title: Assessment of RET/PTC oncogene activation and clonality in thyroid nodules with incomplete morphological evidence of papillary carcinoma: a search for the early precursors of papillary cancer.
abstract: Noninvasive thyroid nodules that exhibit borderline morphological signs of papillary cancer are difficult to diagnose and we do not know if they represent papillary carcinoma precursor lesions. Forty-six such nodules were analyzed for RET activation by immunohistochemistry and, in selected cases, by reverse transcriptase-polymerase chain reaction performed on RNA extracted after laser capture microdissection (LCM) of the tumor foci with and without papillary carcinoma features and positive RET immunoreactivity. RET immunoreactivity was identified, at least focally, in 30 of 46 (65.2%) of the nodules where it closely paralleled the morphological changes. Enough RNA was obtained after LCM in seven samples. RET/PTC1 or RET/PTC3 were detected in microscopic foci with papillary carcinoma features in most of the thyroid nodules (five of seven cases). No RET/PTC1 or RET/PTC3 rearrangements were detected in areas of the same tumors that lacked the cytological alterations. Analysis of clonality in the same nodules selected for LCM demonstrated that two were monoclonal and six were polyclonal. We conclude that RET activation closely parallels the morphological changes, that it is restricted to those areas of the tumor with the cytological alterations and that it is detectable in both mono- and polyclonal tumors. Although the finding of microscopic foci indicative of papillary carcinoma in a hyperplastic or adenomatous nodule does not justify the interpretation of the entire lesion as papillary carcinoma, it is possible that such foci may precede the development of invasive papillary cancer.
authors.affiliation: Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Gennaro
authors.initials: G
authors.lastname: Chiappetta
authors.forename: Pei
authors.initials: P
authors.lastname: Hui
authors.forename: Ginesa
authors.initials: G
authors.lastname: Garcia-Rostan
authors.forename: Lauren
authors.initials: L
authors.lastname: Golden
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Kinder
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Dillon
authors.forename: Ada
authors.initials: A
authors.lastname: Giuliano
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cirafici
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.forename: Juan
authors.initials: J
authors.lastname: Rosai
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000473:pathology*; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D016606:Thyroid Nodule / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors
chemical_list: D029721:Drosophila Proteins; D005819:Genetic Markers; D008565:Membrane Proteins; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011518:Proto-Oncogene Proteins; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C093573:ret-PTC fusion oncoproteins, human