Molekulare Pathogenese von Schilddrüsenknoten – Bedeutung für die klinische Versorgung

Zusammenfassung

Schilddrüsenknoten stellen heterogene Tumore dar, mit unterschiedlichen molekularen Signaturen. Während benigne Schilddrüsenknoten poly- oder monoklonalen Tumoren entsprechen, sind Schilddrüsenkarzinome monoklonale und damit „echte“ Neoplasien. Ursächlich für die Neoplasien sind somatische Mutationen, welche zur konstitutiven Aktivierung spezifischer Signalkaskaden führen und den jeweiligen histologischen, teilweise auch den funktionellen Phänotyp des Schilddrüsentumors bestimmen. Eine Dedifferenzierung von Schilddrüsenkarzinomen geht mit dem Auftreten weiterer Mutationen in den Tumoren einher. Die Mutationslast der Schilddrüsenkarzinome korreliert mit deren biologischem Verhalten.

Im klinischen Alltag kann die Kenntnis der ursächlichen somatischen Mutation in der zytologischen Differenzialdiagnose helfen. In der prognostischen Einschätzung von Schilddrüsentumoren hat der Nachweis von klassischen Onkogenmutationen (BRAF, RAS) wenig Relevanz. Andere genetische Veränderungen, insbesondere TERT Promoter Mutationen, die mit zunehmender Häufigkeit in fortgeschrittenen SD-Karzinomen auftreten, haben wahrscheinlich eine prognostische Bedeutung. Von großer Relevanz ist die molekulare Signatur jedoch für die Entwicklung und Anwendung passgenauer „zielgerichteter“ Therapien bei fortgeschrittenen Karzinomen (radioiodrefraktäres DTC, PDTC und ATC, metastasiertes medulläres Karzinom). Hierfür gibt es aus klinischen Studien sowie Einzelfallberichten zunehmend Hinweise, die das Konzept der „Oncogen-Addiction“ als pathogenetisch relevanten Mechanismus der SD-Tumorigenese und Karzinogenese unterstreichen.

Abstract

Thyroid nodules represent heterogeneous tumors with distinct molecular signatures. While benign thyroid nodules correspond to poly- or monoclonal tumors, thyroid carcinomas are monoclonal and thus “real” neoplasms. These are caused by somatic mutations that lead to the constitutive activation of specific signaling cascades and determine the corresponding histology and also partly the functional phenotype of the thyroid tumor. Dedifferentiation of thyroid carcinomas is accompanied by the occurrence of additional mutations in the tumors. The mutation load of thyroid carcinomas correlates with their biological behavior.

In clinical practice, detection of somatic mutations can help in the cytological differential diagnosis. In the prognostic assessment of thyroid tumors, proof of classical oncogene mutations (BRAF, RAS) has little relevance. Other genetic alterations, especially TERT promoter mutations that occur with increasing frequency in advanced thyroid carcinomas, probably have a prognostic significance. The molecular signature, however, is of great relevance for the development and application of targeted therapies in advanced carcinomas (radioactive iodine-refractory DTC, PDTC and ATC, metastatic medullary carcinoma). For this, there is increasing evidence from clinical studies and case reports that underline the concept of “oncogene addiction” as a pathogenetically relevant mechanism of thyroid tumorigenesis and carcinogenesis.

Schlüsselwörter

Schilddrüsenkarzinom - somatische Mutation - TERT Promoter Mutation - molekulare Signatur - Oncogen-Addiction

Key words

thyroid carcinoma - somatic mutation - TERT promoter mutation - molecular signature - oncogene addiction

Publication History

Article published online:
07 September 2017

• Literatur

• 1 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 2013; 98: E364-E369
• 2 Ameziane-El-Hassani 1 R, Talbot 2 M, de Souza Dos Santos 3 MC. et al NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. Proc Natl Acad Sci U S A 2015; 112: 5051-5056
• 3 Cancer Genome Atlas Research N . Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159: 676-690
• 4 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 2003; 88: 354-357
• 5 Driessens N, Versteyhe S, Ghaddhab C. et al. Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ. Endocr Relat Cancer 2009; 16: 845-856
• 6 Dummer R, Schadendorf D, Ascierto PA. et al. Integrating first-line treatment options into clinical practice: what’s new in advanced melanoma?. Melanoma Res 2015; 25: 461-469
• 7 Elisei R, Alevizaki M, Conte-Devolx B. et al. 2012 European Thyroid Association Guidelines for genetic testing and its clinical consequences in medullary thyroid cancer. Eur Thyroid J 2012; 1: 216-231
• 8 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 2008; 93: 682-687
• 9 Falchook GS, Millward M, Hong D. et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid 2015; 25: 71-77
• 10 Führer D, Bockisch A, Schmid KW. Euthyroid goiter with and without nodules – diagnosis and treatment. Dtsch Arztebl Int 2012; 109: 506-515
• 11 Führer D, Gimm O, Brabant G. et al Schilddrüsenkarzinom. Rationelle Diagnostik und Therapie in Endokrinologie, Diabetologie und Stoffwechsel. Lehnert HH. Thieme Verlag; 3. Auflage. . 2014
• 12 Führer D, Holzapfel HP, Wonerow P. et al 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: 3885-3891
• 13 Führer D, Schmid KW. Benign thyroid nodule or thyroid cancer?. Internist (Berl) 2010; 51: 611-619
• 14 Godbert Y, Henriques de Figueiredo B, Bonichon F. et al Remarkable Response to Crizotinib in Woman With Anaplastic Lymphoma Kinase-Rearranged Anaplastic Thyroid Carcinoma. J Clin Oncol 2015; 33: e84-e87
• 15 Karger S, Krause K, Engelhardt C. et al. Distinct pattern of oxidative DNA damage and DNA repair in follicular thyroid tumours. J Mol Endocrinol 2012; 48: 193-202
• 16 Karger S, Weidinger C, Krause K. et al. FOXO3a: a novel player in thyroid carcinogenesis?. Endocr Relat Cancer 2009; 16: 189-199
• 17 Kelly LM, Barila G, Liu P. et al. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc Natl Acad Sci U S A 2014; 111: 4233-4238
• 18 Kim KB, Cabanillas ME, Lazar AJ. et al. Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF(V600E) mutation. Thyroid 2013; 23: 1277-1283
• 19 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 2003; 63: 1454-1457
• 20 Kimura T, Van Keymeulen A, Golstein J. et al. Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. Endocr Rev 2001; 22: 631-656
• 21 Kleinau 1 G, Neumann S, Grüters A. et al. Novel insights on thyroid-stimulating hormone receptor signal transduction. Endocr Rev 2013; 34: 691-724
• 22 Krause K, Prawitt S, Eszlinger M. et al. Dissecting molecular events in thyroid neoplasia provides evidence for distinct evolution of follicular thyroid adenoma and carcinoma. Am J Pathol 2011; 179: 3066-3074
• 23 Krohn K, Führer D, Bayer Y. et al. Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev 2005; 26: 504-524
• 24 Krohn K, Führer D, Holzapfel HP. et al. Clonal origin of toxic thyroid nodules with constitutively activating thyrotropin receptor mutations. J Clin Endocrinol Metab 1998; 83: 130-134
• 25 Kunstman JW, Juhlin CC, Goh G. et al. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum Mol Genet 2015; 24: 2318-2312
• 26 Landa I, Ibrahimpasic T, Boucai L. et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest; 2016
• 27 Latteyer S, Tiedje V, König K. et al. Next generation sequencing mutation profiling reveals novel putative tumor candidates in anaplastic thyroid cancer. Endocrine 2016, in press.
• 28 Liu T, Wang N, Cao J. et al. The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene 2014; 33: 4978-4984
• 29 Maier J, van Steeg H, van Oostrom C. et al. Deoxyribonucleic acid damage and spontaneous mutagenesis in the thyroid gland of rats and mice. Endocrinology 2006; 147: 3391-3397 Epub 2006 Apr 20.
• 30 Melo M, da Rocha AG, Vinagre J. et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab 2014; 99: E754-E765
• 31 Müller K, Führer D, Mittag J. et al TSH compensates thyroid-specific IGF-I receptor knockout and causes papillary thyroid hyperplasia. Mol Endocrinol 2011; 25: 1867-1879
• 32 Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res 2011; 71: 4403-4411
• 33 Nikiforova MN, Lynch RA, Biddinger PW. 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: 2318-2326
• 34 Nikiforova MN, Stringer JR, Blough R. et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 2000; 290: 138-141
• 35 Ricarte-Filho JC, Ryder M, Chitale DA. et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res 2009; 69: 4885-4893
• 36 Rosove MH, Peddi PF, Glaspy JA. BRAF V600E inhibition in anaplastic thyroid cancer. N Engl J Med 2013; 368: 684-685
• 37 Shi X, Liu R, Qu S. et al. Association of TERT promoter mutation 1,295,228 C>T with BRAF V600E mutation, older patient age, and distant metastasis in anaplastic thyroid cancer. J Clin Endocrinol Metab 2015; 100: E632-E637
• 38 Smith N, Nucera C. Personalized therapy in patients with anaplastic thyroid cancer: targeting genetic and epigenetic alterations. J Clin Endocrinol Metab 2015; 100: 35-42
• 39 Soares P, Trovisco V, Rocha AS. et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 2003; 22: 4578-4580
• 40 Studer H, Derwahl M. Mechanisms of nonneoplastic endocrine hyperplasia–a changing concept: a review focused on the thyroid gland. Endocr Rev 1995; 16: 411-426
• 41 Tiedje V, Kroiss M, Dralle H. et al. Protokoll zur multimodalen Therapie des anaplastischen Schilddrüsenkarzinoms. Endokrinologie Informationen. 2015
• 42 Tiedje V, Ting S, Dralle H. et al. Medullary thyroid carcinoma. Internist (Berl) 2015; 56: 1019-1031
• 43 Tiedje V, Ting S, Walter RF. et al. Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients. ur J Endocrinol. 2016
• 44 Ting S, Schmid ST, Synoracki S. et al. Thyroid C cells and their pathology: Part 1: normal C cells, - C cell hyperplasia, - precursor of familial medullary thyroid carcinoma]. Pathologe 2015; 36: 571
• 45 Versteyhe S, Driessens N, Ghaddhab C. et al. Comparative analysis of the thyrocytes and T cells: responses to H2O2 and radiation reveals an H2O2-induced antioxidant transcriptional program in thyrocytes. J Clin Endocrinol Metab 2013; 98: E1645-E1654
• 46 Wagle N, Grabiner BC, Van Allen EM. et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med 2014; 371: 1426-1433
• 47 Wells Jr SA, Asa SL, Dralle H. et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567-610
• 48 Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet 2013; 381: 1058-1069
• 49 Xing M, Liu R, Liu X. et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol 2014; 32: 2718-2726
• 50 Zhang Y, Yu J, Lee C. et al. Genomic binding and regulation of gene expression by the thyroid carcinoma-associated PAX8-PPARG fusion protein. Oncotarget 2015; 6: 40418-40432