The Oncogenic Activity of RET Point Mutants for Follicular Thyroid Cells May Account for the Occurrence of Papillary Thyroid Carcinoma in Patients Affected by Familial Medullary Thyroid Carcinoma

Abstract

Activating germ-line point mutations in the RET receptor are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma (MTC), whereas somatic RET rearrangements are prevalent in papillary thyroid carcinomas (PTCs). Some rare kindreds, carrying point mutations in RET, are affected by both cancer types, suggesting that, under specific circumstances, point mutations in RET can drive the generation of PTC. Here we describe a family whose siblings, affected by both PTC and MTC, carried a germ-line point mutation in the RET extracellular domain, converting cysteine 634 into serine. We tested on thyroid follicular cells the transforming activity of RET(C634S), RET(K603Q), another mutant identified in a kindred with both PTC and MTC, RET(C634R) a commonly isolated allele in MEN2A, RET(M918T) responsible for MEN2B and also identified in kindreds with both PTC and MTC, and RET/ PTC1 the rearranged oncogene that characterizes bona fide PTC in patients without MTC. We show that the various RET point mutants, but not wild-type RET, scored constitutive kinase activity and exerted mito- Medullary thyroid carcinoma (MTC) is a malignant tumor arising from neural crest-derived calcitonin-secreting C cells of the thyroid, 1 whereas papillary thyroid carcinoma (PTC) derives from endoderm-derived follicular cells. 2 MTC often occurs in the context of autosomal dominant multiple endocrine neoplasia type 2 syndromes (MEN2), whereas PTC is sporadic in most of the cases. 3 This notwithstanding, some rare MEN2 kindreds are affected by both cancer types, the molecular mechanism for this association still remaining unclear.Both MTC and PTC are strictly linked to activating mutations in the RET gene. RET is a transmembrane tyrosine kinase receptor for glial-derived neurotrophic factor (GDNF). 4 RET rearrangements, caused by chromosomal inversions or translocations, are present in 20 to 40% of cases of PTC. 5 These rearrangements result in

RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation

“…The latter domain has a negative effect on the RET signaling. 23 Both BCR and FGFR1OP domains kept in the fusion proteins have dimerization properties. 14,24 Consequently, the oncogenic activity of RET fusion proteins could be a combination of a constitutive dimerization, higher expression and loss of negative regulatory elements.…”

A study of histopathological features of medullary carcinoma of the thyroid: Cases from a single institute in India

“…[11] However, a study describes that point mutations in RET can drive the generation of PTC. [12] It is intriguing therefore to speculate on the possible reasons for the higher frequency of association of medullary carcinoma with PTC, and the hitherto unreported finding of benign thyroid follicles in the vicinity of MTC showing nuclear changes of PTC. Further investigations to confirm our observations and probe the affected cells for RET alterations would be needed to elucidate the underlying mechanisms for this relationship.…”

RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture

“…2). As in the case of other receptors, the juxtamembrane domain negatively affects RET mitogenic signaling although the molecular mechanisms governing this process are not clear (60). On the other hand, all the translocated amino termini fused to RET are predicted to fold into coiled-coils (Figs 1 and 2 mechanism no.…”