Ret/PTC activation in benign and malignant thyroid tumors arising in a population exposed to low-dose external-beam irradiation in childhood.
Ionizing radiation is the strongest risk factor known for the development of thyroid neoplasia. Although ret/PTC rearrangements have been identified in both spontaneous and radiation-induced papillary thyroid cancer, they seem more frequent among radiation-associated tumors. We studied the frequency of ret/PTC activation in a group of sporadic and radiation-induced thyroid carcinomas (n = 49) and adenomas (n = 13) among 44 individuals treated for Tinea Capitis with low-dose external irradiation as well as in 18 nonirradiated subjects. Total RNA recovered from paraffin-embedded thyroid cancer surgical specimens was analyzed for ret/PTC 1, 2, and 3 mutations using RT-PCR with Southern blotting to maximize detection sensitivity. Ret/PTC rearrangements were identified in 42.9% of thyroid carcinoma and 46.2% of adenoma subjects. Among the positive carcinoma specimens, three were follicular carcinomas. Ret/PTC 1, the predominant rearrangement, was more prevalent in nonirradiated compared with irradiated carcinomas (66.7 vs. 27.0%; P = 0.04). Ret/PTC activation was associated with male gender. The strengths of this study included analysis of age-, gender-, and ethnicity-matched groups; molecular analysis using two techniques; and a complete blinding of laboratory analysis from clinical features. The differences seen between these and other published results may be related to differences in radiation doses to the thyroid, latency period between time of radiation exposure and development of clinically apparent thyroid cancer, and ethnic background of the study populations.
Sadetzki
Siegal
S
The Cancer Epidemiology Unit, Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. siegals@gertner.health.gov.il
Calderon-Margalit
Ronit
R
Modan
Baruch
B
Srivastava
Shefali
S
Tuttle
R Michael
RM
D000236:Adenoma / Q000378:metabolism*; D000328:Adult; D002277:Carcinoma / Q000378:metabolism*; D016022:Case-Control Studies; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism*; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D016037:Single-Blind Method; D013964:Thyroid Neoplasms / Q000378:metabolism*; D014006:Tinea Capitis / Q000532:radiotherapy; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human