seventy cases of papillary thyroid carcinomas (PTCs) have been reviewed, 51 of them displaying a normal karyotype (73%). In 10 cases non recurrent structural or numerical changes were observed. In particular, 9 cases showed recurrent structural changes including:

inv10(q11.2q21.2) in 5 tumors,

a t(10;17)(q11.2;q23) in two cases, and

a der(1) in the last two tumors

RET (REarranged during Transfection)

10q11.21

the RET proto-oncogene codes for the tyrosine kinase receptor of GDNF (Glial cell Derived Neurotrophic Factor) and Neurturin (NTN); activation of RET by GDNF or NTN has been shown to require one of two accessory proteins, GDNFRa and GDNFRb.

germline mutations of proto-RET result in human diseases including familial medullary thyroid carcinoma MTC, multiple endocrine neoplasia type 2A and 2B (MEN2A and MEN2B) and Hirschsprung¼s disease

RET is expressed in the thyroid by normal C cells and their pathologic counterpart, medullary thyroid carcinoma (MTC); moreover, RET expression can be detected in normal adrenal medulla and pheochromocytomas

CCDC6 (coiled-coil domain containing 6)

10q21.2

AKAP10 (A-kinase anchoring protein 10)

17p11.2

NCOA4 (Nuclear Receptor Coactivator 4)

10q11.23

NTRK1 (neurotrophic receptor tyrosine kinase 1)

1q23.1

the NTRK1 proto-oncogene encodes the high affinity receptor for Nerve Growth Factor (NGF)

NTRK1 is primarily expressed in the nervous system

mice carrying a germline mutation that eliminates NTRK1 show severe sensory and sympathetic neuropathies, including the loss of neurons of the dorsal root ganglia associated with nociceptive functions, and most die within one month of birth; interestingly, point mutations leading to the inactivation of the NTRK1 receptor, have been identified in patient with CIPA (Congenital Insensitivity to Pain with Anhidrosis), an autosomal-recessive disorder characterized by absence of reaction to noxious stimuli; thus NGF signalling via NTRK1 appears essential for the development and maintenance of both the peripheral and central nervous systems

TPM3 (tropomyosin 3)

1q21.3

TPR (Translocated promoter region)

1q31.1

TFG (TRK-fused gene)

3q12.2

the RET/PTC1 oncogene, represents the first example of oncogene activation in solid tumors due to an acquired chromosomal abnormality

RET/PTC1 is a chimeric transforming sequence generated by the fusion of the TK domain of RET to the 5 terminal sequence of the gene H4/D10S170; both partners in the fusion have been localized to chromosome 10q and their fusion is the molecular event consequent to a paracentromeric inversion of chromosome 10q, inv 10 (q11.2 q21.2)

H4/D10S170 has been shown to display a coiled-coil sequence which confers to the oncoprotein the ability to form dimers, resulting in a constitutive activation of the TK function

in fact Ret/ptcs oncoproteins and in some cases Trk oncoproteins were demonstrated to bind and activate PLCg, an SH2-containing enzyme catalyzing the hydrolisis of phosphatydilinositol biphospate to inositol trophoshate and diacyl glicerol, and Shc, an adaptor protein belonging to the Ras pathway; the relocalization in the cytoplasm of RET and NTRK1 enzymatic activity could allow their interaction with unusual substrata, perhaps modifying their functional properties