Abstract
Deficiencies in DNA mismatch repair (MMR) result in replication errors that cause frameshift mutations and/or point mutations within key tumor suppressor genes or oncogenes. Heterozygous germline mutations in MMR genes are the cause of hereditary nonpolyposis colorectal cancer (HNPCC). In these cancers, mutations in mononucleotide repeat sequences in TGFbRII, BAX, etc. have been frequently reported. Homozygous germline mutations of MMR genes are also manifested by an early onset of childhood T- or B-cell leukemia, but the target gene was not identified yet. Mlh1-/- mice spontaneously develop T-cell lymphoma and colorectal tumor from 10-week-old and 15-week-old, respectively. In this study, we aimed to determine the age dependency of colorectal tumor induction after exposure to radiation, and to clarify the histological and molecular characteristics of the tumors.
For induction of colorectal tumor, Mlh1+/+, Mlh1+/-, and Mlh1-/- mice were exposed to whole-body X-irradiation at 2 Gy at the age of 2 or 7-week-old, and/or treated with 10% dextran sulfate sodium (DSS) in their drinking water for one week at the age of 10-week-old. Thymectomy was performed at 4 weeks of age to exclude the confounding of T-cell lymphomas. All mice were scarified at the 25-week-old.
The incidence of colorectal tumor in Mlh1-/- mice was 10% and 0% after irradiation at the age of 2 and 7-week-old, respectively. DSS treatment only resulted in 40%. In the group with combined exposure, tumor induction increased 70% and 50%, respectively. Irradiation at 2-weeks of age increased the number of tumors compared with the irradiation at 7-week-old. This indicates that infant mice are slightly more susceptible to radiation than adults. Mlh1+/+ mice did not induce any intestine tumor in this study. The pathological and molecular analyses of induced tumors will be shown.
