Genomics and Epigenomics of Medullary Thyroid Carcinoma: From Sporadic Disease to Familial Manifestations

Abstract

Our understanding of the genomics and epigenomics of medullary thyroid carcinoma (MTC) has advanced since the initial recognition of RET as a driver of MTC tumorigenesis in familial MTC. We now have insight into the frequency and prognostic significance of specific RET mutations in sporadic MTC. For example, the most common RET mutation in sporadic MTC is the RET Met918Thr mutation, the same mutation that underlies MEN2B and a poor prognosticator. This mutation is relatively infrequent in medullary thyroid microcarcinomas but is over-represented in advanced-stage disease. RAS mutations are detected in 70% of sporadic, RET wild-type MTC. Although next-generation and whole-exome sequencing studies have shown that tumors that are wild-type for RET and RAS mutations essentially lack other recurrent mutations, additional pathways and epigenetic alterations have been implicated in MTC tumorigenesis. Increased insight into the clinical course of patients with familial MTC with specific RET mutations has guided treatment recommendations for these patients. Finally, an understanding of the genomics has informed treatment for patients with advanced MTC. In this review, we will examine the genomics and epigenomics of sporadic and familial MTC, along with the prognostic significance of molecular alterations, management of patients with germline RET mutations, and treatment strategies for MTC patients.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. JAMA 317: 1338-1348, 2017.

    Article  Google Scholar 

  2. 2.

    Pereira M, Williams VL, Hallanger Johnson J, Valderrabano P Thyroid Cancer Incidence Trends in the United States: Association with Changes in Professional Guideline Recommendations. Thyroid 30: 1132-1140, 2020.

    PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Hazard JB, Hawk WA, Crile G, Jr. Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. J Clin Endocrinol Metab 19: 152-161, 1959.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Williams ED Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol 19: 114–118, 1966.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Takahashi M, Ritz J, Cooper GM Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42: 581-588, 1985.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Carlson KM, Dou S, Chi D et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A 91: 1579-1583, 1994.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Donis-Keller H, Dou S, Chi D et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2: 851-856, 1993.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Eng C, Smith DP, Mulligan LM et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3: 237-241, 1994.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Hofstra RM, Landsvater RM, Ceccherini I et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367: 375-376, 1994.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Marsh DJ, Learoyd DL, Andrew SD et al. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 44: 249-257, 1996.

    CAS  Article  Google Scholar 

  11. 11.

    Mulligan LM, Kwok JB, Healey CS et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363: 458-460, 1993.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88: 1139-1148, 2000.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Modigliani E, Cohen R, Campos JM et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'etude des tumeurs a calcitonine. Clin Endocrinol (Oxf) 48: 265–273, 1998.

  14. 14.

    Kuo EJ, Sho S, Li N, Zanocco KA, Yeh MW, Livhits MJ Risk Factors Associated With Reoperation and Disease-Specific Mortality in Patients With Medullary Thyroid Carcinoma. JAMA Surg 153: 52-59, 2018.

    PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Roman S, Lin R, Sosa JA Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 107: 2134-2142, 2006.

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Ishizaka Y, Itoh F, Tahira T et al. Human ret proto-oncogene mapped to chromosome 10q11.2. Oncogene 4: 1519–1521, 1989.

  17. 17.

    Avantaggiato V, Dathan NA, Grieco M et al. Developmental expression of the RET protooncogene. Cell Growth Differ 5: 305-311, 1994.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Pasini B, Hofstra RM, Yin L et al. The physical map of the human RET proto-oncogene. Oncogene 11: 1737-1743, 1995.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3: 571-578, 1988.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Romei C, Ciampi R, Elisei R A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 12: 192-202, 2016.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Anders J, Kjar S, Ibanez CF Molecular modeling of the extracellular domain of the RET receptor tyrosine kinase reveals multiple cadherin-like domains and a calcium-binding site. J Biol Chem 276: 35808-35817, 2001.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Ibanez CF Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspect Biol 5, 2013.

  23. 23.

    Asai N, Iwashita T, Matsuyama M, Takahashi M Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 15: 1613-1619, 1995.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Gujral TS, Singh VK, Jia Z, Mulligan LM Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res 66: 10741-10749, 2006.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Salvatore D, Melillo RM, Monaco C et al. Increased in vivo phosphorylation of ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B. Cancer Res 61: 1426-1431, 2001.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Boichard A, Croux L, Al Ghuzlan A et al. Somatic RAS mutations occur in a large proportion of sporadic RET-negative medullary thyroid carcinomas and extend to a previously unidentified exon. J Clin Endocrinol Metab 97: E2031-2035, 2012.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Ciampi R, Romei C, Ramone T et al. Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing. iScience 20: 324–336, 2019.

  28. 28.

    Elisei R, Cosci B, Romei C et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab 93: 682-687, 2008.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Mian C, Pennelli G, Barollo S et al. Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification. Eur J Endocrinol 164: 971-976, 2011.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Moura MM, Cavaco BM, Pinto AE et al. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer 100: 1777-1783, 2009.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Romei C, Ugolini C, Cosci B et al. Low prevalence of the somatic M918T RET mutation in micro-medullary thyroid cancer. Thyroid 22: 476-481, 2012.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Moura MM, Cavaco BM, Pinto AE, Leite V High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 96: E863-868, 2011.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Romei C, Casella F, Tacito A et al. New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations. J Med Genet 53: 729-734, 2016.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Romei C, Ciampi R, Casella F et al. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. Oncotarget 9: 9875-9884, 2018.

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Eng C, Mulligan LM, Healey CS et al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56: 2167-2170, 1996.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Ciampi R, Romei C, Cosci B et al. Chromosome 10 and RET gene copy number alterations in hereditary and sporadic Medullary Thyroid Carcinoma. Mol Cell Endocrinol 348: 176-182, 2012.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  37. 37.

    Agrawal N, Jiao Y, Sausen M et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab 98: E364-369, 2013.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Simbolo M, Mian C, Barollo S et al. High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas. Virchows Arch 465: 73-78, 2014.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Schilling T, Burck J, Sinn HP et al. Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer 95: 62-66, 2001.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Vuong HG, Odate T, Ngo HTT et al. Clinical significance of RET and RAS mutations in sporadic medullary thyroid carcinoma: a meta-analysis. Endocr Relat Cancer 25: 633-641, 2018.

    PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Chang YS, Chang CC, Huang HY, Lin CY, Yeh KT, Chang JG Detection of Molecular Alterations in Taiwanese Patients with Medullary Thyroid Cancer Using Whole-Exome Sequencing. Endocr Pathol 29: 324-331, 2018.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Heilmann AM, Subbiah V, Wang K et al. Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma. Oncology 90: 339-346, 2016.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Grubbs EG, Williams MD, Scheet P et al. Role of CDKN2C Copy Number in Sporadic Medullary Thyroid Carcinoma. Thyroid 26: 1553-1562, 2016.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Lyra J, Vinagre J, Batista R et al. mTOR activation in medullary thyroid carcinoma with RAS mutation. Eur J Endocrinol 171: 633-640, 2014.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Tamburrino A, Molinolo AA, Salerno P et al. Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases. Clin Cancer Res 18: 3532-3540, 2012.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Papotti M, Olivero M, Volante M et al. Expression of Hepatocyte Growth Factor (HGF) and its Receptor (MET) in Medullary Carcinoma of the Thyroid. Endocr Pathol 11: 19-30, 2000.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Sponziello M, Durante C, Boichard A et al. Epigenetic-related gene expression profile in medullary thyroid cancer revealed the overexpression of the histone methyltransferases EZH2 and SMYD3 in aggressive tumours. Mol Cell Endocrinol 392: 8-13, 2014.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Wang N, Kjellin H, Sofiadis A et al. Genetic and epigenetic background and protein expression profiles in relation to telomerase activation in medullary thyroid carcinoma. Oncotarget 7: 21332-21346, 2016.

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Volinia S, Calin GA, Liu CG et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 103: 2257-2261, 2006.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Abraham D, Jackson N, Gundara JS et al. MicroRNA profiling of sporadic and hereditary medullary thyroid cancer identifies predictors of nodal metastasis, prognosis, and potential therapeutic targets. Clin Cancer Res 17: 4772-4781, 2011.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Ceolin L, Goularte APP, Ferreira CV, Romitti M, Maia AL Global DNA methylation profile in medullary thyroid cancer patients. Exp Mol Pathol 105: 110-114, 2018.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Santoro M, Carlomagno F, Romano A et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267: 381-383, 1995.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Larouche V, Akirov A, Thomas CM, Krzyzanowska MK, Ezzat S A primer on the genetics of medullary thyroid cancer. Curr Oncol 26: 389-394, 2019.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Wells SA, Jr., Asa SL, Dralle H et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25: 567-610, 2015.

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Guilmette J, Nose V Hereditary and familial thyroid tumours. Histopathology 72: 70-81, 2018.

    PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Li SY, Ding YQ, Si YL, Ye MJ, Xu CM, Qi XP 5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine. Front Endocrinol (Lausanne) 11: 543246, 2020.

  57. 57.

    Nose V Diagnostic Familial Cancer Syndromes: 170–187, 2020.

  58. 58.

    Wells SA, Jr. Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors. Endocr Relat Cancer 25: T1-T13, 2018.

    PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Sponziello M, Benvenuti S, Gentile A et al. Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer. Hum Mutat 39: 371-377, 2018.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205–216, 2000.

  61. 61.

    Wells SA, Jr., Robinson BG, Gagel RF et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30: 134-141, 2012.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Elisei R, Schlumberger MJ, Muller SP et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31: 3639-3646, 2013.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Sherman SI, Clary DO, Elisei R et al. Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. Cancer 122: 3856-3864, 2016.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Subbiah V, Velcheti V, Tuch BB et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol 29: 1869-1876, 2018.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Wirth LJ, Sherman E, Robinson B et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 383: 825-835, 2020.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Subbiah V, Gainor JF, Rahal R et al. Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov 8: 836-849, 2018.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Lim SM, Chang H, Yoon MJ et al. A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes. Ann Oncol 24: 3089-3094, 2013.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Schneider TC, de Wit D, Links TP et al. Beneficial Effects of the mTOR Inhibitor Everolimus in Patients with Advanced Medullary Thyroid Carcinoma: Subgroup Results of a Phase II Trial. Int J Endocrinol 2015: 348124, 2015.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Castellone MD, Melillo RM RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2). Endocr Relat Cancer 25: T105-T119, 2018.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Justine A. Barletta.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Barletta, J.A., Nosé, V. & Sadow, P.M. Genomics and Epigenomics of Medullary Thyroid Carcinoma: From Sporadic Disease to Familial Manifestations. Endocr Pathol (2021). https://doi.org/10.1007/s12022-021-09664-3

Download citation

Keywords

  • Medullary thyroid carcinoma
  • RET
  • Sporadic medullary thyroid carcinoma
  • Familial medullary thyroid carcinoma
  • Medullary thyroid cancer