Thyroid: Papillary carcinoma/Adenocarcinoma

2000-08-01   Marco A Pierotti 

1.Istituto Nazionale dei Tumori, Dept. of Experimental Oncology, Via Venezian, 1 20133 Milan, Italy

Classification

Note

  • Papillary Thyroid Carcinomas (PTCs) derives from the thyroid follicular cells, as the other type of well-differentiated thyroid carcinomas, the follicular ones; however these differentiated thyroid cancers are regarded as different entities:
  • the follicular carcinoma, solitary and encapsulated, is associated with endemic goiter, a diet with low iodine intake and metastatizes almost exclusively via the blood stream, often to bones
  • the papillary carcinoma, on the contrary, is multifocal and associated with a previous radiation exposure, high iodine intake and metastatizes through lymphatic spread to regional lymph-nodes
  • Cytogenetics

    Cytogenetics morphological

    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
  • Genes Involved and Proteins

    Note

  • these abnormalities represent the cytogenetic mechanisms which activate the receptor tyrosine kinase (RTK) proto-oncogenes RET on chromosome 10 and NTRK1 on chromosome 1, respectively
  • the alternative involvement of the RET and NTRK1 tyrosine kinases receptors in the development of a consistent fraction (45%) of PTCs has been demonstrated
  • somatic rearrangements, both intra and interchromosomal, of RET and NTRK1 produce several forms of oncogenes
  • in all cases, RET or NTRK1 tyrosine kinase (TK) domains are fused to the amino-terminus of different gene products. The latter have been defined as activating genes.
  • Atlas Image

    Gene name

    RET (REarranged during Transfection)

    Location

    10q11.21

    Protein description

    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.

    Germinal mutations

    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

    Somatic mutations

    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

    Gene name

    CCDC6 (coiled-coil domain containing 6)

    Location

    10q21.2

    Gene name

    AKAP10 (A-kinase anchoring protein 10)

    Location

    17p11.2

    Gene name

    NCOA4 (Nuclear Receptor Coactivator 4)

    Location

    10q11.23

    Gene name

    NTRK1 (neurotrophic receptor tyrosine kinase 1)

    Location

    1q23.1

    Dna rna description

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

    Protein description

    NTRK1 is primarily expressed in the nervous system

    Germinal mutations

    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

    Gene name

    TPM3 (tropomyosin 3)

    Location

    1q21.3

    Gene name

    TPR (Translocated promoter region)

    Location

    1q31.1

    Gene name

    TFG (TRK-fused gene)

    Location

    3q12.2

    Result of the chromosomal anomaly

    Note

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

    Description

    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)

    Oncogenesis

    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

    To be Noted

    Note

    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

    Bibliography

    Pubmed IDLast YearTitleAuthors
    169460102007RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis.Ciampi R et al

    External Links

    Citation

    Marco A Pierotti

    Thyroid: Papillary carcinoma/Adenocarcinoma

    Atlas Genet Cytogenet Oncol Haematol. 2000-08-01

    Online version: http://atlasgeneticsoncology.org/solid-tumor/5053/papilthyroidcarid5053