Radiation carcinogenesis in Mlh1 deficient mice

Abstract

Deficiencies in DNA mismatch repair (MMR) result in replication errors within key tumor related genes, and cause hereditary nonpolyposis colorectal cancer (HNPCC) and hematological malignancy. In this study, we examined the possible effects of MMR on radiation tumorigenesis using Mlh1 knockout mice. Mlh1-/- mice spontaneously develop intestinal tumors and lymphomas, and therefore are a good model for HNPCC. Irradiation of 2Gy to 2- or 10-week-old Mlh1-/- mice accelerated both lymphoma and intestinal tumor development. In order to infer the role of radiation, we analyzed mutations of tumor suppressor genes, Ikaros, in lymphomas. Spontaneous lymphomas frequently lacked Ikaros protein expression, which resulted from a frameshift mutation that created a stop codon. Lymphomas induced by radiation harbored a combination of multiple frameshift and point mutations. These results suggest that radiation accelerates replication errors, which is associated with an increased cell proliferation during recovery from massive cell death after irradiation. In addition, pre-existing pre-malignant cells may have chance to expand during recovery. In conclusion, MMR deficiency cooperates with radiation in tumorigenesis via enhancing replication errors. This study was supported by a grant from LRI by JCIA.