Skip to main content
SpringerLink
Log in

Classical point mutations of RET, BRAF and RAS oncogenes are not shared in papillary and medullary thyroid cancer occurring simultaneously in the same gland

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background

Papillary (PTC) and medullary (MTC) thyroid carcinomas represent two distinct entities, but quite frequently, they may occur simultaneously.

Aim

To provide genetic analysis of PTC and MTC occurring in the same patient (PTC/MTC) to elucidate their origin.

Methods

Sequencing analysis of RAS, BRAF and RET oncogenes hot spots mutations in tumoral and normal tissues of 24 PTC/MTC patients.

Results

Two of 24 patients (8.3 %) were affected by familial MTC (FMTC) harboring RET germline mutations in all tissues. Eight of 22 (36.4 %) sporadic cases did not show any somatic mutation in the three tissue components. Considering the MTC component, 10/22 (45.4 %) patients did not show any somatic mutation, 7 of 22 (31.8 %) harbored the M918T RET somatic mutation and 4/22 (18.2 %) presented mutations in the H-RAS gene. In an additional case (1/22, 4.6 %), H-RAS and RET mutations were simultaneously present. Considering the PTC component, 1 of 24 (4.2 %) patients harbored the V600E BRAF mutation, 1 of 24 (4.2 %) the T58A H-RAS mutation and 1 of 24 (4.2 %) the M1T K-RAS mutation, while the remaining PTC cases did not show any somatic mutation. In one case, the MTC harbored a RET mutation and the PTC a BRAF mutation. None of the mutations found were present in both tumors.

Conclusions

To our knowledge, this is the first study analyzing a possible involvement of RET, BRAF and RAS oncogene mutations in PTC/MTC. These data clearly suggest that the classical activating mutations of the oncogenes commonly involved in the pathogenesis of PTC and MTC may not be responsible for their simultaneous occurrence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Rosai J (2005) Handling of thyroid follicular patterned lesions. Endocr Pathol 16:279–283

    Article  PubMed  Google Scholar 

  2. Ball DW (2007) Medullary thyroid cancer: therapeutic targets and molecular markers. Curr Opin Oncol 19:18–23

    Article  CAS  PubMed  Google Scholar 

  3. Adnan Z, Arad E, Dana J, Shendler Y, Baron E (2013) Simultaneous occurrence of medullary and papillary thyroid microcarcinomas: a case series and review of the literature. J Med Case Rep 7:26

    Article  PubMed  PubMed Central  Google Scholar 

  4. Erhamamci S, Reyhan M, Kocer NE, Nursal GN, Torun N, Yapar AF (2014) Simultaneous occurrence of medullary and differentiated thyroid carcinomas. Report of 4 cases and brief review of the literature. Hell J Nucl Med 17:148–152

    PubMed  Google Scholar 

  5. Mazziotti G, Rotondi M, Manganella G et al (2001) Medullary thyroid cancer, papillary thyroid microcarcinoma and Graves’ disease: an unusual clinical coexistence. J Endocrinol Invest 24:892–896

    Article  CAS  PubMed  Google Scholar 

  6. Rotondi M, Ercolino T, Fonte R et al (2009) Occurrence of medullary thyroid carcinoma, bronchial carcinoid tumor, and papillary thyroid carcinoma in a family bearing the RET G691S polymorphism. J Endocrinol Investig 32:115–118

    Article  CAS  Google Scholar 

  7. Hedinger C, Williams ED, Sobin LH (1989) The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 63:908–911

    Article  CAS  PubMed  Google Scholar 

  8. Biscolla RP, Ugolini C, Sculli M et al (2004) Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior. Thyroid 14:946–952

    Article  PubMed  Google Scholar 

  9. Decker RA (1993) Expression of papillary thyroid carcinoma in multiple endocrine neoplasia type 2A. Surgery 114:1059–1063

    CAS  PubMed  Google Scholar 

  10. Papi G, Corrado S, Pomponi MG, Carapezzi C, Cesinaro A, LiVolsi VA (2003) Concurrent lymph node metastases of medullary and papillary thyroid carcinoma in a case with RET oncogene germline mutation. Endocr Pathol 14:269–276

    Article  CAS  PubMed  Google Scholar 

  11. Brauckhoff M, Gimm O, Hinze R, Ukkat J, Brauckhoff K, Dralle H (2002) Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation. Thyroid 12:557–561

    Article  CAS  PubMed  Google Scholar 

  12. Kosem M, Kotan C, Algun E, Topal C (2002) Simultaneous occurrence of papillary intrafollicular and microcarcinomas with bilateral medullary microcarcinoma of the thyroid in a patient with multiple endocrine neoplasia type 2A: report of a case. Surg Today 32:623–628

    Article  PubMed  Google Scholar 

  13. Fugazzola L, Cerutti N, Mannavola D et al (2002) Multigenerational familial medullary thyroid cancer (FMTC): evidence for FMTC phenocopies and association with papillary thyroid cancer. Clin Endocrinol 56:53–63

    Article  CAS  Google Scholar 

  14. Shifrin AL, Ogilvie JB, Stang MT et al (2010) Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation. Surgery 148:1274–1280 (discussion 80-1)

    Article  PubMed  Google Scholar 

  15. Shifrin AL, Xenachis C, Fay A, Matulewicz TJ, Kuo YH, Vernick JJ (2009) One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome—MEN 2C? Surgery 146:998–1005

    Article  PubMed  Google Scholar 

  16. Febrero B, Rodriguez JM, Rios A, Portillo P, Parrilla P (2015) Papillary thyroid carcinoma and multiple endocrine neoplasia type 2. J Endocrinol Investig 38:1233–1237

    Article  CAS  Google Scholar 

  17. Cancer Genome Atlas Research N (2014) Integrated genomic characterization of papillary thyroid carcinoma. Cell 159:676–690

    Article  Google Scholar 

  18. Elisei R, Molinaro E, Agate L et al (2014) Ret oncogene and thyroid carcinoma. J Genet Syndr Gene Ther 5:10

    Google Scholar 

  19. Ciampi R, Mian C, Fugazzola L et al (2013) Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid 23:50–57

    Article  CAS  PubMed  Google Scholar 

  20. Moura MM, Cavaco BM, Pinto AE, Leite V (2011) High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 96:E863–E868

    Article  CAS  PubMed  Google Scholar 

  21. Nikiforov YE, Nikiforova MN (2011) Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol 7:569–580

    Article  CAS  PubMed  Google Scholar 

  22. Elisei R (2008) Routine serum calcitonin measurement in the evaluation of thyroid nodules. Best Pract Res Clin Endocrinol Metab 22:941–953

    Article  CAS  PubMed  Google Scholar 

  23. Cooper DS, Doherty GM, Haugen BR et al (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19:1167–1214

    Article  PubMed  Google Scholar 

  24. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W (2006) European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154:787–803

    Article  CAS  PubMed  Google Scholar 

  25. Elisei R, Cosci B, Romei C et al (2004) Identification of a novel point mutation in the RET gene (Ala883Thr), which is associated with medullary thyroid carcinoma phenotype only in homozygous condition. J Clin Endocrinol Metab 89:5823–5827

    Article  CAS  PubMed  Google Scholar 

  26. Romei C, Ciampi R, Faviana P et al (2008) BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocr Relat Cancer 15:511–520

    Article  CAS  PubMed  Google Scholar 

  27. Cosci B, Vivaldi A, Romei C et al (2011) In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer 18:603–612

    Article  CAS  PubMed  Google Scholar 

  28. Hrafnkelsson J, Jonasson JG, Sigurdsson G, Sigvaldason H, Tulinius H (1988) Thyroid cancer in Iceland 1955–1984. Acta Endocrinol 118:566–572

    CAS  PubMed  Google Scholar 

  29. Mathe E, Olivier M, Kato S, Ishioka C, Hainaut P, Tavtigian SV (2006) Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods. Nucleic Acids Res 34:1317–1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Michiels FM, Chappuis S, Caillou B et al (1997) Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation. Proc Natl Acad Sci USA 94:3330–3335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Acton DS, Velthuyzen D, Lips CJ, Hoppener JW (2000) Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice. Oncogene 19:3121–3125

    Article  CAS  PubMed  Google Scholar 

  32. Pacini F, Elisei R, Romei C, Pinchera A (2000) RET proto-oncogene mutations in thyroid carcinomas: clinical relevance. J Endocrinol Investig 23:328–338

    Article  CAS  Google Scholar 

  33. Rossi S, Fugazzola L, De Pasquale L et al (2005) Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumour: report of three cases with molecular analysis and review of the literature. Endocr Relat Cancer 12:281–289

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Johnston D, Hatzis D, Sunday ME (1998) Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma. Oncogene 16:167–177

    Article  CAS  PubMed  Google Scholar 

  36. Medici M, Kwong N, Angell TE et al (2015) The variable phenotype and low-risk nature of RAS-positive thyroid nodules. BMC Med 13:184

    Article  PubMed  PubMed Central  Google Scholar 

  37. Goutas N, Vlachodimitropoulos D, Bouka M, Lazaris AC, Nasioulas G, Gazouli M (2008) BRAF and K-RAS mutation in a Greek papillary and medullary thyroid carcinoma cohort. Anticancer Res 28:305–308

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by Grants from “Associazione Italiana per la Ricerca sul Cancro (AIRC)” (Grant Number: IG2014, ID 15431) and from “Istituto Toscano Tumori (ITT)” (Grant Number: 539999_2013_Elisei_322). The authors would like to acknowledge Martin Zenker from the Institute of Human Genetics, University Hospital Magdeburg, Magdeburg 39120, Germany, and Mohammad R. Ahmadian and Kazem Nouri from the Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, 40225, Düsseldorf, Germany, for providing the H-RAS plasmids used in the cell transformation assays.

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine (Endocrine Unit), Univesity-Hospital of Pisa, Pisa, Italy

    R. Ciampi, C. Romei, L. Pieruzzi, A. Tacito, E. Molinaro, L. Agate, V. Bottici, F. Casella & R. Elisei

  2. Department of Surgical, Medical and Molecular Pathology and Critical Care, University-Hospital of Pisa, Pisa, Italy

    C. Ugolini, G. Materazzi & F. Basolo

Authors
  1. R. Ciampi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Romei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Pieruzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Tacito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Molinaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Agate
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Bottici
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Casella
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Ugolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G. Materazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F. Basolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. R. Elisei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Ciampi.

Ethics declarations

Conflict of interests

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

An informed consent was provided to the participants and the study was approved by the local ethics committee and by our institutional review board.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ciampi, R., Romei, C., Pieruzzi, L. et al. Classical point mutations of RET, BRAF and RAS oncogenes are not shared in papillary and medullary thyroid cancer occurring simultaneously in the same gland. J Endocrinol Invest 40, 55–62 (2017). https://doi.org/10.1007/s40618-016-0526-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-016-0526-5

Keywords

Search

Navigation