Genetic polymorphisms and susceptibility to cancer development.
Humans show heterogeneous susceptibility to cancer development, suggesting the involvement of various genetic backgrounds in control of the production of endogenous carcinogens, the metabolism of carcinogens, the repair of DNA damage, cell proliferation and defence mechanisms including 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) induced gastric cancers in Wistar rats. Subsequently the Buffalo strain of rats was reported to be resistant to MNNG stomach carcinogenesis, while ACI rats were very sensitive. In a carcinogenesis study using F1 and F2 rats, we suggested that this trait of MNNG stomach carcinogenesis-resistance was regulated by a single autosomal dominant allele. The O6-methylguanine adduct levels in gastric mucosa induced by MNNG were 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 carcinogenesis is now in progress and its identification will hopefully give us clues to the involvement of genetic traits in susceptibility to gastric cancer in humans. In addition, the genetic background of susceptibility to breast cancer is also being studied. In Japan, about 5% of all cases of breast cancer are familial. We have studied BRCA1, the breast cancer susceptibility gene, as a determinant of susceptibility to breast cancer by linkage analyses in 11 families, but our results indicate that BRCA1 may not be important for development of familial breast cancer in Japanese.(ABSTRACT TRUNCATED AT 250 WORDS)
Sugimura
T
T
National Cancer Center Research Institute, Tokyo, Japan.
Inoue
R
R
Ohgaki
H
H
Ushijima
T
T
Canzian
F
F
Nagao
M
M
D000818:Animals; D019313:BRCA1 Protein; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008126:Lod Score; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics; D011110:Polymorphism, Genetic; D051381:Rats; D011912:Rats, Inbred ACI; D011915:Rats, Inbred BUF; D017208:Rats, Wistar; D013045:Species Specificity; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D019313:BRCA1 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors; D008769:Methylnitronitrosoguanidine