Exp Clin Endocrinol Diabetes 2019; 127(07): 423-436
DOI: 10.1055/a-0869-7355
Article
© Georg Thieme Verlag KG Stuttgart · New York

The Mitochondrial DNA Control Region Might Have Useful Diagnostic and Prognostic Biomarkers for Thyroid Tumors

Rıfat Bircan
1   Faculty of Arts and Sciences, Department of Molecular Biology & Genetics, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
,
Hülya Ilıksu Gözü
2   School of Medicine, Department of Endocrinology and Metabolism, Marmara University, İstanbul, Turkey
,
Esra Ulu
1   Faculty of Arts and Sciences, Department of Molecular Biology & Genetics, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
,
Şükran Sarıkaya
3   Department of Pathology, Dr. Lütfi Kırdar Kartal Education & Research Hospital, İstanbul, Turkey
,
Aylin Ege Gül
3   Department of Pathology, Dr. Lütfi Kırdar Kartal Education & Research Hospital, İstanbul, Turkey
,
Duygu Yaşar Şirin
1   Faculty of Arts and Sciences, Department of Molecular Biology & Genetics, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
,
Serhat Özçelik
4   Section of Endocrinology and Metabolism, Haydarpaşa Education & Research Hospital, İstanbul, Turkey
,
Cenk Aral
1   Faculty of Arts and Sciences, Department of Molecular Biology & Genetics, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
› Author Affiliations
Further Information

Publication History

received 15 August 2018
revised 14 November 2018

accepted 04 March 2019

Publication Date:
15 April 2019 (online)

Abstract

The literature suggests that mitochondrial DNA (mtDNA) defects are associated with a large number of diseases including cancers. The role of mtDNA variations in thyroid cancer is a highly controversial topic. Therefore, we investigated the role of mt-DNA control region (CR) variations in thyroid tumor progression and the influence of mtDNA haplogroups on susceptibility to thyroid tumors. For this purpose, in total, 108 hot thyroid nodules (HTNs), 95 cold thyroid nodules (CTNs), 48 papillary thyroid carcinoma (PTC) samples with their surrounding tissues and 104 healthy control subjects’ blood samples were screened for all mtDNA CR variations using Sanger sequencing. We found that MtDNA haplogroup U was significantly associated with susceptibility to benign thyroid entities. In addition, eight single nucleotide polymorphisms (SNPs) (T146C, G185A, C194T, C295T, G16129A, T16304C, A16343G and T16362C) in the mtDNA CR were associated with the occurrence of benign and malign thyroid nodules in the Turkish population. As compared with samples taken from a healthy Turkish population and HTNs, the frequency of C7 repeats in D310 polycytosine sequence was found to be higher in CTNs and the PTC samples. In addition, the frequency of somatic mutations in mtMSI regions including T16189C and D514 CA dinucleotide repeats were found to be higher in PTC samples than benign thyroid nodules. Conversely, the frequency of somatic mutations in D310 was found to be higher in HTNs than CTNs and PTCs. In conclusion, mtDNA D310 instability does not play a role in the tumorigenesis of PTC but the results indicate that it might be used as a diagnostic clonal expansion biomarker for premalignant thyroid tumor cells. In addition, D514 CA instability might be considered as a prognostic biomarker for benign to malign transformation in thyroid tumors.

Supporting Information

 
  • References

  • 1 Tipirisetti NR, Govatati S, Pullari P. et al. Mitochondrial control region alterations and breast cancer risk: a study in South Indian population. PLoS One 2014; 9: e85363 DOI: doi:10.1371/journal.pone.0085363
  • 2 Warburg O, Wind F, Negelein E. The Metabolism of Tumors in the Body. J Gen Physiol 1927; 8: 519-530
  • 3 Lee HC, Wei YH, Mitochondrial DNA. instability and metabolic shift in human cancers. Int J Mol Sci 2009; 10: 674-701 DOI: doi: 10.3390/ijms10020674
  • 4 Su X, Wang W, Ruan G. et al. A comprehensive characterization of mitochondrial genome in papillary thyroid cancer. Int J Mol Sci 2016; 1 DOI: doi:10.3390/ijms17101594
  • 5 Nicholls DG, Ferguson SJ. Bioenergetics. 4th ed UK: Academic Press; 2013
  • 6 Cobb LJ, Lee C, Xiao J. et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging; Albany NY: 2016. 8 796-809 DOI: DOI: 10.18632/aging.100943
  • 7 Duarte FV, Palmeira CM, Rolo AP. The Role of microRNAs in Mitochondria: Small Players Acting Wide. Genes; Basel: 2014. 5 865-886 DOI: doi:10.3390/genes5040865
  • 8 Payne BA, Wilson IJ, Yu-Wai-Man P. et al. Universal heteroplasmy of human mitochondrial DNA. Hum Mol Genet 2013; 22: 384-390 DOI: doi:10.1093/hmg/dds435
  • 9 Sharma H, Singh A, Sharma C. et al. Mutations in the mitochondrial DNA D-loop region are frequent in cervical cancer. Cancer Cell Int 2005; 5: 34 DOI: doi:10.1186/1475-2867-5-34
  • 10 Nicholls TJ, Minczuk M. In D-loop: 40 years of mitochondrial 7S DNA. Exp Gerontol 2014; 56: 175-181 DOI: doi:10.1016/j.exger.2014.03.027
  • 11 De Paepe B. Mitochondrial markers for cancer: Relevance to diagnosis, therapy, and prognosis and general understanding of malignant disease mechanisms. ISRN. Pathology 2012; 2012: 15 DOI: doi:10.5402/2012/217162
  • 12 Ashtiani ZO, Heidari M, Hasheminasab SM. et al. Mitochondrial D-Loop polymorphism and microsatellite instability in prostate cancer and benign hyperplasia patients. Asian Pac J Cancer Prev 2012; 13: 3863-3868
  • 13 Cai FF, Kohler C, Zhang B. et al. Mutations of mitochondrial DNA as potential biomarkers in breast cancer. Anticancer Res 2011; 31: 4267-4271
  • 14 Zhang W, Wang W, Jia Z. Single nucleotide polymorphisms in the mitochondrial displacement loop region modifies malignant melanoma: a study in Chinese Han population. Mitochondrial. DNA 2015; 26: 205-207 DOI: doi:10.3109/19401736.2014.900613
  • 15 Cocos R, Schipor S, Badiu C. et al. Mitochondrial DNA haplogroup K as a contributor to protection against thyroid cancer in a population from southeast Europe. Mitochondrion 2017; DOI: DOI: 10.1016/j.mito.2017.08.012.
  • 16 Gozu H, Avsar M, Bircan R. et al. Does a Leu 512 Arg thyrotropin receptor mutation cause an autonomously functioning papillary carcinoma?. Thyroid 2004; 14: 975-980 DOI: doi:10.1089/thy.2004.14.975
  • 17 Krohn K, Fuhrer D, Bayer Y. et al. Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev 2005; 26: 504-524 DOI: doi:10.1210/er.2004-0005
  • 18 Popoveniuc G, Jonklaas J. Thyroid nodules. Med Clin North Am 2012; 96: 329-349 DOI: doi:10.1016/j.mcna.2012.02.002
  • 19 Gharib H, Papini E. Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am 2007; 36: 707-735 vi DOI: doi:10.1016/j.ecl.2007.04.009
  • 20 Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 2013; 13: 184-199 DOI: doi:10.1038/nrc3431
  • 21 Lohrer HD, Hieber L, Zitzelsberger H. Differential mutation frequency in mitochondrial DNA from thyroid tumours. Carcinogenesis 2002; 23: 1577-1582
  • 22 Ding Z, Ji J, Chen G. et al. Analysis of mitochondrial DNA mutations in D-loop region in thyroid lesions. Biochim Biophys Acta 2010; 1800: 271-274 DOI: doi:10.1016/j.bbagen.2009.05.009
  • 23 Maximo V, Lima J, Soares P. et al. Mitochondrial D-Loop instability in thyroid tumours is not a marker of malignancy. Mitochondrion 2005; 5: 333-340 DOI: doi:10.1016/j.mito.2005.06.003
  • 24 Gozu H, Avsar M, Bircan R. et al. Mutations in the thyrotropin receptor signal transduction pathway in the hyperfunctioning thyroid nodules from multinodular goiters: a study in the Turkish population. Endocr J 2005; 52: 577-585
  • 25 Gozu HI, Bircan R, Krohn K. et al. Similar prevalence of somatic TSH receptor and Gsalpha mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey. Eur J Endocrinol 2006; 155: 535-545 DOI: doi:10.1530/eje.1.02253
  • 26 Eszlinger M, Krohn K, Beck M. et al. Comparison of differential gene expression of hot and cold thyroid nodules with primary epithelial cell culture models by investigation of co-regulated gene sets. Biochim Biophys Acta 2006; 1763: 263-271 DOI: doi:10.1016/j.bbamcr.2005.12.001
  • 27 Vuong HG, Kondo T, Oishi N. et al. Genetic alterations of differentiated thyroid carcinoma in iodine-rich and iodine-deficient countries. Cancer Med 2016; 5: 1883-1889 DOI: doi:10.1002/cam4.781
  • 28 Levin BC, Cheng H, Reeder DJ. A human mitochondrial DNA standard reference material for quality control in forensic identification, medical diagnosis, and mutation detection. Genomics 1999; 55: 135-146 DOI: doi:10.1006/geno.1998.5513
  • 29 Xu C, Tran-Thanh D, Ma C. et al. Mitochondrial D310 mutations in the early development of breast cancer. Br J Cancer 2012; 106: 1506-1511 DOI: doi:10.1038/bjc.2012.74
  • 30 Aral C, Kaya H, Ataizi-Celikel C. et al. A novel approach for rapid screening of mitochondrial D310 polymorphism. BMC Cancer 2006; 6: 21 DOI: doi:10.1186/1471-2407-6-21
  • 31 Yacoubi-Loueslati B, Cherni L, Frigi S. et al. Polymorphisme du microsatellite mitochondrial D310 dans la population tunisienne. Antropologie 2009; XLVII 89-94
  • 32 Mueller EE, Eder W, Ebner S. et al. The mitochondrial T16189C polymorphism is associated with coronary artery disease in Middle European populations. PLoS One 2011; 6: e16455 DOI: doi:10.1371/journal.pone.0016455
  • 33 Wallace DC. Genetics: Mitochondrial DNA in evolution and disease. Nature 2016; 535: 498-500 DOI: doi:10.1038/nature18902
  • 34 Mergen H, Oner R, Oner C. Mitochondrial DNA sequence variation in the Anatolian Peninsula (Turkey). J Genet 2004; 83: 39-47
  • 35 Guney O, Ak H, Atay S. et al. Mitochondrial DNA polymorphisms associated with longevity in the Turkish population. Mitochondrion 2014; 17: 7-13 DOI: doi:10.1016/j.mito.2014.04.013
  • 36 Fang H, Shen L, Chen T. et al. Cancer type-specific modulation of mitochondrial haplogroups in breast, colorectal and thyroid cancer. BMC Cancer 2010; 10: 421 DOI: doi:10.1186/1471-2407-10-421
  • 37 Sbisa E, Tanzariello F, Reyes A. et al. Mammalian mitochondrial D-loop region structural analysis: identification of new conserved sequences and their functional and evolutionary implications. Gene 1997; 205: 125-140
  • 38 van Oven M, Kayser M. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat 2009; 30: E386-E394 DOI: doi:10.1002/humu.20921
  • 39 Mueller EE, Schaier E, Brunner SM. et al. Mitochondrial haplogroups and control region polymorphisms in age-related macular degeneration: a case-control study. PLoS One 2012; 7: e30874 DOI: doi:10.1371/journal.pone.0030874
  • 40 Zhou S, Kachhap S, Sun W. et al. Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck. Proc Natl Acad Sci USA 2007; 104: 7540-7545 DOI: doi:10.1073/pnas.0610818104
  • 41 Chatterjee A, Dasgupta S, Sidransky D. Mitochondrial subversion in cancer. Cancer Prev Res (Phila) 2011; 4: 638-654 DOI: doi:10.1158/1940-6207.CAPR-10-0326
  • 42 Mambo E, Gao X, Cohen Y. et al. Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations. Proc Natl Acad Sci U S A 2003; 100: 1838-1843 DOI: doi:10.1073/pnas.0437910100
  • 43 Fliss MS, Usadel H, Caballero OL. et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 2000; 287: 2017-2019
  • 44 Ha PK, Tong BC, Westra WH. et al. Mitochondrial C-tract alteration in premalignant lesions of the head and neck: a marker for progression and clonal proliferation. Clin Cancer Res 2002; 8: 2260-2265
  • 45 Tang M, Baez S, Pruyas M. et al. Mitochondrial DNA mutation at the D310 (displacement loop) mononucleotide sequence in the pathogenesis of gallbladder carcinoma. Clin Cancer Res 2004; 10: 1041-1046
  • 46 Liu VW, Wang Y, Yang HJ. et al. Mitochondrial DNA variant 16189T>C is associated with susceptibility to endometrial cancer. Hum Mutat 2003; 22: 173-174 DOI: doi:10.1002/humu.10244
  • 47 Liou CW, Lin TK, Chen JB. et al. Association between a common mitochondrial DNA D-loop polycytosine variant and alteration of mitochondrial copy number in human peripheral blood cells. J Med Genet 2010; 47: 723-728 DOI: doi:10.1136/jmg.2010.077552
  • 48 Lu J, Sharma LK, Bai Y. Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Res 2009; 19: 802-815 DOI: doi:10.1038/cr.2009.69
  • 49 Aral C, Akkiprik M, Caglayan S. et al. Investigation of relationship of the mitochondrial DNA 16189 T>C polymorphism with metabolic syndrome and its associated clinical parameters in Turkish patients. Hormones (Athens) 2011; 10: 298-303
  • 50 Brandon M, Baldi P, Wallace DC. Mitochondrial mutations in cancer. Oncogene 2006; 25: 4647-4662 DOI: doi:10.1038/sj.onc.1209607
  • 51 Mambo E, Chatterjee A, Xing M. et al. Tumor-specific changes in mtDNA content in human cancer. Int J Cancer 2005; 116: 920-924 DOI: doi:10.1002/ijc.21110
  • 52 Reznik E, Miller ML, Senbabaoglu Y. et al. Mitochondrial DNA copy number variation across human cancers. Elife 2016; 5 DOI: doi:10.7554/eLife.10769
  • 53 Pang LJ, Shao JY, Liang XM. et al. Mitochondrial DNA somatic mutations are frequent in nasopharyngeal carcinoma. Cancer Biol Ther 2008; 7: 198-207
  • 54 Kleist B, Meurer T, Poetsch M. et al. alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers. Tumour Biol 2017; 39: 1010428317692246 DOI: doi:10.1177/1010428317692246
  • 55 Schon EA, DiMauro S, Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 2012; 13: 878-890 DOI: 10.1038/nrg3275