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Genetic predisposition to transplacentally induced renal cell carcinomas in the Eker rat
O Hino1, H Mitani, A G Knudson
1Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
Abstract:
N-Ethyl-N-nitrosourea-induced transplacental renal carcinogenesis in the rat results primarily in Wilms' tumors, apparently because primitive nephroblasts are the preferred target. Our question is whether N-ethyl-N-nitrosourea-induced mutations in the fetal kidney would increase the number of adult-type renal cell carcinomas in the Eker rat, which is heterozygous for a mutation that predisposes to renal cell carcinoma. Surprisingly, renal cell tumors but no Wilm's tumors began to appear from as early as 1 week after birth. Thus, the inheritance of a renal cell carcinoma mutation determines the specificity of tumor histology even with in utero carcinogenesis.
Insights
N-Ethyl-N-nitrosourea exposure during gestation causes kidney tumors in rats. Inherited mutations predisposing to cancer specifically lead to adult-type renal cell carcinomas, not Wilms' tumors, even with in utero exposure.
Area of Science:
- Oncology
- Developmental Biology
- Toxicology
Background:
- N-Ethyl-N-nitrosourea (ENU) is a known transplacental carcinogen.
- Prenatal exposure to ENU in rats typically induces Wilms' tumors.
- The Eker rat model is heterozygous for a mutation predisposing to renal cell carcinoma.
Purpose of the Study:
- To investigate if ENU-induced mutations in fetal kidneys alter tumor type in Eker rats.
- To determine if genetic predisposition influences transplacental carcinogenesis outcomes.
Main Methods:
- Transplacental administration of N-Ethyl-N-nitrosourea to pregnant Eker rats.
- Histopathological examination of offspring kidneys for tumor development.
- Analysis of tumor types (Wilms' tumors vs. renal cell carcinomas).
Main Results:
- Renal cell carcinomas, not Wilms' tumors, were observed in offspring.
- Tumor development was evident as early as one week after birth.
- The presence of the inherited mutation dictated tumor histology.
Conclusions:
- Inherited genetic mutations can override the typical carcinogenic pathway induced by N-Ethyl-N-nitrosourea.
- The Eker rat model demonstrates that genetic predisposition determines tumor specificity in transplacental carcinogenesis.
- This highlights the critical role of germline mutations in cancer development, even under potent exogenous carcinogen exposure.