Endocrine Pathology

, Volume 15, Issue 4, pp 319–327

Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas

EPS Proceedings

Abstract

Recent molecular studies have provided new insights into thyroid carcinogenesis. In thyroid papillary carcinomas at least three initiating events may occur, which are point mutations in the BRAF and RAS genes and RET/PTC rearrangements. Tumors harboring mutant BRAF and RAS are prone to progression to poorly differentiated and anaplastic carcinoma, but most likely require additional mutations to trigger this process. In thyroid follicular carcinomas, two known initiating events are RAS mutations and PAX8-PPARγ rearrangements, and RAS predisposes to dedifferentiation of follicular carcinomas. p53 and β-catenin mutations, found with increasing incidence in poorly differentiated and anaplastic carcinomas but not in well-differentiated tumors, may serve as a direct molecular trigger of tumor dedifferentiation. Additional evidence for progression from a preexisting well-differentiated carcinoma to poorly differentiated and anaplastic carcinoma comes from the studies of loss of heterozygosity and comparative genomic hybridization. Molecular studies, although limited by the lack of uniform histologic criteria for poorly differentiated carcinomas, revealed no genetic mutations or chromosomal abnormalities that are unique for poorly differentiated carcinoma and not present in well-differentiated or anaplastic carcinomas. This suggests that poorly differentiated carcinoma, as a group, represents a distinct step in the evolution from well-differentiated to anaplastic thyroid carcinoma, rather than an entirely separate type of thyroid malignancy.

Key Words

Poorly differentiated thyroid carcinoma anaplastic carcinoma papillary carcinoma follicular carcinoma dedifferentiation BRAF RAS RET/PTC PAX8-PPARγ p53 

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References

  1. 1.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 417:949–954, 2002.PubMedCrossRefGoogle Scholar
  2. 2.
    Kimura ET, Nikiforova MN, Zhu Z, et al. 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 63:1454–1457, 2003.PubMedGoogle Scholar
  3. 3.
    Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 95:625–627, 2003.PubMedCrossRefGoogle Scholar
  4. 4.
    Xu X, Quiros RM, Gattuso P, et al. High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines. Cancer Res 63:4561–4567, 2003.PubMedGoogle Scholar
  5. 5.
    Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578–4580, 2003.PubMedCrossRefGoogle Scholar
  6. 6.
    Fukushima T, Suzuki S, Mashiko M, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene 22:6455–6457, 2003.PubMedCrossRefGoogle Scholar
  7. 7.
    Namba H, Nakashima M, Hayashi T, et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 88:4393–4397, 2003.PubMedCrossRefGoogle Scholar
  8. 8.
    Nikiforova MN, Kimura ET, Gandhi M, 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 88:5399–5404, 2003.PubMedCrossRefGoogle Scholar
  9. 9.
    Lemoine NR, Mayall ES, Wyllie FS, et al. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 4:159–164, 1989.PubMedGoogle Scholar
  10. 10.
    Namba H, Gutman RA, Matsuo K, et al. H-ras protooncogene mutations in human thyroid neoplasms. J Clin Endocrinol Metab 71:223–229, 1990.PubMedGoogle Scholar
  11. 11.
    Suarez HG, du Villard JA, Severino M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene 5:565–570, 1990.PubMedGoogle Scholar
  12. 12.
    Karga H, Lee JK, Vickery AL, Jr, et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 73:832–836, 1991.PubMedCrossRefGoogle Scholar
  13. 13.
    Manenti G, Pilotti S, Re FC, et al. Selective activation of ras oncogenes in follicular and undifferentiated thyroid carcinomas. Eur J Cancer 30A:987–993, 1994.PubMedCrossRefGoogle Scholar
  14. 14.
    Hara H, Fulton N, Yashiro T, et al. N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma. Surgery 116:1010–1016, 1994.PubMedGoogle Scholar
  15. 15.
    Ezzat S, Zheng L, Kolenda J, et al. Prevalence of activating ras mutations in morphologically characterized thyroid nodules. Thyroid 6:409–416, 1996.PubMedGoogle Scholar
  16. 16.
    Esapa CT, Johnson SJ, Kendall-Taylor P, et al. Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf) 50:529–535, 1999.CrossRefGoogle Scholar
  17. 17.
    Basolo F, Pisaturo F, Pollina LE, et al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid 10:19–23, 2000.PubMedGoogle Scholar
  18. 18.
    Motoi N, Sakamoto A, Yamochi T, et al. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract 196:1–7, 2000.PubMedGoogle Scholar
  19. 19.
    Garcia-Rostan G, Zhao H, Camp RL, et al. ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. J Clin Oncol 21:3226–3235, 2003.PubMedCrossRefGoogle Scholar
  20. 20.
    Bond JA, Wyllie FS, Rowson J, et al. In vitro reconstruction of tumour initiation in a human epithelium. Oncogene 9:281–290, 1994.PubMedGoogle Scholar
  21. 21.
    Monaco C, Califano D, Chiappetta G, et al. Mutated human Kirsten ras, driven by a thyroglobulin promoter, induces a growth advantage and partially dedifferentiates rat thyroid epithelial cells in vitro. Int J Cancer 63:757–760, 1995.PubMedCrossRefGoogle Scholar
  22. 22.
    Portella G, Vitagliano D, Borselli C, et al. Human N-ras, TRK-T1, and RET/PTC3 oncogenes, driven by a thyroglobulin promoter, differently affect the expression of differentiation markers and the proliferation of thyroid epithelial cells. Oncol Res 11:421–427, 1999.PubMedGoogle Scholar
  23. 23.
    Santelli G, de Franciscis V, Portella G, et al. Production of transgenic mice expressing the Ki-ras oncogene under the control of a thyroglobulin promoter. Cancer Res 53:5523–5527, 1993.PubMedGoogle Scholar
  24. 24.
    Rochefort P, Caillou B, Michiels FM, et al. Thyroid pathologies in transgenic mice expressing a human activated Ras gene driven by a thyroglobulin promoter. Oncogene 12:111–118, 1996.PubMedGoogle Scholar
  25. 25.
    Saavedra HI, Knauf JA, Shirokawa JM, et al. The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway. Oncogene 19:3948–3954, 2000.PubMedCrossRefGoogle Scholar
  26. 26.
    Asakawa H, Kobayashi T. Multistep carcinogenesis in anaplastic thyroid carcinoma: a case report. Pathology 34:94–97, 2002.PubMedCrossRefGoogle Scholar
  27. 27.
    Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol 13:3–16, 2002.PubMedCrossRefGoogle Scholar
  28. 28.
    Tallini G, Asa SL. RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol 8:345–354, 2001.PubMedCrossRefGoogle Scholar
  29. 29.
    Santoro M, Carlomagno F, Hay ID, et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 89:1517–1522, 1992.PubMedGoogle Scholar
  30. 30.
    Wynford-Thomas D. In vitro models of thyroid cancer. Cancer Surv 16:115–134, 1993.PubMedGoogle Scholar
  31. 31.
    Tallini G, Santoro M, Helie M, 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 4:287–294, 1998.PubMedGoogle Scholar
  32. 32.
    Nikiforov YE (unpublished).Google Scholar
  33. 33.
    Santoro M, Papotti M, Chiappetta G, et al. RET activation and clinicopathologic features in poorly differentiated thyroid tumors. J Clin Endocrinol Metab 87:370–379, 2002.PubMedCrossRefGoogle Scholar
  34. 34.
    Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgammal fusion oncogene in human thyroid carcinoma [corrected]. Science 289:1357–1360, 2000.PubMedCrossRefGoogle Scholar
  35. 35.
    Ying H, Suzuki H, Zhao L, et al. Mutant thyroid hormone receptor beta represses the expression and transcriptional activity of peroxisome proliferator-activated receptor gamma during thyroid carcinogenesis. Cancer Res 63:5274–5280, 2003.PubMedGoogle Scholar
  36. 36.
    Marques AR, Espadinha C, Catarino AL, et al. Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 87:3947–3952, 2002.PubMedCrossRefGoogle Scholar
  37. 37.
    Nikiforova MN, Biddinger PW, Caudill CM, et al. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 26:1016–1023, 2002.PubMedCrossRefGoogle Scholar
  38. 38.
    Cheung L, Messina M, Gill A, et al. Detection of the PAX8-PPAR gamma fusion oncogene in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 88:354–357, 2003.PubMedCrossRefGoogle Scholar
  39. 39.
    French CA, Alexander EK, Cibas ES, et al. Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol 162:1053–1060, 2003.PubMedGoogle Scholar
  40. 40.
    Dwight T, Thoppe SR, Foukakis T, et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearaangement in follicular thyroid tumors. J Clin Endocrinol Metab 88:4440–4445, 2003.PubMedCrossRefGoogle Scholar
  41. 41.
    Nakamura T, Yana I, Kobayashi T, et al. p53 gene mutations associated with anaplastic transformation of human thyroid carcinomas. Jpn J Cancer Res 83:1293–1298, 1992.PubMedGoogle Scholar
  42. 42.
    Fagin JA, Matsuo K, Karmakar A, et al. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 91:179–184, 1993.PubMedCrossRefGoogle Scholar
  43. 43.
    Donghi R, Longoni A, Pilotti S, et al. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J Clin Invest 91:1753–1760, 1993.PubMedGoogle Scholar
  44. 44.
    Ito T, Seyama T, Mizuno T, et al. Genetic alterations in thyroid tumor progression: association with p53 gene mutations. Jpn J Cancer Res 84:526–531, 1993.PubMedGoogle Scholar
  45. 45.
    Zou M, Shi Y, Farid NR. p53 mutations in all stages of thyroid carcinomas. J Clin Endocrinol Metab 77:1054–1058, 1993.PubMedCrossRefGoogle Scholar
  46. 46.
    Dobashi Y, Sugimura H, Sakamoto A, et al. Stepwise participation of p53 gene mutation during dedifferentiation of human thyroid carcinomas. Diagn Mol Pathol 3:9–14, 1994.PubMedCrossRefGoogle Scholar
  47. 47.
    Ho YS, Tseng SC, Chin TY, et al. p53 gene mutation in thyroid carcinoma. Cancer Lett 103:57–63, 1996.PubMedCrossRefGoogle Scholar
  48. 48.
    Takeuchi Y, Daa T, Kashima K, et al. Mutations of p53 in thyroid carcinoma with an insular component. Thyroid 9:377–381, 1999.PubMedGoogle Scholar
  49. 49.
    Carcangiu ML, Zampi G, Rosai J. Poorly differentiated (“insular”) thyroid carcinoma. A reinterpretation of Langhans’ “wuchernde Struma.” Am J Surg Pathol 8:655–668, 1984.PubMedCrossRefGoogle Scholar
  50. 50.
    Matias-Guiu X, Villanueva A, Cuatrecasas M, et al. p53 in a thyroid follicular carcinoma with foci of poorly differentiated and anaplastic carcinoma. Pathol Res Pract 192:1242–1249; discussion 1250–1241, 1996.Google Scholar
  51. 51.
    La Perle KM, Jhiang SM, Capen CC. Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas. Am J Pathol 157:671–677, 2000.PubMedGoogle Scholar
  52. 52.
    Powell Jr DJ, Russell JP, Li G, et al. Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53-/- mice. Oncogene 20:3235–3246, 2001.CrossRefPubMedGoogle Scholar
  53. 53.
    Moretti F, Farsetti A, Soddu S, et al. p53 re-expression inhibits proliferation and restores differentiation of human thyroid anaplastic carcinoma cells. Oncogene 14:729–740, 1997.PubMedCrossRefGoogle Scholar
  54. 54.
    Fagin JA, Tang SH, Zeki K, et al. Reexpression of thyroid peroxidase in a derivative of an undifferentiated thyroid carcinoma cell line by introduction of wild-type p53. Cancer Res 56:765–771, 1996.PubMedGoogle Scholar
  55. 55.
    Van Aken E, De Wever O, Correia da Rocha AS, et al. Defective E-cadherin/catenin complexes in human cancer. Virchows Arch 439:725–751, 2001.PubMedGoogle Scholar
  56. 56.
    Garcia-Rostan G, Camp RL, Herrero A, et al. 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 158:987–996, 2001.PubMedGoogle Scholar
  57. 57.
    Miyake N, Maeta H, Horie S, et al. Absence of mutations in the beta-catenin and adenomatous polyposis coli genes in papillary and follicular thyroid carcinomas. Pathol Int 51:680–685, 2001.PubMedCrossRefGoogle Scholar
  58. 58.
    Rocha AS, Soares P, Fonseca E, et al. E-cadherin loss rather than beta-catenin alterations is a common feature of poorly differentiated thyroid carcinomas. Histopathology 42:580–587, 2003.PubMedCrossRefGoogle Scholar
  59. 59.
    Ward LS, Brenta G, Medvedovic M, et al. Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas. J Clin Endocrinol Metab 83:525–530, 1998.PubMedCrossRefGoogle Scholar
  60. 60.
    Kleer CG, Bryant BR, Giordano TJ, et al. Genetic changes in chromosomes 1p and 17p in thyroid cancer progression. Endocr Pathol 11:137–143, 2000.PubMedCrossRefGoogle Scholar
  61. 61.
    Kitamura Y, Shimizu K, Tanaka S, et al. Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Genes Chromosomes Cancer 27:244–251, 2000.PubMedCrossRefGoogle Scholar
  62. 62.
    Hunt JL, Tometsko M, LiVolsi VA, et al. Molecular evidence of anaplastic transformation in coexisting well-differentiated and anaplastic carcinomas of the thyroid. Am J Surg Pathol 27:1559–1564, 2003.PubMedCrossRefGoogle Scholar
  63. 63.
    Hemmer S, Wasenius VM, Knuutila S, et al. DNA copy number changes in thyroid carcinoma. Am J Pathol 154:1539–1547, 1999.PubMedGoogle Scholar
  64. 64.
    Wreesmann VB, Ghossein RA, Patel SG, et al. Genome-wide appraisal of thyroid cancer progression. Am J Pathol 161:1549–1556, 2002.PubMedGoogle Scholar
  65. 65.
    Santoro M, Melillo RM, Carlomagno F, et al. Molecular mechanisms of RET activation in human cancer. Ann NY Acad Sci 963:116–121, 2002.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of CincinnatiCincinnati

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