Genetic factors behind susceptibility to radiation-induced cancer identified in model mice

A research group including Assistant Professor Silvia Natsuko Akutsu, Graduate Student Risa Matsumura, Associate Professor Takaki Asano, Professor Shinya Matsuura, Professor Megumi Sasatani, and Professor Shinji Yoshinaga at the Research Institute for Radiation Biology and Medicine, Hiroshima University, alongside Professor Tatsuo Miyamoto at the Graduate School of Medicine, Yamaguchi University, created model mice possessing mutations in the MRE11 gene found from patients with ataxia telangiectasia-like disorder (ATLD) using genome editing. Investigating the model mice, it was found that when receiving radiation under specific genetic conditions, the number of tumors formed in the small intestine increases significantly. The results were published in Scientific Reports.

In diseases where mechanisms repairing DNA when damaged do not work well, individuals are vulnerable to radiation, and many may develop constitutions prone to cancer. As a representative disease, ataxia-telangiectasia (AT) caused by the ATM gene is known. On the other hand, ATLD is a rare autosomal recessive disorder onset by MRE11 gene mutations. While exhibiting cerebellar ataxia, oculomotor apraxia, and dystonia similar to AT, it differs from AT in points of not showing cancer predisposition. Clinical diversity of ATLD patients is considered to originate from types of MRE11 gene mutations. To date, approximately 20 different kinds of mutations have been reported from 39 cases. While radiation sensitivity is enhanced in ATLD accompanying MRE11 mutations, potential impacts that these mutations exert on carcinogenesis predisposition have not been clarified sufficiently.

The research group introduced a mutation (A47V) in the MRE11 gene found in a patient with ATLD into mice, investigating how much tumors increase when receiving radiation. In a 2-year-old boy with ATLD, 2 changes were found in the MRE11 gene: an A47V (c.140C>T) missense mutation and a c.658A>C splice mutation.

The research group created mice possessing A47V, crossed them with Apc^Min/+ mice, and irradiated 2 Gy of radiation. Subsequently, at 24 weeks of age, observing small intestines, they counted the number of tumors.

As a result, even in cases of not applying radiation, mice where 2 of A47V were present (homozygotes) tended to possess many tumors. Applying radiation, tumors increased in mice of any genotype, but it was found that in mice where 2 of A47V were present, they increased particularly significantly.

From these results, when 2 of A47V are present, possibilities were shown of becoming constitutions where tumors are likely to increase via radiation. This achievement serves as an important clue in understanding mechanisms of carcinogenesis caused by radiation. In addition, it is expected to serve usefully as a new model evaluating "susceptibility to cancer" in DNA repair disorders.

Journal Information
Publication: Scientific Reports
Title: ATLD-derived MRE11 variant enhances radiation-induced intestinal tumorigenesis in Apc^Min/+ mice
DOI: 10.1038/s41598-026-66205-w