RET oncogene amplification in thyroid cancer: correlations with radiation-associated and high-grade malignancy.
A radiation etiology is well known in thyroid carcinogenesis. RET oncogene rearrangement is the most common oncogenic alteration in Chernobyl-related papillary thyroid cancer (PTC). To find the characteristic alteration associated with RET rearrangements in radiation-induced thyroid cancers, we analyzed the RET oncogene by fluorescence in situ hybridization. The fluorescence in situ hybridization technique has the possibility of detecting RET rearrangements at a single-cell level regardless of the specific fusion partner involved and directly reveals RET copy number on a per-cell basis. Our study demonstrated RET amplification in all 3 cases of radiation-associated thyroid cancers but not in sporadic well-differentiated PTC (n = 11). Furthermore, RET amplification was observed in all 6 cases of sporadic anaplastic thyroid cancers (ATCs). The frequency of RET amplification-positive cells was higher in ATC (7.2%-24.1%) than in PTC (1.5%-2.7%). The highest frequency of RET amplification-positive cells was observed among ATC cases with a strong p53 immunoreactivity. In conclusion, we found RET amplification, which is a rare oncogenic aberration, in thyroid cancer. This report is the first one to suggest the presence of RET amplification in PTC and ATC. RET amplification was correlated with radiation-associated, high-grade malignant potency, and p53 accumulation, suggesting genomic instability. RET amplification might be induced by a high level of genomic instability in connection with progression of thyroid carcinogenesis and, subsequently, be associated with radiation-induced and/or high-grade malignant cases.
Nakashima
Masahiro
M
Tissue and Histopathology Section, Division of Scientific Data Registry, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan. moemoe@nagasaki-u.ac.jp
Takamura
Noboru
N
Namba
Hiroyuki
H
Saenko
Vladimir
V
Meirmanov
Serik
S
Matsumoto
Naomichi
N
Hayashi
Tomayoshi
T
Maeda
Shigeto
S
Sekine
Ichiro
I
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human