[Microsatellite instability and allele-specific chromosome 3p deletion in breast cancer and precancerous lesions].
OBJECTIVE
To investigate the incidence and clinicopathologic significance of MSI and LOH on 3P in breast carcinoma and its precancerous lesions, intraductal papillary adenoma and ductal carcinoma in situ.


METHODS
41 paired sporadic invasive breast carcinomas, 13 archival precancerous lesion specimens of the breast and 14 couples of benign hyperplasia were collected. Twelve microsatellites on chromosomes 2p, 3p, 5q, 6q, 16q, 17q, eleven markers on chromosome 3p were amplified for MSI and LOH, respectively, by polymerase chain reaction ( PCR ) with designed primers and detecting after polyacrylamide gel electrophoresis. In addition, the expression of protein of hMSH2, hMLHI, FHIT, ER, and PR were detected by immunohistochemistry.


RESULTS
MSI was observed, at least two microsatellite markers, in 15 out of 41 (36. 6%) of the carcinomas, almost all belonging to poorly or intermediately differentiated carcinoma. Instability was shown in 9 of the 13 cases of precancerous lesions, but only 2 among them had more than 2 MSI sites. There was no MSI in benign hyperplasia. MSI was targeted predominately at D3S1766, D2S2739 in both carcinomas and precancerous lesions. Of the 11 loci examined, D3S1295, D3S1029 and D3S1038 were identified as the locus with most frequent LOH which were all correlated significantly with some clinicopathological parameters such as histological type, lymph node metastasis in breast cancer, while D3S1295 and D3S1029 were the most frequent markers in precancerous lesions. LOH of D3S1295 had significant correlation with negative expression of FHIT. Positive expression of hMLH1 and hMSH2 protein was detected in breast carcinomas in scattered distribution and their positive rate was 45% and 40% , respectively. In precancerous lesions, hMLH1 and hMSH2 protein showed diffuse expression and their positive rate was 61. 54% and 76. 92% , respectively, significantly lower than that in the control tissues.


CONCLUSIONS
Defective expression of MMR genes is closely associated with the development of breast cancer. Genomic instability might play a role in the early stage during multi-step mammary carcinogenesis. MSI indicates poor histological differentiation in breast carcinoma. D3S1766 and D2S2739 might be the sensitive sites to detect MSI in breast carcinoma and precancerous lesions. The smallest common LOH deletion regions seem likely to be situated between 3p14 and 3p25, indicating the existence of breast tumor related genes in those regions and some of them might affect tumor development.
Fu
Qiong
Q
Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310006, China.
Yao
Gen-you
GY
Tang
Xuan-li
XL
Chen
Li-rong
LR
Zheng
Zhen-xiao
ZX
D017766:Acid Anhydride Hydrolases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000099170:Bis(5'-adenosyl)triphosphatase; C501486:MLH1 protein, human; C088996:PMS1 protein, human