Interstitial chromosomal deletion of the Tsc2 locus is a signature for radiation-associated renal tumors in Eker rats.

Ionizing radiation can damage DNA and thus is a risk factor for cancer. Eker rats, which carry a heterozygous germline mutation in the tumor-suppressor gene Tsc2, are susceptible to radiation-induced renal carcinogenesis. However, the molecular mechanisms involved in Tsc2 inactivation are unclear. We subjected Fischer 344 × Eker (Long Evans Tsc2+/- ) F1 hybrid rats to gamma-irradiation (2 Gy) at gestational day 19 (GD19) or postnatal day 5 (PND5) and investigated the patterns of genomic alterations in the Tsc2 allele of renal tumors that developed at 1 year after irradiation (N = 24 tumors for GD19, N = 10 for PND5), in comparison with spontaneously developed tumors (N = 8 tumors). Gamma-irradiation significantly increased the multiplicity of renal tumors. The frequency of LOH at the chromosome 10q12 region, including the Tsc2 locus, was 38%, 29%, and 60% in renal carcinomas developed from the nonirradiated, GD19, and PND5 groups, respectively. Array CGH analysis revealed that the LOH patterns on chromosome 10 in renal carcinomas were classified into chromosomal missegregation, mitotic recombination and chromosomal deletion types. LOH of the interstitial chromosomal deletion type was observed only in radiation-associated carcinomas. Sequence analysis for the wild-type Tsc2 allele in the LOH-negative carcinomas identified deletions (nonirradiated: 26%; GD19: 21%) and base-substitution mutations (GD19: 4%). Reduced expression of Tsc2 was also observed in the majority of the LOH-negative carcinomas. Our results suggest that interstitial chromosomal deletion is a characteristic mutagenic event caused by ionizing radiation, and it may contribute to the assessment of radiation-induced cancer risk.

Cancer science. 2020 Jan 11 [Epub ahead of print]

Tatsuya Inoue, Toshiaki Kokubo, Kazuhiro Daino, Hiromi Yanagihara, Fumiko Watanabe, Chizuru Tsuruoka, Yoshiko Amasaki, Takamitsu Morioka, Shino Homma-Takeda, Toshiyuki Kobayashi, Okio Hino, Yoshiya Shimada, Shizuko Kakinuma

Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan., Laboratory Animal and Genome Sciences Section, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan., Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan., Department of Pathology and Oncology, Juntendo University Faculty of Medicine, Tokyo, 113-8421, Japan., National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan.

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