Abstract. There are two different pathways for the development of colorectal carcinoma (CRC), adenomacarcinoma 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.
An increasing number of tumor suppressor genes (TSGs) that are inactivated by hypermethylation of CpG islands in the promoter have been reported in gastric carcinomas. The aim of this study is to evaluate the clinical significance of TSG protein expression, which correlates with the promoter status, methylated or not, during the early stages of gastric carcinogenesis and to examine its relationship with mucin phenotype. The protein expression of 4 TSGs including Fhit, Mlh1, p16 INK4A and E-cadherin was examined using immunohistochemical methods in 103 early gastric neoplasias, comprising 41 adenomas and 62 intramucosal carcinomas, obtained by endoscopic mucosal resection. In addition, phenotypic expression patterns (gastric-, intestinal-and mixed-phenotypes) were also examined. The expression of Fhit, Mlh1, p16 and E-cadherin was lost or reduced in 7.3, 12.2, 12.2 and 9.8% of the adenomas and in 35.5, 29.0, 29.0 and 32.3% of the intramucosal carcinomas, respectively. The absent expression of p16 was significantly associated with the degree of dysplasia in the adenomas (p=0.038). The average number of proteins among the 4 TSGs, whose expression was lost or reduced per sample, was significantly higher in the intramucosal carcinomas (1.35) than in the adenomas (0.41) (p=0.00013). Similarly, the average number was significantly higher in the gastric-type tumors (2.05) than in the intestinal-type tumors (0.49) (p=0.0000019). We demonstrated an increase in the number of TSG proteins whose expression is reduced or lost in the early stages of gastric tumorigenesis, and that this increase is associated with histological grade and gastric phenotype.
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