The Relationship Between Chromosome Instability Of 16q,17p And Pathogenesis Of Breast Carcinoma

Objective: To detected the frequencies of loss of heterozygosity(LOH)/microsatellite instability(MSI)in usual breast hyperplasia(UDH),atypical hyperplasia(ADH),ductal carcinoma in situ(DCIS)and invasive ductal breast carcinoma(IDC)on chromosome 16 q and 17 p,and the abnormal methylation of promoter in p53 and CDH13 genes.To search for significant molecular markers which could be used to evaluate the UDH progressing IDC.Method: 101 breast lesions which composed of UDH(n=31),ADH(n=10),DCIS(n=32)and IDC(n=28)were examined the LOH/MSI frequencies of 13 micro loci on 16 q and 17 p by PCR-SSCP.Methylation specific PCR(MS-PCR)method and agarose gel electrophoresis were used to detect the abnormal methylation of p53 and CDH13 genes.Results: The frequencies in DCIS group and IDC group were significant higher than UDH group(P<0.05),respectively.The frequencies of D16S515,D16S507,D16S422 on 16q23,and D17S261 on 17p12,and D17S654 on 17p13 were31.7%,21.8%,30.7%,25.7%,22.8%(P<0.05).After pairwise comparison,the results shown that the frequencies of LOH/MSI in UDH group were significantly lower than ADH,DCIS,and IDC groups(P<0.05)on D16S507 and D16S515 locations;The occurrence frequency of LOH/MSI on D17S654 and D16S422 the UDH group was significantly lower than DCIS group and IDC group(P<0.05);UDH on the D17S261 group was significantly lower than the IDC group(P<0.05).In the IDC group,the MS on 16 q and 17 p were significantly correlated with the frequency of LOH/MSI.Aberrant methylations of CpG islands in the promoter region of p53 and CDH13 in UDH were very low,but p53 in breast carcinoma were significantly higher than UDH group and ADH group(P<0.05);CDH13 in breast carcinoma were significantlyhigher than UDH group(P<0.05).In UDH group and IDC group,the LOH/MSI were correlated with p53 methylation(P<0.05);Analyzed the correlation between chromosome LOH/MSI and CDH13 gene methylation,UDH group and IDC group were positive correlated(P<0.05).There was no significant difference in the incidence of abnormal methylation of p53 and CDH13 gene promoter and the incidence of LOH/MSI in four groups of breast ductal lesions(P>0.05).Conclusions:The changes in LOH/MSI at sites D16S515,D16S507,D16S422 and D17S654,D17S261 may play a key role in the development of UDH for IDC,an early molecular event of breast cancer.Abnormal methylation of the promoter of p53 gene may be involved in the early molecular events of UDH and ADH development for IDC.Abnormal methylation of promoter of CDH13 promoter may be one of the important molecular biology markers of UDH development for IDC.