Exome of Radiation-induced Rat Mammary Carcinoma Shows Copy-number Losses and Mutations in Human-relevant Cancer Genes
Hitomi Moriyama, Kazuhiro Daino, Atsuko Ishikawa, Tatsuhiko Imaoka, Mayumi Nishimura, Yukiko Nishimura, Masaru Takabatake, Takamitsu Morioka, Kazumasa Inoue, Masahiro Fukushi, Yoshiya Shimada, Shizuko Kakinuma
Abstract
BACKGROUND/AIM: Our understanding of cancer risk from neutron exposure is limited. We aimed to reveal the characteristics of mammary carcinomas induced by neutrons. MATERIALS AND METHODS: Mammary carcinomas obtained from female Sprague-Dawley rats irradiated at 7 weeks of age with 0.97 Gy neutrons or 4 Gy γ-rays and from non-irradiated rats were classified into luminal and non-luminal subtypes by immunohistochemistry. Their mutational landscapes were determined by whole-exome sequencing. RESULTS: Neutrons significantly raised the incidence of luminal mammary carcinomas over the non-luminal subtype. Somatic mutations were identified in cancer genes involved in several signalling pathways, including Keap1/Nrf2, Pi3k/Akt and Wnt/β-catenin. Focal copy-number losses involving cancer genes were observed mainly in carcinomas from the irradiated rats. CONCLUSION: Neutrons increase the incidence of luminal mammary carcinomas, probably through gene mutations similar to those found in human breast cancers, and focal copy-number losses including cancer genes that are characteristics of radiation-induced mammary carcinomas.