Fhit, Mlh1, P53 and phenotypic expression in the early stage of colorectal neoplasms

Abstract

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.

Clinicopathological differences of colorectal cancers according to tumor origin: Identification of possibly de novo lesions

“…We also examined their correlation with particular clinicopathological characteristics (stage, grade and site). The study was conducted in a sample mainly comprising 'advanced' CRC (i.e., tumors invading beyond the submucosa), consistent with certain previous studies (7,12,13,20,23), although in contrast to most Japanese (5,6,10,18,19) and certain Western studies (8,11) focusing on early (T1) lesions. Consistent with the findings reported by Chen et al, the ascertained incidence of potentially de novo tumors in our series was 28.5% (12).…”

“…Moreover, de novo lesions exhibited a predilection for proximal tumor location (7,16), an association strongly suggesting genetic disparity, given the considerable predominance of the microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) tumorigenic pathways among proximal tumors (4). Other genetic and epigenetic alterations correlated with de novo tumors have also been detected (15,(17)(18)(19), although inconsistently (9,11).…”

Reduced FHIT Expression Is Associated with Mismatch Repair Deficient and High CpG Island Methylator Phenotype Colorectal Cancer

“…Failure to repair damages would instigate apoptosis, a process that is regulated by FHIT, as loss of FHIT relieves apoptotic stress. It is possible that FHIT plays a critical role in gastrointestinal (GI) cellular lineages' DNA replication control, since p53 does not seem to be effective in warding off the effects of replicative stress in the pathogenesis of GI cancer (Kitamura et al 2001;Gorgoulis et al 2005;Yasugi et al 2008). The specific association of high methylation with FHIT low expression would allow for the accumulation of aggressive genomic silencing that would provide the basis for tumor progression and invasion.…”

Squamous morula formation in colorectal adenoma: Immunohistochemical and molecular analyses

“…The SMCs of all four samples that we could fully examine expressed both cytokeratin 5/6 (cytoplasm) and ␤-catenin (cytoplasm and nucleus), whereas none of these samples expressed Ki-67, which indicates very low proliferative activity. Although p53 nuclear accumulation has been detected in 24-57% of colorectal adenomas having carcinoma components [16][17][18][19], none of the SMCs had any expression of p53. Cytokeratin 5/6, ␤-catenin, Ki-67 and p53 seem to be useful immunohistochemical markers for distinguishing between SMCs and progressive malignant components in colorectal adenomas.…”