RET rearrangements in familial papillary thyroid carcinomas

Abstract

Familial papillary thyroid carcinoma (FPTC) is an inherited tumor characterized by a more aggressive phenotype than that of its sporadic counterpart. Its mode of inheritance as well as its genetic and molecular bases are still poorly understood. On the contrary, genetic alterations in sporadic papillary thyroid carcinoma (PTC) are better characterized, the most common one involving the activation of the proto-oncogene RET through somatic rearrangements. In the present study, we investigated by interphase fluorescence in situ hybridization the presence of RET rearrangements in a series of 20 FPTC. We show that one FPTC and the adenoma from the same patient carry a RET rearrangement (type PTC1) and that this rearrangement is absent in the germline. Furthermore, we excluded a RET haplotype sharing in two brothers of the same family. These results show that RET rearrangements can indeed be found in FPTC and confirm that RET is not involved in the inherited predisposition to FPTC.

Introduction

Thyroid carcinomas of follicular cell origin have been repeatedly reported as occurring in families [1], [2], [3], [4], [5], [6] and the proportion of familial papillary thyroid carcinomas (FPTCs) is estimated to be 3–7% of all thyroid tumors. FPTC is more aggressive than its sporadic counterpart, is usually multifocal and shows an early age of onset [7], [8]. Although the familial relative risk in first-degree relatives of thyroid cancer probands is highest amongst all primary cancer sites [9], little is known about the molecular basis of FPTC. On the contrary, somatic mutations in sporadic papillary thyroid carcinomas (PTC) are better characterized, the most frequent ones involving the RET proto-oncogene, which maps to the long arm of chromosome 10 at band q11.2. These somatic chromosomal mutations (inversions or translocations) always involve intron 11 of RET and lead to the juxtaposition of its intracellular tyrosine kinase (TK) domain to the 5′ portion of different donor genes constitutively expressed in the thyroid [10]. By fusing with the intracellular domain of RET, these genes contribute a novel amino-terminal portion which makes RET activation ligand-independent.

Three main rearranged forms of RET have been described in PTCs: PTC1 [11], PTC2 [12] and PTC3 [13]. PTC1 and PTC3 arise from paracentric inversions of the long arm of chromosome 10 [14], [15], whereas PTC2 originates from a translocation involving chromosome 10 and chromosome 17 [16]. Five novel types of rearrangements, named PTC5, PTC6, PTC7, RET/ELKS and RET/PCM-1 [17], [18], [19], [20] have recently been identified.

We previously developed a dual-color fluorescence in situ hybridization (FISH) approach to detect RET rearrangements in interphase nuclei of sporadic thyroid lesions [21]. This led to the detection of known RET rearrangements in sporadic PTCs and adenomas. More interestingly, this approach allowed to identify a novel type of rearrangement in which the TK domain of RET is fused to the 5′-end of the PCM-1 gene [20].

Germline mutations of the RET proto-oncogene are found in the majority of familial medullary thyroid carcinomas (FMTCs) and somatic mutations have been detected in sporadic MTCs [10]. Overall, the involvement of RET in sporadic PTC on the one hand and in familial and isolated forms of MTC on the other, suggests that it might be a strong candidate in the predisposition of FPTC.