Prevalence, Significance, and Biological Behavior of ret/PTC1 Associated Papillary Thyroid Carcinomac

Francesco Cetta

University of Siena Nuovo Policlinico Siena, Italy

Recent papers published in both The Journal of Clinical Endocrinology and Metabolism (Sugg et al.) (1) and Endocrinology have dealt with ret/PTC1 rearrangements in human thyroid carcinoma.

In particular, Jhiang et al. (2) showed that "transgenic mice with targeted expression of the ret/PTC1 oncogene developed thyroid carcinomas with considerable similarities to human papillary thyroid carcinomas" and suggested that "ret/PTC1 is not only an associated biomarker," but also "the only proven specific genetic event leading to the development of papillary thyroid carcinoma."

In addition, in the January 1996 issue, JCEM published an interesting article by Nikiforov et al. (3) and an editorial by Williams (4) on the great increase in papillary carcinomas in children after exposure to fall-out radiation from Chernobyl. A high rate of ret/PTC1 activation (57–67%) has been reported in these tumours (5).

Our group has recently observed ret/PTC activation by immunohistochemical analysis according to Viglietto (6) in 2 of 3 siblings with FAP (familial adenomatous polyposis)-associated papillary thyroid tumors. Further characterization of the mutation as ret/PTC1, 2 or 3 is in progress. All patients carried a germ-line mutation of the APC gene at codon 1061(7). Our group was the first to detect ret/PTC oncogene in papillary thyroid tumors, and we have made an important contribution to the knowledge and significance of ret/PTC oncogene and its biological properties. In particular, more than 250 consecutive thyroid tumors have been analyzed for ret/PTC activation. Activation of ret/PTC, while showing significant differences among various series (also depending on geographic areas and method of detection), showed some well-defined characteristics in humans, i.e. 1) it is restricted to the papillary histotype; 2) it is found in 10–20% of a consecutive series of papillary thyroid tumors, (40% in a recent series with more sensitive detection methods), but up to 50% in occult thyroid carcinoma, and up to 66.6% in thyroid cancer found after the Chernobyl nuclear disaster and in our patients with FAP-associated thyroid tumors. Therefore, it seems that these 2 subgroups (FAP-associated and radiation determined thyroid tumors) had higher rates of ret/PTC activation. Interestingly, ret/PTC-associated tumors, despite showing local invasion, had a relatively less malignant behavior (because of earlier detection?), compared with other papillary tumors not showing this marker.

I am the project leader of a European cooperative study (within the framework of the Biomed II project) aimed at obtaining a better molecular and biological characterization of FAP-associated thyroid tumors.

The recent paper by Jhiang (2) gives evidence that ret/PTC1 is a genetic event, leading by itself to the development of thyroid carcinoma. The same authors showed that in vitro irradiation of thyroid-cell lines were able to determine malignant changes. The recent data from the Chernobyl area confirm that radiation exposure certainly plays an etiologic role. However, present data show that APC mutation is another genetic event, possibly involved in tumorigenesis (even antecedent to ret/PTC activation). In addition, this is the first time that APC and ret were found to cooperate in vivo to determine thyroid carcinomas.

Footnotes

a Received May 14, 1996. Address correspondence to: H. J. Roberts, Department of Medicine, Palm Beach Institute for Medical Research, Inc., 304 27th Street, West Palm Beach, Florida 33407.

b Received January 8, 1997. Address correspondence to: Julio M. Pardo, Department of Pediatrics/Endocrinology, Physicians Group Clinic, 700 North 7th Street, Springfield, Illinois 62702.

c Received December 12, 1996. Address correspondence to: Francesco Cetta, Institute of Surgical Clinics, University of Siena, Nuovo Policlinico, Viale Bracci, Siena, Italy 53100.

References

  1. Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S, Asa SL. 1996 ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential? J Clin Endocrinol Metab. 82:3360–3365.
  2. Jhiang SM, Sagartz JE, Tong Q, et al. 1996 Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology. 137:375–378.[Abstract]
  3. Nikiforov Y, Gnepp DR, Fagin JA. 1996 Thyroid lesions in children and adolescents after the Chernobyl disaster: implications for the study of radiation tumorigenesis. J Clin Endocrinol Metab. 81:9–14.[Abstract]
  4. Williams D. 1996 Editorial: thyroid cancer and the Chernobyl accident. J Clin Endocrinol Metab. 81:6–8.[Medline]
  5. Fugazzola, L, Pilotti S, Pinchera A, et al. 1995 Oncogenic rearrangements of the RET-proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res. 55:5617–5620.[Abstract]
  6. Viglietto G, Chiappetta G, Marchinez-Tello FJ, et al. 1995 RET-PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene. 11:1207–1210.[Medline]
  7. Cetta F. 1995 Progression of tumorigenesis in patients with papillary carcinoma of the thyroid associated with familial adenomatous polyposis. Gastroenterology. 110:A502.




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