The Relationship Between Chromosome Instability Of 1p、3p And Breast Carcinoma

Purpose: To detect the rules of loss of heterozygosity(LOH) /micro--satellite instability(MSI) in usual breast hyperplasia(UDH), atypical hyperplasia(ADH), ductal carcinoma in situ(DCIS) and invasive ductal breast carcinoma(IDC) on chromosome 1p and 3p, and the clonal origin in all groups have been analyzed. To investigate the alterations of genetic features for the ductal hyperplasia lesions progressing to invasive breast cancer. Method: The cases of UDH(n=25), ADH(n=10), DCIS(n=32) and IDC(n=30) were selected after the neutral buffered formalin fixed and paraffin embedding. PCR-SSCP was used to detect the LOH/MSI on 15 loci which were D1S193, D1S463, D1S2881, D1S2885, D1S234, D1S252, D1S368, D1S2885, D1S2137, D3S1038, D3S1067, D3S1067, D3S1076, D3S1583, D3S659, D3S1228, D3S1611. The restriction fragment length poly morphism Hpaâ…¡ and nested PCR amplification were analyzed the inactivation of androgen receptor(AR) gene on X-chromosome for clonal analysis. Results: 1. The total frequencies of LOH/MSI were 32.0% in UDH,40.0% in ADH,59.4% in DCIS and 60.0% in IDC, respectively. And compared to each group, the significant difference were not found(P=0.114). 2. The frequencies of LOH/MSI on 1p were 8.2% in D1S368, 23.7% in D1S463, 16.5% in D1S193, 9.3% in D1S2137, 14.4% in D1S252, 11.3% in D1S2881, 15.5% in D1S2885 and 3.1% in D1S234. The comparison among groups of UDH, ADH, DCIS and IDC were shown any significant difference(P>0.05). Only on D1S463, the frequency of UDH group was lower than DCIS(P<0.008) and IDC group(P<0.008), but appeared any difference with other group(P>0.008). 3. The frequencies of LOH/MSI on 3p were 12.0%, 20.0%, 46.8%, 53.3% in group of UDH, ADH, DCIS and IDC, respectively. To compare among groups of UDH, ADH, DCIS and IDC, the results were shown significant difference between UDH and DCIS(P<0.05); UDH and IDC(P<0.05); however, the significant differences were not detected between other groups(P>0.05); the frequencies of LOH/MSI on D3S1038 were 4.2%, 10.0%,15.6%, 33.3% in group of UDH, ADH, DCIS and IDC, respectively; the group of UDH was lower than IDC(P<0.008).4. The results of Correlation detection in UDH, ADH, DCIS were not found any relationship of LOH/MSI between 1p and 3p(P>0.008). In IDC group, the significant positive correlation between 1p and 3p(P<0.05). 5. The results of clonal analysis showed 22 cases of UDH were polyclone and 2 cases were monoclone,and 8 cases of ADH were polyclone and 2 cases were monoclone. But all cases of DCIS(n=30) and IDC were monoclone(n=30). 6. In UDH group, LOH/MSI occurrence and monoclonal feature revealed positive correlation(P<0.05), the correlation coefficient was 0.426. But no significant correlation was found between LOH/MSI and monoclonal origin(P>0.05) in ADH group. Conclusion: 1. The genetic instability on chromosome 1p and 3p are early events for the development of breast carcinoma, and the alterations of D1S463 and D3S1038 maybe play a key role for ductal hyperplasia progressing to carcinoma. 2. The cases of UDH which companies LOH/MSI with monoclonal origin maybe the precursor lesions for invasive ductal carcinoma.