مروری بر آسیب‌شناسی مولکولی تومورهای اپی‌تلیال تیروئید

نوع مقاله : مقاله مروری

نویسندگان

1 دکتری بیوشیمی، گروه زیست‌شناسی، دانشکده‌ی علوم پایه، واحد علوم و تحقیقات تهران، دانشگاه آزاد اسلامی، تهران، ایران

2 استاد، گروه ژنتیک پزشکی، دانشکده‌ی پزشکی، دانشگاه علوم پزشکی تهران، تهران، ایران

3 استاد، گروه زیست‌شناسی، دانشکده‌ی علوم پایه، واحد علوم و تحقیقات تهران، دانشگاه آزاد اسلامی، تهران، ایران

4 دانشیار، مرکز تحقیقات سلولی و مولکولی غدد درون‌ریز، پژوهشکده‌ی علوم غدد درون‌ریز و متابولیسم، دانشگاه علوم پزشکی شهید بهشتی، تهران، ایران

چکیده

ومورهای اپی‌تلیال تیروئید، همگی از تیروسیت‌ها یا همان سلول‌های اپی‌تلیال فولیکولار تیروئید به وجود می‌آیند. اگر این سلول‌ها از مکانیسم‌های طبیعی رشد، تقسیم سلولی و آپوپتوز سرپیچی کنند و وارد مرحله‌ی رشد بی‌رویه‌ شوند، تومور تیروئید ایجاد می‌گردد. بیشتر این تومورها خوش‌خیم می‌باشند، اما برخی از آن‌ها بدخیمی‌هایی با رشد آهسته و تعداد معدودی از آن‌ها نیز سرطان‌های بسیار تهاجمی هستند. سرپیچی از مکانیسم‌های طبیعی و ایجاد تومور، می‌تواند در نتیجه‌ی بروز تغییرات ژنتیک و اپی‌ژنتیک در پروتوآنکوژن‌ها و ژن‌های سرکوبگر تومور باشد. درک صحیح از آسیب‌شناسی مولکولی تومورهای اپی‌تلیال تیروئید و شناخت تغییرات مولکولی پروتوآنکوژن‌ها و ژن‌های سرکوبگر تومور، می‌تواند ویژگی‌های بالینی متنوع آن‌ها را توضیح دهد و به ارایه‌ی اطلاعات در زمینه‌ی تشخیص، پیش‌آگهی و کشف درمان‌های مؤثر بینجامد. از طرفی، فرصت تحقیقات بیشتر را در حوزه‌های تشخیص، پیش‌آگهی و درمان فراهم می‌نماید. این مقاله‌ی مروری، با هدف مرور و بررسی آسیب‌شناسی مولکولی تومورهای اپی‌تلیال تیروئید انجام شد.

کلیدواژه‌ها

عنوان مقاله [English]

A Review on the Molecular Pathology of Epithelial Thyroid Tumors

نویسندگان [English]

  • Seyedeh Adeleh Razavi 1
  • Mohammad Hossein Modarressi 2
  • Parichehreh Yaghmaei 3
  • Mehdi Hedayati 4
1 PhD in Biochemistry, Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
2 Professor, Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
3 Professor, Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
4 Associate Professor, Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
چکیده [English]

Epithelial thyroid tumors are all from the thyrocytes, the follicular epithelial cells of the thyroid. If these cells do not replicate the normal mechanisms of growth, cell division, and apoptosis, and enter to the uncontrolled growth phase, thyroid tumors arise. Most of these tumors are benign, but some of them are slow-growing malignancies, and a small number of them are also highly-invasive cancers. Failure of the natural mechanisms, and creation a tumor can be due to genetic and epigenetic changes in proto-oncogenes and tumor suppressor genes. Understanding molecular pathology of epithelial thyroid tumors, and recognizing molecular changes of proto-oncogenes and tumor suppressor genes can explain their different clinical features, providing diagnostic and prognostic information, and discovering of the effective treatments. On the other hand, it can provide further research opportunities in the diagnosis, prognosis, and treatment areas. This review article targeted the molecular pathology of epithelial thyroid tumors.

کلیدواژه‌ها [English]

  • Pathology
  • Molecular
  • Epithelial tumor
  • Thyroid
  • Proto-oncogenes
  • Tumor suppressor genes

مراجع

  1. DeLellis RA, Lloyd RV, Heitz PU, Eng C. WHO Classification of Tumours: Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: International Agency for Research on Cancer (IARC); 2004.
  2. Segev DL, Umbricht C, Zeiger MA. Molecular pathogenesis of thyroid cancer. Surg Oncol 2003; 12(2): 69-90.
  3. Nozhat Z, Hedayati M. PI3K/AKT pathway and its mediators in thyroid carcinomas. Mol Diagn Ther 2016; 20(1): 13-26.
  4. Bozorg-Ghalati F, Hedayati M. Molecular biomarkers of anaplastic thyroid carcinoma. Curr Mol Med 2017; 17(3): 181-8.
  5. Hedayati M, Zarif YM, Sheikholeslami S, Afsari F. Diversity of mutations in the RET proto-oncogene and its oncogenic mechanism in medullary thyroid cancer. Crit Rev Clin Lab Sci 2016; 53(4): 217-27.
  6. de LA, Bursell J, Gregory JW, Rees DA, Ludgate M. TSH receptor activation and body composition. J Endocrinol 2010; 204(1): 13-20.
  7. Mard-Soltani M, Rasaee MJ, Sheikhi A, Hedayati M. Eliciting an antibody response against a recombinant TSH containing fusion protein. J Immunoassay Immunochem 2017; 38(3): 257-70.
  8. Fuhrer D, Holzapfel HP, Wonerow P, Scherbaum WA, Paschke R. Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules. J Clin Endocrinol Metab 1997; 82(11): 3885-91.
  9. Malchoff CD, Reardon G, MacGillivray DC, Yamase H, Rogol AD, Malchoff DM. An unusual presentation of McCune-Albright syndrome confirmed by an activating mutation of the Gs alpha-subunit from a bone lesion. J Clin Endocrinol Metab 1994; 78(3): 803-6.
  10. Bignell GR, Canzian F, Shayeghi M, Stark M, Shugart YY, Biggs P, et al. Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer. Am J Hum Genet 1997; 61(5): 1123-30.
  11. Abubaker J, Jehan Z, Bavi P, Sultana M, Al-Harbi S, Ibrahim M, et al. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab 2008; 93(2): 611-8.
  12. Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 2008; 93(8): 3106-16.
  13. Razavi SA, Modarressi MH, Yaghmaei P, Tavangar SM, Hedayati M. Circulating levels of PTEN and KLLN in papillary thyroid carcinoma: can they be considered as novel diagnostic biomarkers? Endocrine 2017; 57(3): 428-35.
  14. Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW, Tallini G, et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab 2003; 88(5): 2318-26.
  15. Belge G, Rippe V, Meiboom M, Drieschner N, Garcia E, Bullerdiek J. Delineation of a 150-kb breakpoint cluster in benign thyroid tumors with 19q13.4 aberrations. Cytogenet Cell Genet 2001; 93(1-2): 48-51.
  16. Rippe V, Drieschner N, Meiboom M, Murua EH, Bonk U, Belge G, et al. Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene 2003; 22(38): 6111-4.
  17. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003; 63(7): 1454-7.
  18. Rabes HM, Demidchik EP, Sidorow JD, Lengfelder E, Beimfohr C, Hoelzel D, et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 2000; 6(3): 1093-103.
  19. Hedayati M, Yaghmaei P, Pooyamanesh Z, Zarif Yeganeh M, Hoghooghi Rad L. Leptin: A correlated peptide to papillary thyroid carcinoma? J Thyroid Res 2011; 2011: 832163.
  20. Rajabi S, Hedayati M. Medullary Thyroid Cancer: Clinical Characteristics and New Insights into Therapeutic Strategies Targeting Tyrosine Kinases. Mol Diagn Ther 2017; 21(6): 607-20.
  21. Hayashi H, Ichihara M, Iwashita T, Murakami H, Shimono Y, Kawai K, et al. Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Oncogene 2000; 19(39): 4469-75.
  22. Klugbauer S, Demidchik EP, Lengfelder E, Rabes HM. Molecular analysis of new subtypes of ELE/RET rearrangements, their reciprocal transcripts and breakpoints in papillary thyroid carcinomas of children after Chernobyl. Oncogene 1998; 16(5): 671-5.
  23. Santoro M, Thomas GA, Vecchio G, Williams GH, Fusco A, Chiappetta G, et al. Gene rearrangement and Chernobyl related thyroid cancers. Br J Cancer 2000; 82(2): 315-22.
  24. Ciampi R, Nikiforov YE. RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinology 2007; 148(3): 936-41.
  25. Santoro M, Melillo RM, Fusco A. RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur J Endocrinol 2006; 155(5): 645-53.
  26. Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin Cancer Res 1998; 4(1): 223-8.
  27. Bongarzone I, Fugazzola L, Vigneri P, Mariani L, Mondellini P, Pacini F, et al. Age-related activation of the tyrosine kinase receptor protooncogenes RET and NTRK1 in papillary thyroid carcinoma. J Clin Endocrinol Metab 1996; 81(5): 2006-9.
  28. Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997; 57(9): 1690-4.
  29. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003; 95(8): 625-7.
  30. Hou P, Liu D, Xing M. Functional characterization of the T1799-1801del and A1799-1816ins BRAF mutations in papillary thyroid cancer. Cell Cycle 2007; 6(3): 377-9.
  31. Trovisco V, Soares P, Preto A, de Castro IV, Lima J, Castro P, et al. Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness. Virchows Arch 2005; 446(6): 589-95.
  32. Caronia LM, Phay JE, Shah MH. Role of BRAF in thyroid oncogenesis. Clin Cancer Res 2011; 17(24): 7511-7.
  33. Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 2013; 309(14): 1493-501.
  34. Guerra A, Sapio MR, Marotta V, Campanile E, Rossi S, Forno I, et al. The primary occurrence of BRAF(V600E) is a rare clonal event in papillary thyroid carcinoma. J Clin Endocrinol Metab 2012; 97(2): 517-24.
  35. Xing M. BRAFV600E mutation and papillary thyroid cancer: Chicken or egg? J Clin Endocrinol Metab 2012; 97(7): 2295-8.
  36. Fagin JA, Mitsiades N. Molecular pathology of thyroid cancer: diagnostic and clinical implications. Best Pract Res Clin Endocrinol Metab 2008; 22(6): 955-69.
  37. Rivera M, Ricarte-Filho J, Knauf J, Shaha A, Tuttle M, Fagin JA, et al. Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol 2010; 23(9): 1191-200.
  38. Liu X, Qu S, Liu R, Sheng C, Shi X, Zhu G, et al. TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab 2014; 99(6): E1130-E1136.
  39. He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, et al. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 2005; 102(52): 19075-80.
  40. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159(3): 676-90.
  41. Cong D, He M, Chen S, Liu X, Liu X, Sun H. Expression profiles of pivotal microRNAs and targets in thyroid papillary carcinoma: an analysis of The Cancer Genome Atlas. Onco Targets Ther 2015; 8: 2271-7.
  42. Xing M. Gene methylation in thyroid tumorigenesis. Endocrinology 2007; 148(3): 948-53.
  43. Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, et al. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer 2006; 119(10): 2322-9.
  44. Hou P, Liu D, Xing M. Genome-wide alterations in gene methylation by the BRAF V600E mutation in papillary thyroid cancer cells. Endocr Relat Cancer 2011; 18(6): 687-97.
  45. Malchoff CD, Malchoff DM. The genetics of hereditary nonmedullary thyroid carcinoma. J Clin Endocrinol Metab 2002; 87(6): 2455-9.
  46. Cetta F, Chiappetta G, Melillo RM, Petracci M, Montalto G, Santoro M, et al. The ret/ptc1 oncogene is activated in familial adenomatous polyposis-associated thyroid papillary carcinomas. J Clin Endocrinol Metab 1998; 83(3): 1003-6.
  47. Canzian F, Amati P, Harach HR, Kraimps JL, Lesueur F, Barbier J, et al. A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2. Am J Hum Genet 1998; 63(6): 1743-8.
  48. Malchoff CD, Sarfarazi M, Tendler B, Forouhar F, Whalen G, Joshi V, et al. Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab 2000; 85(5): 1758-64.
  49. Hishinuma A, Fukata S, Kakudo K, Murata Y, Ieiri T. High incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations. Thyroid 2005; 15(9): 1079-84.
  50. Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000; 289(5483): 1357-60.
  51. Raman P, Koenig RJ. Pax-8-PPAR-gamma fusion protein in thyroid carcinoma. Nat Rev Endocrinol 2014; 10(10): 616-23.
  52. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, et al. PPARgamma signaling and metabolism: The good, the bad and the future. Nat Med 2013; 19(5): 557-66.
  53. Skelhorne-Gross G, Nicol CJ. The Key to Unlocking the Chemotherapeutic Potential of PPARgamma Ligands: Having the Right Combination. PPAR Res 2012; 2012: 946943.
  54. Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer 2014; 120(6): 799-807.
  55. Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 2014; 99(5): E754-E765.
  56. Worby CA, Dixon JE. PTEN. Annu Rev Biochem 2014; 83: 641-69.
  57. Gustafson S, Zbuk KM, Scacheri C, Eng C. Cowden syndrome. Semin Oncol 2007; 34(5): 428-34.
  58. Alvarez-Nunez F, Bussaglia E, Mauricio D, Ybarra J, Vilar M, Lerma E, et al. PTEN promoter methylation in sporadic thyroid carcinomas. Thyroid 2006; 16(1): 17-23.
  59. Hou P, Ji M, Xing M. Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors. Cancer 2008; 113(9): 2440-7.
  60. Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW, et al. Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis. Cancer Res 2004; 64(5): 1664-8.
  61. Gasparre G, Porcelli AM, Bonora E, Pennisi LF, Toller M, Iommarini L, et al. Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors. Proc Natl Acad Sci USA 2007; 104(21): 9001-6.
  62. Maximo V, Botelho T, Capela J, Soares P, Lima J, Taveira A, et al. Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid. Br J Cancer 2005; 92(10): 1892-8.
  63. Corver WE, Ruano D, Weijers K, den Hartog WC, van Nieuwenhuizen MP, de MN, et al. Genome haploidisation with chromosome 7 retention in oncocytic follicular thyroid carcinoma. PLoS One 2012; 7(6): e38287.
  64. Musholt PB, Musholt TJ, Morgenstern SC, Worm K, Sheu SY, Schmid KW. Follicular histotypes of oncocytic thyroid carcinomas do not carry mutations of the BRAF hot-spot. World J Surg 2008; 32(5): 722-8.
  65. Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993; 91(1): 179-84.
  66. Garcia-Rostan G, Camp RL, Herrero A, Carcangiu ML, Rimm DL, Tallini G. Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Am J Pathol 2001; 158(3): 987-96.
  67. Bozorg-Ghalati F, Hedayati M, Dianatpour M, Azizi F, Mosaffa N, Mehrabani D. Effects of a Phosphoinositide-3-Kinase Inhibitor on Anaplastic Thyroid Cancer Stem Cells. Asian Pac J Cancer Prev 2017; 18(8): 2287-91.
  68. Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G, Chiappetta G, et al. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 1998; 4(2): 287-94.
  69. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 2003; 88(11): 5399-404.
  70. Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T, et al. Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab 2013; 98(9): E1562-E1566.
  71. Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X. Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 2005; 103(11): 2261-8.
  72. Garcia-Rostan G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R, Hermsem MJ, et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res 2005; 65(22): 10199-207.
  73. Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res 2011; 71(13): 4403-11.
مجله دانشکده پزشکی اصفهان
دوره 36، شماره 492 - شماره پیاپی 492
مهر و آبان 1397
صفحه 964-974

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  • تاریخ دریافت: 18 فروردین 1397
  • تاریخ بازنگری: 01 اردیبهشت 1403
  • تاریخ پذیرش: 17 فروردین 1401

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