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Letter to the Editor |
University of Siena 53100 Siena, Italy
University of Naples Naples, Italy
To the editor:
The interesting article by Nikiforov et al. (1) and the Editorial by Williams in the same issue of JCEM (2) outline that "the great increase in papillary carcinomas in children recently reported in Belarus and in Ukraine can be attributed beyond reasonable doubt to exposure to fall-out radiation from Chernobyl" (2). In particular, most tumors were papillary carcinomas, with surprisingly few follicular carcinomas. Secondly, the highest incidence was observed in children who were very young (0–5 yr) at the time of exposure, with declining rate of occurrence with increasing age at exposure. In fact, thyroid cells have a limited number of mitoses, all occurring before 20 yr of age. Therefore, exposure to radiation during the first years of life, before the occurrence of planned cell divisions, increases the risk of malignant changes (2). These thyroid tumors had a particularly increased rate of ret/PTC activation (57– 67%; mainly PTC3) (4, 5).
We recently reported that patients with familial adenomatous polyposis (FAP), a multitumoral disease determined by mutation of the APC gene, frequently have thyroid carcinomas (6), with ret/PTC activation in 66.6% of cases. It can be outlined that PTC3activation was mainly found in the Chernobyl subjects, while the PTC1 variant was always observed in FAP tumors. Preliminary data collected in a recent European collaborative study have shown that APC mutations tend to cluster in exon 15, in the genomic area usually associated with congenital hypertrophy of the retinal pigment epithelium (codons 463-1387). Observed APC mutations were at codon 1061, 1309, and 848 (7), respectively. However, thyroid cancer affected only some of the siblings carrying the same APC mutation. Interestingly, in addition to modifier genes, environmental events could play a role in explaining variability within individuals of the same family with an identical mutation. In particular, within the five affected members of one kindred, the two oldest members (mother and uncle) had polyps but not not thyroid cancer, the intermediate aunt had thyroid cancer, but not ret/PTC activation, the two youngest sisters, ages 20 and 22 yr, in addition to polyposis, had both thyroid cancer and ret/PTC activation. It can be inferred that, at least for thyroid cancer, intrafamilial variability could be explained by age differences at the time of exposure to radioiodine in the atmosphere, including the effect of the Chernobyl accident or other unknown disasters in close or distant countries. Thyroid tumors in the Italian kindred were found 9 years after Chernobyl, and the youngest siblings were 11 and 13 yr old, while other affected members were older than 25. Interestingly, a still younger affected girl, presently 15, but 6 yr old at the time of the Chernobyl accident, already has thyroid nodules (even if evident malignant changes are not detectable at fine needle biopsy for the moment). Therefore, it is likely that, in patients who are genetically predisposed for thyroid cancer, subliminal doses of radiation induce a rate of occurrence of thyroid cancer similar to that observed after the Chernobyl disaster, with declining rate of occurrence with increasing age of exposure.
Three main conclusions can be suggested. 1) FAP-associated and "after Chernobyl" thyroid tumors not only show striking similarities, but also could share a common cofactor, namely exposure to radiation. 2) The comparative analyses of FAP-associated and fall-out related thyroid tumors could provide a deeper insight into mechanisms of tumor-igenesis. In particular, because ras activation and ret/PTC activation seem to be mutually exclusive in the progression of tumorigenesis of thyroid carcinoma (the former restricted to the follicular histotype, the latter specific to the papillary one), present data, if further confirmed, strongly suggest that APC mutations in germ-line cells cooperate with ras for the progression of colonic polyps to carcinoma (8), whereas they cooperate with ret/PTC, but not with ras, for the occurrence of thyroid carcinoma in the same subjects. Analogously, it can be inferred that exposure of thyroid cells to 131I radiation determines activation of ret/ PTC but not of ras, which on the contrary is likely activated by mutagenic events different from fall-out radiation. Therefore, the mutagenic stimulus for neoplastic proliferation varies from one tissue to another in the same subject, leading to the activation of oncogenes, which are both "tissue specific" and "stimulus related." 3) Finally, because hereditary predisposition to develop multiple tumors interacts with epigenetic or environmental factors, it is likely that exposure to common environmental mutagens does not determine comparable consequences in all subjects. In particular, for fall-out radiation and thyroid tumors, at least two independent factors must be taken into account: first, the presence in a yet unknown proportion of the general population of individuals with congenital predisposition to tumoral changes, who can develop tumors even after exposure to subliminal doses of mutagens; second, the age of subjects at the time of exposure. The awareness of these possibilities is of paramount importance while trying to evaluate the mid- and long-term side effects of nuclear disasters or ecologic catastrophes. This means that the biological consequences of most past, present, and future environmental changes are probably greater than estimated if they are measured not only in terms of risk to healthy subjects but also to congenitally frail patients or categories such as children at higher risk for thyroid cancer, when exposed to 131I radiation.
Footnotes
1 Received January 28, 1997. Address correspondence to: Francesco Cetta, M.D., Professor of Surgery, Institute of Surgical Clinics, University of Siena, Nuovo Policlinico, Viale Bracci, 53100 Siena, Italy. 
2 This study has been supported in part by: National Research Institute (CNR), Grants no. 93.00239.CT04, no. 94.02376.CT04, no. 95.00897.CT04; Regione Toscana Grant no. 358/C, 1995; Murst 40% Murst 60%.
References
This article has been cited by other articles:
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  F. Cetta, M. Gori, G. Montalto, M. Zuckermann, and P. Toti Different Significance of ret/PTC1 and ret/PTC3 Rearrangements in Thyroid Carcinogenesis: Lesson from Two Subgroups of Patients with Papillary Thyroid Carcinomas Showing the Highest Incidence of ret/PTC Activation J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1429 - 1429. [Full Text]
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F. Cetta, M. C. Curia, G. Montalto, M. Gori, A. Cama, P. Battista, and A. Barbarisi Thyroid Carcinoma Usually Occurs in Patients with Familial Adenomatous Polyposis in the Absence of Biallelic Inactivation of the Adenomatous Polyposis Coli Gene J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 427 - 432. [Abstract] [Full Text]
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F. Cetta, G. Montalto, M. Gori, M. C. Curia, A. Cama, and S. Olschwang Germline Mutations of the APC Gene in Patients with Familial Adenomatous Polyposis-Associated Thyroid Carcinoma: Results from a European Cooperative Study J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 286 - 292. [Abstract] [Full Text]
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 F. Cetta, M. R. Pelizzo, M. C. Curia, and A. Barbarisi Genetics and Clinicopathological Findings in Thyroid Carcinomas Associated with Familial Adenomatous Polyposis Am. J. Pathol., July 1, 1999; 155(1): 7 - 9. [Full Text] [PDF]
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F. Cetta Comment on Carney Complex and Related Syndromes and their Genetic Loci J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1491 - 1491. [Full Text]
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F. Cetta Familial Nonmedullary Thyroid Carcinomas: A Heterogeneous Syndrome with Different Natural History and Variable Long-Term Prognosisb J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4274a - 4275. [Full Text]
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