The drs gene was originally isolated as a transformation suppressor gene against the v-src oncogene. Expression of drs mRNA is down-regulated by retroviral oncogenes such as v-src and v-K-ras in the rat cell line F2408. Expression of drs mRNA is also markedly reduced in a variety of human cancer cell lines, including those of carcinomas of the colon, bladder, and ovary, suggesting that down-regulation of drs mRNA is correlated with the development of human cancers. To clarify the correlation between down-regulation of the drs gene and malignant tumor formation in human colorectal neoplasms, we examined expression of drs mRNA in a variety of colon cancer tissues by in situ hybridization. A total of 53 morphologically distinct neoplastic specimens were divided into the following five groups according to morphology: low and high grade adenoma in 7 and 12 cases, respectively (groups A, B), protruded-type carcinoma in 16 (group C), superficial-type carcinoma with an adenomatous component in 10 (group D) or superficial-type carcinomas without any adenomatous component in 8 (group E). Expression of drs mRNA was detected in normal mucosa, low-grade adenoma and most superficial-type carcinomas without any adenomatous component. On the other hand, the rate of drs mRNA expression was significantly lower in protruded-type adenocarcinoma and superficial-type carcinoma with an adenomatous component. Our results indicate that down-regulation of drs mRNA is closely correlated with carcinomas which arise from adenomatous polyps in the course of the adenoma-carcinoma sequence, but that most carcinomas arising de novo are independent of the tumor suppressor function of the drs gene.