There are two different pathways for the development of colorectal carcinoma (CRC), adenoma-carcinoma sequence (ACS) and de novo (DN) carcinogenesis. To clarify the molecular and clinicopathological characteristics in colorectal carcinogenesis, we examined endoscopically resected specimens of 30 adenomas, 30 carcinoma in adenomas (CIAs), and 18 early pure colorectal carcinomas without any adenoma component (EPCs, so called DN carcinoma) and compared the expression of Fhit, Mlh1, Msh2, P53 and cellular phenotype (HGM, MUC2 and CD10). Markedly reduced or absent Fhit expression was noted in 8 (44%) of 18 EPCs, but none of the adenomas or CIAs (p<0.0001). Six (33%) of 18 EPCs showed loss of Mlh1 expression, but rarely in adenomas and CIAs (p=0.008). This altered Fhit expression was significantly higher in submucosal invasive cancers (p=0.001), lymphatic or venous invasive cancers (p=0.0018), and tumors with altered expression of Mlh1 (p=0.01). The incidence of P53 overexpression was significantly higher in EPCs (39%) and CIAs (27%) than in adenomas (3.3%) (p<0.05). There were significant differences in phenotypic expression between the adenomatous and carcinomatous areas. Moreover, in CIAs and EPCs, the rate of P53 overexpression was significantly higher in the CD10-positive cases (53%) than CD10-negative cases (19%) (p=0.04). The present findings suggested that aberrant Fhit and Mlh1 expression could be related to DN carcinogenesis and that P53 overexpression and changes in phenotypic expression could contribute to the malignant transformation of colorectal precursor lesions.