Genetic Background May Confer Susceptibility to PTC in Benign Multinodular Thyroid Disease

Sivatharsiny Thavarajah, Frank Weber

Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany..

DOI: 10.4236/jct.2012.36128                

Abstract

Purpose: The incidence of hyperplastic thyroid nodular disease has been consistently rising over the last decades. In addition, unsuspected papillary thyroid carcinoma (PTC) can be found in up to 34% of patients operated for benign thyroid lesions. PTC tends to occur multi-focally and is commonly of polyclonal origin. We set out to test the hypothesis that in benign thyroid disease, a unique genetic signature can already be identified in the benign pathology, which is associated with a susceptibility of the thyroid tissue to neoplastic transformation in the context of additional growth promoting stimuli. Patients and Methods: We obtained a set of 23 samples from patients with multinodular goiter (MNG), 12 of whom also harbored an unsuspected PTC. We used global gene expression analysis to evaluate for dissimilarities in the gene expression patterns between these two groups. We also compared these patterns to the profiles of 3 normal thyroid and 7 PTC samples. Results: We were able to accurately distinguish between hyperplastic nodules of patients with multinodular goiter and those that were associated with a PTC. One of the strongest differentially expressed genes, CDC42, has been implicated to respond to environmental factors such as UVB radiation and might point to novel factors contributing to PTC genesis in the setting of pre-existing benign proliferative disease. Conclusion: While the comparison between histologically identical samples cannot distinguish the two groups of goiters, unsupervised or supervised approaches allowed us to identify a molecular signature associated with PTC susceptibility in multinodular goiter.

Keywords

Multinodular Goiter; Cancer Suceptibility; Gene Expression; Papillary Thyroid Carcinoma

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	L. Hegedus, “Clinical Practice. The Thyroid Nodule,” New England Journal of Medicine, Vol. 351, No. 17, 2004, pp. 1764-1771.
[2]	M. Piersanti, S. Ezzat and S. L. Asa, “Controversies in Papillary Microcarcinoma of the Thyroid,” Endocrine Pathology, Vol. 14, No. 3, 2003, pp. 183-191. doi:10.1007/s12022-003-0011-5
[3]	P. P. Gandolfi, A. Frisina, M. Raffa, F. Renda, O. Rocchetti, C. Ruggeri and A. Tombolini, “The Incidence of Thyroid Carcinoma in Multinodular Goiter: Retrospective Analysis,” Acta Biomed Ateneo Parmense, Vol. 75, 2004, pp. 114-117
[4]	A. McCall, H. Jarosz, A. M. Lawrence and E. Paloyan, “The Incidence of Thyroid Carcinoma in Solitary Cold Nodules and in Multinodular Goiters,” Surgery, Vol. 100, No. 6, 1986, pp. 1128-1132
[5]	T. M. Shattuck, W. H. Westra, P. W. Ladenson and A. Arnold, “Independent Clonal Origins of Distinct Tumor Foci in Multifocal Papillary Thyroid Carcinoma,” New England Journal of Medicine, Vol. 352, No. 23, 2005, pp. 2406-2412. doi:10.1056/NEJMoa044190
[6]	H. Studer and M. Derwahl, “Mechanisms of Nonneoplastic Endocrine Hyperplasia—A Changing Concept: A Review Focused on the Thyroid Gland,” Endocrine Reviews, Vol. 16, No. 4, 1995, pp. 411-426. doi:10.1210/er.16.4.411
[7]	F. Weber, S. Lei, M. A. Aldred, C. Morrison, M. D. Ringel, M. Saji, F. Schuppert, A. Frilling, C. E. Broelsch and C. Eng, “Genetic Classification of Benign and Malignant Thyroid Follicular Neoplasoa Based on a 3-Gene Combination,” Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 5, 2005, pp. 2512-2521. doi:10.1210/jc.2004-2028
[8]	G. W. Wright and R. M. Simon, “A Random Variance Model for Detection of Differential Gene Expression in Small Microarray Experiments,” Bioinformatics, Vol. 19, No. 18, 2003, pp. 2448-2455. doi:10.1093/bioinformatics/btg345
[9]	L. M. McShane, M. D. Radmacher, B. Freidlin, R. Yu, M. C. Li and R. Simon, “Methods for Assessing Reproducibility of Clustering Patterns Observed in Analyses of Microarray Data,” Bioinformatics, Vol. 18, No. 11, 2002, pp. 1462-1469. doi:10.1093/bioinformatics/18.11.1462
[10]	N. Ahuja and J. P. Issa, “Aging, Methylation and Cancer,” Histology and Histopathology, Vol. 15, No. 3, 2000, pp. 835-842.
[11]	B. J. Braakhuis, M. P. Tabor, J. A. Kummer, C. R. Leemans and R. H. Brakenhoff, “A Genetic Explanation of Slaughter’s Concept of Field Cancerization: Evidence and Clinical Implications,” Cancer Research, Vol. 63, No. 8, 2003, pp. 1727-1730
[12]	C. Hafner, R. Knuechel, R. Stoehr and A. Hartmann, “Clonality of Multifocal Urothelial Carcinomas: 10 Years of Molecular Genetic Studies,” International Journal of Cancer, Vol. 101, No. 1, 2002, pp. 1-6 doi:10.1002/ijc.10544
[13]	M. Seo, C. H. Cho, Y. I. Lee, E. Y. Shin, D. Park, C. D. Bae, J. W. Lee, E. S. Lee and Y. S. Juhnn, “Cdc42-Dependent Mediation of UV-Induced p38 Activation by G Protein Betagamma Subunits,” Journal of Biological Chemistry, Vol. 279, No. 17, 2004, pp. 17366-17375 doi:10.1074/jbc.M312442200
[14]	O. A. Coso, M. Chiariello, J. C. Yu, H. Teramoto, P. Crespo, N. Xu, T. Miki and J. S. Gutkind, “The Small GTP-Binding Proteins Rac1 and Cdc42 Regulate the Activity of the JNK/SAPK Signaling Pathway,” Cell, Vol. 81, No. 7, 1995, pp. 1137-1146 doi:10.1016/S0092-8674(05)80018-2
[15]	W. B. Grant, “An Ecologic Study of Cancer Mortality Rates in Spain with Respect to Indices of Solar UVB Irradiance and Smoking,” International Journal of Cancer, Vol. 120, 2007, pp. 1123-1128. doi:10.1002/ijc.22386