The Prevalence of RET/PTC Mutations in Papillary Thyroid Cancers in Turkish Population and its Relation Between Tumor Histopathology and Prognostic Factors

Abstract

Objective: In recent years, thyroid cancer has been at the forefront of molecular pathology as a result of the consequences of the Chernobyl disaster and the recognition of the role of RET/PTC rearrangements in papillary thyroid carcinomas (PTCs). Correlation of RET/PTC expression with clinical outcome is controversial. This study aims to identify the prevalence of RET/PTC oncogene expression in Turkey, and to investigate the correlation between RET/PTC oncogene expression and the known prognostic factors of PTC in 101 patients.

Methods: The RET rearrangements were examined by means of reverse transcriptase-polymerase chain reaction analysis, with primers flanking the chimeric region. Statistical evaluation was performed by using Independent samples t-test, One-sample Chi-square test and Pearson Chi-square or Fisher's Exact Test.

Results: RET/PTC was determined positive in 67(66.3%) of totally 101 patients (p<0.001). RET/PTC1 in 32(31.7%), RET/PTC3 in 21(20.8%), RET/PTC1+RET/PTC3 both in 10(9.9%) patients were found to be positive. There was RET/PTC2 positiveness in two patients, RET/PTC2,3 positiveness in one patient, and RET/PTC1,2,3 positiveness in one patient. No statistical difference was found between RET/PTC1 and RET/PTC3. None of genetico-clinical analyses showed any significant association between RET/PTC expression and the clinical and pathological features of the cancers.

Conclusion: While this prevalence of the RET/PTC is less than RET/PTC frequency seen after Chernobyl in Belarus, its prevalence in our region is also high (66.3%). As a result, no significant correlation was found in between prognosis and RET/PTC frequency.

Key words

RET/PTC mutations - Turkish Population - prognostic factors

References

• 1 Sheils O. Molecular classification and biomarker discovery in papillary thyroid carcinoma.  Expert Rev Mol Diagn. 2005;  5 ((6)) 927-946
• 2 Finn SP, Smyth P, O’Leary J, Sweeney EC, Sheils O. Ret/PTC chimeric transcripts in an Irish cohort of sporadic papillary thyroid carcinoma.  J Clin Endocrinol Metab. 2003;  88 ((2)) 938-941
• 3 Sadetzki S, Calderon-Margalit R, Modan B, Srivastava S, Tuttle RM. Ret/PTC activation in benign and malignant thyroid tumors arising in a population exposed to low-dose external-beam irradiation in childhood.  J Clin Endocrinol Metab. 2004;  89 ((5)) 2281-2289
• 4 Caudill CM, Zhu Z, Ciampi R, Stringer JR, Nikiforov YE. Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation.  J Clin Endocrinol Metab. 2005;  90 ((4)) 2364-2369
• 5 Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer.  Cytokine Growth Factor Rev. 2005;  16 ((4-5)) 441-467
• 6 Pacini F, Elisei R, Romei C, Pinchera A. RET proto-oncogene mutations in thyroid carcinomas: clinical relevance.  J Endocrinol Invest. 2000;  23 ((5)) 328-338
• 7 Takami H, Ikeda Y, Tajima G, Kan S, Kameyama K. Thyroid carcinoma: genetics, diagnosis, clinical features, and surgical treatment.  Nippon Geka Gakkai Zasshi. 2002;  103 ((6)) 492-494
• 8 Nikiforov YE. R ET/PTC rearrangement in thyroid tumors.  Endocr Pathol. 2002; Spring;  13 ((1)) 3-16
• 9 Puxeddu E, Moretti S, Giannico A. et al . Ret/PTC activation does not influence clinical and pathological features of adult papillary thyroid carcinomas.  Eur J Endocrinol. 2003;  148 ((5)) 505-513
• 10 Tallini G, Asa SL. RET oncogene activation in papillary thyroid carcinoma.  Adv Anat Pathol. 2001;  8 ((6)) 345-354
• 11 Unger K, Zitzelsberger H, Salvatore G. et al . Heterogeneity in the distribution of RET/PTC rearrangements within individual post-Chernobyl papillary thyroid carcinomas.  J Clin Endocrinol Metab. 2004;  89 ((9)) 4272-4279
• 12 Soares P, Trovisco V, Rocha AS. et al . BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC.  Oncogene. 2003; 17;  22 ((29)) 4578-4580
• 13 Wiench M, Wloch J, Oczko M, Gubala E, Jarzab B. Rearrangement of the RET gene in papillary thyroid carcinoma.  Wiad Lek. 2001;  54 ((Suppl 1)) 64-71
• 14 Smanik PA, Furminger TL, Mazzaferri EL, Jhiang SM. Breakpoint characterization of the ret/PTC oncogene in human papillary thyroid carcinoma.  Hum Mol Genet. 1995;  4 ((12)) 2313-2318
• 15 Motomura T, Nikiforov YE, Namba H. et al . Ret rearrangements in Japanese pediatric and adult papillary thyroid cancers.  Thyroid. 1998;  8 ((6)) 485-489
• 16 Nakazawa T, Kondo T, Kobayashi Y. et al . RET gene rearrangements (RET/PTC1 and RET/PTC3) in papillary thyroid carcinomas from an iodine-rich country (Japan).  Cancer. 2005; 1;  104 ((5)) 943-951
• 17 Tuttle RM, Becker DV. The Chernobyl accident and its consequences: update at the millennium.  Semin Nucl Med. 2000;  30 ((2)) 133-140
• 18 Elisei R, Romei C, Vorontsova T. et al . RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults.  J Clin Endocrinol Metab. 2001;  86 ((7)) 3211-3216
• 19 Basolo F, Molinaro E, Agate L. et al . RET protein expression has no prognostic impact on the long-term outcome of papillary thyroid carcinoma.  Eur J Endocrinol. 2001;  145 ((5)) 599-604
• 20 Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.  Cancer Res. 1997; 1;  57 ((9)) 1690-1694
• 21 Santoro M, Melillo RM, Fusco A. RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture.  Eur J Endocrinol. 2006;  155 ((5)) 645-653
• 22 Wang J, Knauf JA, Basu S. et al . Conditional expression of RET/PTC induces a weak oncogenic drive in thyroid PCCL3 cells and inhibits thyrotropin action at multiple levels.  Mol Endocrinol. 2003;  17 ((7)) 1425-1436
• 23 Giordano TJ, Kuick R, Thomas DG. et al . Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis.  Oncogene. 2005; 6;  24 ((44)) 6646-6656
• 24 Hunt Jl. Unusual thyroid tumors: a review of pathologic and molecular diagnosis.  Expert Rev Mol Diagn. 2005;  5 ((5)) 725-734
• 25 Liu RT, Chou FF, Wang CH. et al . Low prevalence of RET rearrange-ments (RET/PTC1, RET/PTC2, RET/PTC3, and ELKS-RET) in sporadic papillary thyroid carcinomas in Taiwan Chinese.  Thyroid. 2005;  15 ((4)) 326-335
• 26 Burgess JR, Skabo S, MacArdle K, Tucker P. Temporal trends and clinical correlates for the ret/PTC1 mutation in papillary thyroid carcinoma.  ANZ J Surg. 2003;  73 ((1-2)) 31-35
• 27 Lam KY, Lo CY, Leung PS. High prevalence of RET proto-oncogene activation (RET/PTC) in papillary thyroid carcinomas.  Eur J Endocrinol. 2002;  147 ((6)) 741-745
• 28 Martinez I, Mantilla A, Medrano ME. et al . High prevalence of RET tyrosine kinase activation in Mexican patients with papillary thyroid carcinomas.  Endocr Pathol. 2001;  12 ((2)) 113-123
• 29 Borrello MG, Alberti L, Fischer A. et al . Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene.  Proc Natl Acad Sci USA. 2005; 11;  102 ((41)) 14825-14830
• 30 Di Cristofaro J, Vasko V, Savchenko V. et al . Ret/PTC1 and ret/PTC3 in thyroid tumors from Chernobyl liquidators: comparison with sporadic tumors from Ukrainian and French patients.  Endocr Relat Cancer. 2005;  12 ((1)) 173-183
• 31 Collins BJ, Chiappetta G, Schneider AB. et al . RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions.  J Clin Endocrinol Metab. 2002;  87 ((8)) 3941-3946
• 32 Powell Jr DJ, Russell J, Nibu K. et al . The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.  Cancer Res. 1998; 1;  58 ((23)) 5523-5528
• 33 Nikiforov YE, Erickson LA, Nikiforova MN, Caudill CM, Lloyd RV. Solid variant of papillary thyroid carcinoma: incidence, clinical-pathologic characteristics, molecular analysis, and biologic behavior.  Am J Surg Pathol. 2001;  25 ((12)) 1478-1484
• 34 Brzeziañska E, Karbownik M, Migdalska-Sek M, Pastuszak-Lewandoska D, Włoch J, Lewiñski A. Molecular analysis of the RET and NTRK1 gene rearrangements in papillary thyroid carcinoma in the Polish population.  Mutat Res. 2006; 25;  599 ((1-2)) 26-35

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