Reduced Fhit expression is associated with mismatch repair deficiency in human advanced colorectal carcinoma

Abstract

The Fragile Histidine Triad gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumour suppressor gene involved in multiple tumour types including colorectal carcinomas. Recently, it has been reported that the Fragile Histidine Triad gene may be a target of damage in a fraction of mismatch deficient tumours. To explore this hypothesis, we analysed both Fragile histidine triad and mismatch repair protein (Msh2 and Mlh1) expression using immumohistochemical methods in 52 advanced colorectal carcinomas (19 well-, 17 moderately-, and 16 poorly-differentiated). In addition, we examined whether the Fragile histidine triad and mismatch repair protein expression correlated with p53 expression and clinicopathological findings. Significant loss or reduction of Fragile histidine triad expression was noted in 18 of the 52 (34.6%) advanced colorectal carcinomas: 2 (10.5%) well-differentiated, 3 (17.6%) moderately-differentiated, 13 (81.3%) poorly-differentiated carcinomas, the frequency being significantly higher in the latter than that in the former two (P<0.0001). Loss of mismatch repair protein (mainly, Mlh1) expression was detected in 21 of the 52 (40.4%) colorectal carcinomas. Moreover, reduced Fragile histidine triad expression was significantly associated with absence of mismatch repair protein expression in the advanced colorectal carcinomas (P<0.0001). However, the Fragile histidine triad and mismatch repair protein expression was not significantly associated with p53 expression. These results suggested that reduced Fragile histidine triad expression might be correlated with mismatch repair expression, but not with p53 expression.

Figure 1

Representative results of Fhit immunostaining in human normal and carcinomatous colorectal tissues. (A), Reduced immunostaining of a tumour and positive immunostaining of normal colonic epithelium; (B), Positive immunostaining of an invasive tumour

Figure 2

Representative results of Mlh1 and Msh2 immunostaining in human normal and carcinomatous colorectal tissues. A and B, Poorly-differentiated carcinoma cells (B) show no nuclear staining for Mlh1 while normal crypt epithelium (A) shows nuclear staining; (C) Normal crypt epithlium shows nuclear staining for Msh2; (D), Moderately-differentiated carcinoma cells show nuclear staining for Msh2