Different significance of ret/PTC(1) and ret/PTC(3) rearrangements in thyroid carcinogenesis: lesson from two subgroups of patients with papillary thyroid carcinomas showing the highest incidence of ret/PTC activation

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* To the editor: The recent paper by Thomas et al. (1) shows that: 1) ret/PTC activation plays a central role in the pathogenesis of papillary thyroid carcinomas (TCs) occurring in children from Ukraine and Belarus after the Chernobyl accident (60.7% of the Ukrainian and 51.3% of the Belarussian cases); and 2) these patients have an increased incidence of the ret/PTC3 isoform (ret fusion with RGF gene) vs. the more frequent ret/PTC1 (ret fusion with H4 gene). In particular, a strong correlation was observed between the ret/PTC3 isoform and the solid-follicular subtype of papillary TC, which was present in 46 of 67 cases. This morphological variant has been considered as evidence of a more malignant phenotype (2). Nineteen of the 24 ret/PTC-positive solid-follicular TCs harbored a ret/PTC3 rearrangement, whereas only 5 had a ret/PTC1 rearrangement. The authors suggest that: 1) “there are good reasons to believe that there is a causal link between radiation exposure and ret/PTC rearrangements” because (a) the prevalence of ret/PTC in post-Chernobyl TCs is higher than the highest frequencies reported in the literature in nonexposed subjects (25–40%); (b) ionizing radiation can induce ret/PTC rearrangement “in vitro ” (3) and patients exposed to external radiation show a high frequency of ret/PTC rearrangements (4); and 2) “there is a strong correlation between the morphological subtype of papillary carcinoma and the type of ret rearrangement,” either in humans or transgenic animals. In fact, the targeted expression of ret/PTC1 to the thyroid gland caused the generation of TCs of the classic type (5), whereas ret/PTC3 mice developed aggressive TCs with a prevalent solid component, which were highly prone to metastasize to regional lymph nodes (6). The authors hypothesize that “although the ret component of the 2 chimeric proteins is identical, some functional differences between the two ret fusion partners may contribute to the different neoplastic phenotypes” (1). Thomas et al. (1) correctly acknowledge that whether ret/PTC activation is “linked primarily to the nature of the carcinogenetic agent (radiation or environmental factors) or the age of the patients (ranging between 6–18 yr in their series) remains to be determined.” In the last 5 yr we have collected the largest series of a very rare subgroup of patients with papillary TCs, namely those associated with familial adenomatous polyposis (FAP), an inherited multitumoral syndrome due to germ-line mutations of the APC gene (7). Ninety-seven patients have been collected from the literature, and 15 personal cases, who had detection of the APC germ-line mutation, have been added (7). Eight of nine of these patients (89%) had ret/PTC activation (8, 9). In particular, an unusual histological variant, the so-called cribriform variant, was very frequent (8), and the ret/PTC1 isoform was always found (9). All these patients were very young (mean age, 24 yr; range, 20–36 yr). All of them were followed up for long time (5–17 yr). A particularly indolent biological behavior was observed, which is in accordance with the low malignancy of the entire series (only 2 of 112 patients had distant metastases; Refs. 7 and 8). Interestingly, the only patient who, after lobectomy and isthmusectomy, had recurrence 17 yr after initial surgery, in addition to ret/PTC1, which was already present in the first tumor, also had ret/PTC3 both in the thyroid and in the regional lymph nodes. p53 mutations were concomitantly found in the thyroid tumoral tissue of this patient (8, 10). The group of patients with FAP-associated (or genetically determined) TC confirms that young age [mean age, 24 yr (in our series)] is a quite constant finding in groups with a high rate of ret/PTC activation. Additional factors could be early detection, due to intensive screening of high-risk populations (siblings of an index case with FAP, subjects exposed to nuclear radiation) and/or small diameter of tumors (,1 cm in three of six subjects of the Italian series). On the contrary, there is less evidence that the histological variant is also predetermined by the type of ret/PTC isoform. In fact, some patients with ret/PTC1 had the solid variant, and some of those with ret/PTC3 had variants other than the solid one. In particular, among patients with FAP-associated TCs, three members of the same kindred with the same germ-line mutation of the APC gene and ret/PTC1 activation had three different variants: classic papillary, cribriform, and follicular, respectively (11). Cumulative data in both groups of patients support the view that: 1) ret activation is highly prevalent in young subjects with small tumors or in patients belonging to special subgroups who are intensively screened for TC; 2) patients with ret/PTC1 isoform usually show an indolent behavior, whereas ret/PTC3 is associated with a more aggressive biological behavior (8, 10); 3) ret/PTC1 may coexist with ret/PTC3 in the same tumor; in particular, ret/PTC3 may develop with age or become more prevalent in patients with previous ret/PTC1 activation, and determine a more aggressive behavior; 4) the solid variant is usually, but not always, associated with ret/PTC3; and 5) whereas the link with radiation is evident in children from Belarus, it is not proven in FAP patients, even if patients from the latter subgroup could have a greater susceptibility to environmental radiation (12). In FAP patients APC mutations alone do not seem sufficient to cause TC (lack of loss of heterozygosity of the APC gene in the thyroid tumoral tissue) (8), but concomitant cofactors [modifier genes, sex-related factors (F:M 5 17:1) or environmental factors] are always required (12). A detailed genetic and clinicopathological analysis, also including long-term follow-up, of these two rare subgroups of patients with papillary TC, namely post- Chernobyl and FAP associated, could give a better insight into the relative role of genetic and environmental factors in thyroid carcinogenesis.