BASE TRANSITIONS DOMINATE THE MUTATIONAL SPECTRUM OF A TRANSGENIC REPORTER GENE IN MSH2 DEFICIENT MICE

Tumors derived from individuals with hereditary nonpolyposis colorecta l cancer syndrome frequently demonstrate mutations in both alleles of hMSH2, a key gene in DNA mismatch repair (MMR). Sporadic tumors also f requently exhibit MMR deficiency. In keeping with the role of MMR in t he maintenance of genome integrity, mice deficient in MSH2 via gene ta rgeting demonstrate a high incidence of thymic lymphomas and small int estinal adenocarcinomas. To investigate the effects of MSH2 deficiency in normal tissues, mice containing a retrievable transgenic lad repor ter gene for mutation detection were crossed with MSH2(-/-) mice, Mice homozygous for MSH2 deficiency revealed 4.8, 11.0 and 15.2-fold eleva tions in spontaneous mutation frequency in DNA obtained from brain, sm all intestine, and thymus, respectively, as compared to heterozygous o r wild-type mice. Mutations most frequently recovered from MSH2(-/-) m ice were single base substitutions (77%), particularly base transition s (64%), Frameshifts occurred less frequently (19%) and fell within ve ry short (3-5 bp) mononucleotide runs. Thus the number of key growth c ontrol genes potentially impacted by MMR deficiency extends beyond tho se containing repetitive sequences. These results highlight the capaci ty for MSH2 deficiency to serve as a potent driving force during the m ulti-step evolution of tumors.