title: Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma.
abstract: Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid occurring sporadically and as a component of the multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma syndrome. The primary genetic cause of multiple endocrine neoplasia type 2 is germline mutation of the RET protooncogene. Somatic point mutations in RET also occur in sporadic MTC. Although RET mutation is likely sufficient to cause C-cell hyperplasia, the precursor lesion to MTC, tumor progression is thought to be due to clonal expansion caused by the accumulation of somatic events. Using the genome-scanning technique comparative genomic hybridization, we identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4) and their ligands glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, and Pacific Laboratory Medicine Services, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. debbie_marsh@med.usyd.edu.au
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: George
authors.initials: G
authors.lastname: Theodosopoulos
authors.forename: Klaus
authors.initials: K
authors.lastname: Martin-Schulte
authors.forename: Anne-Louise
authors.initials: AL
authors.lastname: Richardson
authors.forename: Jeanette
authors.initials: J
authors.lastname: Philips
authors.forename: Hans-Dietrich
authors.initials: HD
authors.lastname: Röher
authors.forename: Leigh
authors.initials: L
authors.lastname: Delbridge
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002116:Calcitonin / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000235:genetics*; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1; D002882:Chromosomes, Human, Pair 13; D002888:Chromosomes, Human, Pair 19; D002892:Chromosomes, Human, Pair 22; D002894:Chromosomes, Human, Pair 4; D029721:Drosophila Proteins; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D009693:Nucleic Acid Hybridization; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila