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Impact of pathognomonic genetic alterations on the prognosis of papillary thyroid carcinoma

ESES vienna presentation

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Abstract

Introduction

BRAF mutations and RET or NTRK1 rearrangements were identified as causing events that drive the malignant transformation of the thyroid follicular cell. The impact of these alterations on the course of papillary thyroid carcinoma (PTC) is still unsettled.

Patients and methods

Tumor tissues of 290 (98 male, 192 female) patients were intra-operatively snap frozen or harvested from archival paraffin-embedded blocks and used for extraction of DNA and RNA. Comprehensive analysis of RET/PTC and NTRK1 rearrangements was carried out by multiplex screening RT-PCR, hybrid-specific RT-PCR and sequencing of detected hybrids. A mutation-specific PCR was used for BRAF analysis.

Results

The BRAF V600E mutation was detected in 122/290 (42%), RET rearrangements in 20/137 (14.6%), and NTRK1 rearrangements in 15/93 (16.1%) PTCs. One hundred forty one out of 290 (48.6%) PTCs demonstrated none of the genetic alterations studied. Eight PTCs expressed two different mutations (1 RET/PTC + BRAF, 6 NTRK1 + BRAF, 1 RET/PTC + NTRK1). Tumor-specific survival analysis (mean follow-up, 5.5 years) demonstrated no significant difference, but a tendency toward worse prognosis of BRAF-positive patients compared to BRAF-negative patients or rearrangement-positive patients, respectively.

Conclusion

Long-term follow-up data on large tumor panels are needed to disclose significant survival differences of prognostic predictors on PTC. This study provides further evidence that patients harboring BRAF-V600E-positive PTCs may experience an unfavorable course of the disease compared to patients with tumors carrying other genetic alterations.

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References

  1. Basolo F, Giannini R, Monaco C et al (2002) Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma. Am J Pathol 160:247–254

    CAS  PubMed  Google Scholar 

  2. Durante C, Puxeddu E, Ferretti E et al (2007) BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J Clin Endocrinol Metab 92:2840–2843

    Article  CAS  PubMed  Google Scholar 

  3. Elisei R, Ugolini C, Viola D et al (2008) BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab 93:3943–3949

    Article  CAS  PubMed  Google Scholar 

  4. Espadinha C, Santos JR, Sobrinho LG et al (2009) Expression of iodine metabolism genes in human thyroid tissues: evidence for age and BRAFV600E mutation dependency. Clin Endocrinol 70:629–635

    Article  CAS  Google Scholar 

  5. Fugazzola L, Puxeddu E, Avenia N et al (2006) Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature. Endocr-Relat Cancer 13:455–464

    Article  CAS  PubMed  Google Scholar 

  6. Guan H, Ji M, Bao R et al (2009) Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J Clin Endocrinol Metab 94:1612–1617

    Article  CAS  PubMed  Google Scholar 

  7. Henderson YC, Shellenberger TD, Williams MD et al (2009) High rate of BRAF and RET/PTC dual mutations associated with recurrent papillary thyroid carcinoma. Clin Cancer Res 15:485–491

    Article  CAS  PubMed  Google Scholar 

  8. Ito Y, Yoshida H, Maruo R et al (2009) BRAF mutation in papillary thyroid carcinoma in a Japanese population: its lack of correlation with high-risk clinicopathological features and disease-free survival of patients. Endocr J 56:89–97

    Article  CAS  PubMed  Google Scholar 

  9. Kebebew E, Weng J, Bauer J et al (2007) The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 246:466–470, discussion 470-461

    Article  PubMed  Google Scholar 

  10. Kim SK, Song KH, Lim SD et al (2009) Clinical and pathological features and the BRAF(V600E) mutation in patients with papillary thyroid carcinoma with and without concurrent Hashimoto thyroiditis. Thyroid 19:137–141

    Article  PubMed  Google Scholar 

  11. Lee JH, Lee ES, Kim YS (2007) Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysis. Cancer 110:38–46

    Article  PubMed  Google Scholar 

  12. Lee X, Gao M, Ji Y et al (2009) Analysis of differential BRAF(V600E) mutational status in high aggressive papillary thyroid microcarcinoma. Ann Surg Oncol 16:240–245

    Article  PubMed  Google Scholar 

  13. Lima J, Trovisco V, Soares P et al (2004) BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. J Clin Endocrinol Metab 89:4267–4271

    Article  CAS  PubMed  Google Scholar 

  14. Lupi C, Giannini R, Ugolini C et al (2007) Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 92:4085–4090

    Article  CAS  PubMed  Google Scholar 

  15. Moses W, Weng J, Khanafshar E et al (2010) Multiple genetic alterations in papillary thyroid cancer are associated with younger age at presentation. J Surg Res 160:179–183

    Article  CAS  PubMed  Google Scholar 

  16. Musholt PB, Imkamp F, Von Wasielewski R et al (2003) RET rearrangements in archival oxyphilic thyroid tumors: new insights in tumorigenesis and classification of Hurthle cell carcinomas? Surgery 134:881–889, discussion 889

    Article  PubMed  Google Scholar 

  17. Musholt TJ, Musholt PB, Khaladj N et al (2000) Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery 128:984–993

    Article  CAS  PubMed  Google Scholar 

  18. Oler G, Cerutti JM (2009) High prevalence of BRAF mutation in a Brazilian cohort of patients with sporadic papillary thyroid carcinomas: correlation with more aggressive phenotype and decreased expression of iodide-metabolizing genes. Cancer 115:972–980

    Article  CAS  PubMed  Google Scholar 

  19. Park SY, Park YJ, Lee YJ et al (2006) Analysis of differential BRAF(V600E) mutational status in multifocal papillary thyroid carcinoma: evidence of independent clonal origin in distinct tumor foci. Cancer 107:1831–1838

    Article  CAS  PubMed  Google Scholar 

  20. Pierotti MA, Vigneri P, Bongarzone I (1998) Rearrangements of RET and NTRK1 tyrosine kinase receptors in papillary thyroid carcinomas. Recent Results Cancer Res 154:237–247

    CAS  PubMed  Google Scholar 

  21. Riesco-Eizaguirre G, Rodriguez I, De La Vieja A et al (2009) The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. Cancer Res 69:8317–8325

    Article  CAS  PubMed  Google Scholar 

  22. Salvatore G, Chiappetta G, Nikiforov YE et al (2005) Molecular profile of hyalinizing trabecular tumours of the thyroid: high prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations. Eur J Cancer 41:816–821

    Article  CAS  PubMed  Google Scholar 

  23. Santoro M, Papotti M, Chiappetta G et al (2002) RET activation and clinicopathologic features in poorly differentiated thyroid tumors. J Clin Endocrinol Metab 87:370–379

    Article  CAS  PubMed  Google Scholar 

  24. Sapio MR, Posca D, Raggioli A et al (2007) Detection of RET/PTC, TRK and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings. Clin Endocrinol 66:678–683

    Article  CAS  Google Scholar 

  25. Sapio MR, Posca D, Troncone G et al (2006) Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA). Eur J Endocrinol 154:341–348

    Article  CAS  PubMed  Google Scholar 

  26. Tallini G, Santoro M, Helie M et al (1998) 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

    CAS  PubMed  Google Scholar 

  27. Tang KT, Lee CH (2010) BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J Chin Med Assoc 73:113–128

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Endocrine Surgery, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany

    Thomas J. Musholt, Christina H. Schwarz, Felix M. Watzka & Petra B. Musholt

  2. Endocrinology and Metabolic Diseases, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany

    Christian Fottner & Matthias M. Weber

  3. Pathology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany

    Sonja Schönefeld, Erik Springer & Arno Schad

  4. Endocrine Surgery, Clinic of General and Abdominal Surgery, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany

    Thomas J. Musholt

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  1. Thomas J. Musholt
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  2. Sonja Schönefeld
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  3. Christina H. Schwarz
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Correspondence to Thomas J. Musholt.

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Musholt, T.J., Schönefeld, S., Schwarz, C.H. et al. Impact of pathognomonic genetic alterations on the prognosis of papillary thyroid carcinoma. Langenbecks Arch Surg 395, 877–883 (2010). https://doi.org/10.1007/s00423-010-0682-6

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  • DOI: https://doi.org/10.1007/s00423-010-0682-6

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