GENETIC POLYMORPHISMS AND SUSCEPTIBILITY TO CANCER DEVELOPMENT

Humans show heterogeneous susceptibility to cancer development, sugges ting the involvement of various genetic backgrounds in control of the production of endogenous carcinogens, the metabolism of carcinogens, t he repair of DNA damage, cell proliferation and defence mechanisms inc luding immune reactions. Gastric cancer is the major cancer in Japan. However, little is known about the genes linked with its development. In 1967, we found that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) ind uced gastric cancers in Wistar rats. Subsequently the Buffalo strain o f rats was reported to be resistant to MNNG stomach carcinogenesis, wh ile ACI rats were very sensitive. In a carcinogenesis study using F-1 and F-2 rats, we suggested that this trait of MNNG stomach carcinogene sis-resistance was regulated by a single autosomal dominant allele. Th e O-6-methylguanine adduct levels in gastric mucosa induced by MNNG we re the same in Buffalo and ACI rats, but cell proliferation induced by MNNG was much higher in ACI than Buffalo animals. Chromosome mapping of the gene responsible for susceptibility to MNNG-induced carcinogene sis is now in progress and its identification will hopefully give us c lues to the involvement of genetic traits in susceptibility to gastric cancer in humans. In addition, the genetic background of susceptibili ty to breast cancer is also being studied. In Japan, about 5% of all c ases of breast cancer are familial. We have studied BRCA1, the breast cancer susceptibility gene, as a determinant of susceptibility to brea st cancer by linkage analyses in 11 families, but our results indicate that BRCA 1 may not be important for development of familial breast c ancer in Japanese, New information on genetic backgrounds should make cancer prevention scientifically more rational and practically more ef ficient.