Alterations Of FHIT, BRCA2, MLH1 And P53 And Hereditary Susceptibility In Esophageal Cancer From The Patients At High-incidence Area For Esophageal Cancer In Linzhou, Henan

Esophageal cancer (EC) is one of the six most common malignant diseases worldwide, and is particularly prevalent in northern China. A remarkable epidemiological characteristic for EC is the dramatic familial aggregation. Several genetic epidemiology surveys have demonstrated that there is evident familial aggregation in Linzhou city or other high-incidence areas for EC; and the members in EC aggregation families (ECAF) have higher risk than the members in sporadic EC families (SECF), and the descendants with positive EC history have even higher tumor liability than those with negative EC history. These studies suggest that genetic factors may play an important role in esophageal carcinogenesis, and especially in those from EC aggregation families.The molecular mechanism underlying the familial aggregation for EC is not clear.Studies in the past decades have indicated that the familial EC liability may be related with the chromosome instability (especially fragile sites) and the disfunction of the DNA damage repair. The gene rearrangement, fragmentation and deletion occur frequently in these fragile sites in human malignant diseases. These fragile sites usually contain tumor suppressor genes or oncogenes, which may be the key molecular basis for human carcinogenesis. The detection rate of the fragile sites of the members in ECAF was obviously higher than these in SECF. There was a close relationship between the fragile sites (especially common fragile sites) and the familial EC liability. In some DNA repair-deficiency tumors, such as breast cancer and large intestine carcinoma, abnormal expression of FHIT obviously step up. Besides, in some cell lines with repair-deficiency, the chromosome breaks have been observed obviously to frequently generate, which indicate that the DNA repair-deficiency may contribute to the chromosome instability, and make the genes easy abnormity in fragile sites. However, the role of the chromosome instability and the disfunction of the DNA damage repair in EC with or without positive family history (ECFH+, ECFH-) and hereditary susceptibility have not been well characterized.To further elucidate the possible mechanisms of esophageal carcinogenesis and the genetic affectability in ECFH+, the present study was undertaken to analyze thealterations of FHIT, BRCA2, MLH1 and P53 in ECFH+ and ECFH-, which may provide molecular clue for high-risk subjects screening and early diagnosis.Materials and MethodsSeventy-four EC patients were enrolled in this study. Of these patients, 33 were ECFH+ with a mean age of 56 ±9 years, and 41 were ECFH- with a mean age of 56 ±9 years. ECFH+ patients come from the families that there were >2 EC patients incontinuous two generations. ECFH- patients were patients without EC and other tumors positive history. All the patients were from Linzhou City. All the surgically resected EC samples were collected from the centre hospital in Linzhou. All the specimens were fixed with 85% ethanol, and paraffin embedded, and serially sectioned for morphology and immunohistochemistry (ABC) analysis. All the EC cases were histopathologically confirmed as squamous cell carcinoma (SCC).The difference in immunoreactivity of BRCA2, MLH1, FHIT, P53 and its correlation with cancer progression and the EC familial genetic affectability was determined on the subjects from ECFH+ and ECFH- cases. The X2 test, matched-pairs chi-square test and Spearman Correlation test were used for the statistic analysis, (p<0.05 was considered significant).ResultsThe negative expression of FHIT gene was significantly higher in ECFH+ (56%, 18/33) than ECFH- (27%, 11/41, p<0.01). The negative expression of BRCA2 gene was significantly higher in EC tissue from the ECFH+ than from the ECFH- (67%, 22/33 vs. 37%, 15/41, p<0.01). The negative expression rate for MLH1 in the ECFH+ (73%, 24/33) was higher than in the ECFH- (27%, 16/41), the difference was significant, (p<0.05). Although the positive expression rate for P53 in ECFH+ (52%, 17/33) was higher than in ECFH- (46 %, 19/41), the difference was not significant, (p >0.05).The negative expression of FHIT gene in EC tissue (39%, 29/74) was much higher than in normal tissue (3%, 1/30) from the high incidence area for EC in Linzhou, (p <0.01). The negative expression of BRCA2 gene in EC tissue (50%, 37/74) was much higher than in normal tissue (13%, 4/30) from the high incidence area for EC in Linzhou,(p<0.01).The rates of concordance the negative expression of BRCA2 and FHIT, MLHl and FHIT in ECFH+ were higher than in ECFH- (39%, 36% vs. 2%, 12%, p<0.05). The rates of consistent negative expression of BRCA2 and MLHl in ECFH+ were higher than in ECFH- (45% vs. 12%, p<0.05). The disconsistent expression rates for P53 and MLHl (P53 positive, MLHl negative) in ECFH+ were higher than in ECFH-(36% vs. 15%,p<0.05).The detection rates of lymph node metastasis were higher in ECFH+ cases (39%, 16/41) than in those of ECFH- cases (18%, 6/33), (P<0.05). The negative expression rates of BRCA2 in female was higher than in those male (37%, 5/41 vs. 27%, 9/33) in ECFH-, (P<0.05).The negative expression of BRCA2, MLHl and FHIT and the positive expression of P53 did not show correlation with gender, EC differentiation, infiltration degree and lymph metastasis, (P>0.05).ConclusionsThe higher negative expression of FHIT and BRCA2 in EC tissue than in normal tissue from the high incidence area for EC in Linzhou, indicates that these molecular changes may be involved in the esophageal carcinogenesis. The higher negative expression rates of FHIT, BRCA2 and MLHl expect the positive expression of P53 in ECFH+ and ECFH- suggest that FHIT, BRCA2 and MLHl may play an important role in the EC familial hereditary susceptibility, and P53 may be an important synergistic agent in the process.The rates of concordance the negative expression of BRCA2 and FHIT, MLHl and FHIT, BRCA2 and MLHl in ECFH+ than in ECFH- and the disconsistent expression rates for MLHl and P53 (P53 positive, MLHl negative) in ECFH+ were higher thanin ECFH- indicate that there may be different molecular mechanism involved in EC carcinogenesis. However, no relationship between the abnormal expression of FHIT and the anomalous expression of BRCA2, MLH1 and P53 was observed, which indicate that these molecules may cooperate with other susceptible factors in the familial carcinogenesis.