability.11,12,14 Most of the mtDNA point mutations are the result of mtDNA aggression by environmental factors, namely by reactive oxygen species,6,7,21,43,44 whereas insertions/deletions could occur via a slipped replication mechanism.45
No mechanism related with nuclear mismatch repair genes has been found to be active in human mtDNA repair to date. In contrast with the results of Habano and colleagues14 our data do not support the assumption that the instability in mitochondrial D-loop region is related with nMSI, because the level of mtDNA instability detected in the present study (48.5%) is much higher than the nMSI found in any type of thyroid tumor.46-49 Furthermore, the histotypes with higher levels of mtDNA instability are those displaying Hürthle cell features in which nMSI was not detected.49 Nuclear microsatellite instability was also not detected in any of the 12 cases in the present series that were analyzed previously (data not shown).
Our study documents a large number of somatic mtDNA mutations in all tumor histotypes. This high frequency is probably because of the high susceptibility of mtDNA to damage by mutagens.5-8 Homoplasmic mtDNA mutations may reflect a replicative advantage for mutated mtDNA copies,14,21,22 a growth advantage for a cell containing certain mtDNA mutations,21,22 and/or tumorigenic properties of mtDNA mutations.21,23 Coller and colleagues50 and Jones and colleagues51 have recently shown, by a mathematical approach, that these mutations could also arise by chance without any physiological advantage or tumorigenic requirement; this possibility is difficult to reconciliate with the occurrence of selection of mtDNA-specific variants in several disease models.21,52-56
The aforementioned hypotheses do not apply equally to silent and nonsilent mutations. The former, which represent almost half of the mtDNA mutations detected in our series (49%, 25 of 51), may have arisen by chance.50,51 However, the same does not hold true for nonsilent mutations. The high frequency of mtDNA somatic mutations in the malignant tumors of our series, namely in complex I genes, suggests a role for these mutations in thyroid cancer. It has been advanced the presence of functionally relevant mtDNA mutations in some types of human tumors.21,23,57 Cell fusion experiment showed that some mtDNA mutations, namely complex I mutations, are dominant, able to replace recipient mtDNA, and achieve homoplasmy in tissue culture quite rapidly.21 These findings fit with the observation that most of the mtDNA somatic mutations described in human cancers are located in complex I genes.14,22
Yeh and colleagues23 reported an association of complex I variants and homoplasmic mtDNA mutations and the occurrence of thyroid papillary carcinomas. Follicular and papillary carcinomas of our series carried a significantly higher prevalence of nonsilent mtDNA 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. Our data thus support the hypothesis advanced by Yeh and colleagues23 that the accumulation of some mtDNA variants and mtDNA somatic mutations seem to be involved in thyroid tumorigenesis.
Our results on the detection of mtDNA sequence variants suggest the existence of an association between germline polymorphisms of ATPase 6 and the occurrence of Hürthle cell tumors. In man, complex V (ATP synthase) of the mitochondrion comprises 10 to 16 subunits encoded by nuclear DNA and two subunits (ATPase 6 and ATPase 8) encoded by mtDNA.42 ATP synthase complex, at least in yeast, is involved in mtDNA genome maintenance and ATPase 6 seems to be one of the most important elements in this phenomenon.39,58-60 In yeast, mutations that abrogate the synthesis of any of the ATPase subunits, even those that are unclearly encoded, cause the same phenotype, ie, high production of petites variants [variants having mtDNA deleted molecules (rho-) or no mtDNA at all (rho0)].39,59
The role of ATP synthase genes in mtDNA maintenance may contribute to explain our findings. It is tempting to suggest that, like in yeast, ATPase 6 may have a role in mtDNA maintenance in humans. The polymorphisms of ATPase 6 could lead to a less efficient mtDNA replication and to mtDNA abnormalities that could contribute to the occurrence of mtDNA CD and Hürthle cell tumors. A larger series is needed to confirm this hypothesis and to find whether or not mutations in ATPase 6 gene can be used as a tool to follow Hürthle cell transformation.
|
Footnotes |
|---|
Supported by the Fundação para a Ciência e a Tecnologia (POCTI/NSE/41055/2001).
Accepted for publication February 1, 2002.
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
s M: Comments on mutations in mitochondrial control region DNA in gastric tumours of Japanese patients. Eur J Cancer 1999, 35:1407-1408
This article has been cited by other articles:
 |
|
 |
|
  H. AL-HUMADI, A. ZARROS, R. AL-SAIGH, and C. LIAPI Genetic Basis and Gene Therapy Trials for Thyroid Cancer Cancer Genomics Proteomics, January 1, 2010; 7(1): 31 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J P. Couto, H Prazeres, P Castro, J Lima, V Maximo, P Soares, and M Sobrinho-Simoes How molecular pathology is changing and will change the therapeutics of patients with follicular cell-derived thyroid cancer J. Clin. Pathol., May 1, 2009; 62(5): 414 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Mayr, D. Meierhofer, F. Zimmermann, R. Feichtinger, C. Kogler, M. Ratschek, N. Schmeller, W. Sperl, and B. Kofler Loss of Complex I due to Mitochondrial DNA Mutations in Renal Oncocytoma Clin. Cancer Res., April 15, 2008; 14(8): 2270 - 2275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dasgupta, M. O. Hoque, S. Upadhyay, and D. Sidransky Mitochondrial Cytochrome B Gene Mutation Promotes Tumor Growth in Bladder Cancer Cancer Res., February 1, 2008; 68(3): 700 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wang, W. R. Bamlet, M. de Andrade, L. A. Boardman, J. M. Cunningham, S. N. Thibodeau, and G. M. Petersen Mitochondrial Genetic Polymorphisms and Pancreatic Cancer Risk Cancer Epidemiol. Biomarkers Prev., July 1, 2007; 16(7): 1455 - 1459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gasparre, A. M. Porcelli, E. Bonora, L. F. Pennisi, M. Toller, L. Iommarini, A. Ghelli, M. Moretti, C. M. Betts, G. N. Martinelli, et al. Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors PNAS, May 22, 2007; 104(21): 9001 - 9006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Bonora, A. M. Porcelli, G. Gasparre, A. Biondi, A. Ghelli, V. Carelli, A. Baracca, G. Tallini, A. Martinuzzi, G. Lenaz, et al. Defective Oxidative Phosphorylation in Thyroid Oncocytic Carcinoma Is Associated with Pathogenic Mitochondrial DNA Mutations Affecting Complexes I and III. Cancer Res., June 15, 2006; 66(12): 6087 - 6096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shidara, K. Yamagata, T. Kanamori, K. Nakano, J. Q. Kwong, G. Manfredi, H. Oda, and S. Ohta Positive Contribution of Pathogenic Mutations in the Mitochondrial Genome to the Promotion of Cancer by Prevention from Apoptosis Cancer Res., March 1, 2005; 65(5): 1655 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.C. WALLACE Mitochondria and Cancer: Warburg Addressed Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 363 - 374. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Sobrinho-Simoes, V. Maximo, I. V. de Castro, E. Fonseca, P. Soares, G. Garcia-Rostan, and M. C. de Oliveira Hurthle (Oncocytic) Cell Tumors of Thyroid: Etiopathogenesis, Diagnosis and Clinical Significance International Journal of Surgical Pathology, January 1, 2005; 13(1): 29 - 35. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Sadetzki, R. Calderon-Margalit, B. Modan, S. Srivastava, and R. M. Tuttle Ret/PTC Activation in Benign and Malignant Thyroid Tumors Arising in a Population Exposed to Low-Dose External-Beam Irradiation in Childhood J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2281 - 2289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S L Asa My approach to oncocytic tumours of the thyroid J. Clin. Pathol., March 1, 2004; 57(3): 225 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lima, V. Maximo, P. Soares, D. Williams, T. Bogdanova, G. A. Thomas, and M. Sobrinho-Simoes Re: Lohrer,H.D., Hieber,L. and Zitzelsberger,H. (2002) Differential mutation frequency in mitochondrial DNA from thyroid tumours. Carcinogenesis, 23, 1577-1582 Carcinogenesis, June 1, 2003; 24(6): 1155 - 1155. [Full Text] [PDF]
|
|
|
|
|
|
L. Cheung, M. Messina, A. Gill, A. Clarkson, D. Learoyd, L. Delbridge, J. Wentworth, J. Philips, R. Clifton-Bligh, and B. G. Robinson Detection of the PAX8-PPAR{gamma} Fusion Oncogene in Both Follicular Thyroid Carcinomas and Adenomas J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 354 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. I. Rogounovitch, V. A. Saenko, Y. Shimizu-Yoshida, A. Yu. Abrosimov, E. F. Lushnikov, P. O. Roumiantsev, A. Ohtsuru, H. Namba, A. F. Tsyb, and S. Yamashita Large Deletions in Mitochondrial DNA in Radiation-associated Human Thyroid Tumors Cancer Res., December 1, 2002; 62(23): 7031 - 7041. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
