Pattern of gene alterations in intraductal breast neoplasms associated with histological type and grade.

To reveal any association between the histological type and grade of intraductal breast neoplasms and the manner of accumulation of gene alterations, eight types of gene alterations, i.e., loss of heterozygosity (LOH) on chromosomal arms 16p, 16q, 17p, 17q, and 18q, amplification of the c-erbB-2 and hst-1/int-2 genes, and mutation of the p53 gene, were examined by Southern blot analysis or single-strand conformation polymorphism analysis in a total of 60 cases of intraductal breast cancer and 18 nonmalignant proliferative lesions. Among the histological types and three histological grade groups of intraductal carcinomas, the gene alterations which occurred most frequently were LOH on 16q alone in non-comedo type and Grade 1, alterations of c-erbB-2, 17p, and 16q in comedo type and Grade 2, and alterations of 17q and p53 as well as those of 16q, 17p, and c-erbB-2 in Grade 3. LOH on 16q and 18q was frequent in intraductal carcinoma of the intracystic papillary type, whereas LOH on 18q alone was detected in 27% of papillomas. Among intraductal carcinomas, the mean number of gene alterations was largest in comedo type and Grade 3, whereas it was smallest in non-comedo type and Grade 1. It was possible that LOH on 18q and 16q was involved frequently in papillary tumori-genesis and acquisition of malignant phenotype, respectively, whereas most of the other gene alterations were involved in acquisition of aggressive biological properties by intraductal carcinoma cells. It was also possible that the phenotype of breast neoplasms was determined by the combination of gene alterations at a relatively early developmental stage.