Accumulation of genetic alterations and progression of primary breast cancer.

In order to detect common regions of deletion, 219 breast tumors were examined for loss of heterozygosity at several loci on chromosomes 3p, 16q, and 17 by restriction fragment length polymorphism analysis. Allelic deletions of loci on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, were analyzed and compared with histopathological and clinical features. Common regions of deletion were detected within chromosomal bands 3p13-14.3, 16q22-23, 17p13 (two separated loci), and 17q21. Concordant losses of alleles on chromosomes 3p, 13q, 16q, 17p, and 17q were observed. A significant association was detected between loss of heterozygosity on chromosomes 17p and 17q and amplification of the erbB2 oncogene (17p, P = 0.000721, by Fisher's exact test; 17q, P less than 0.001, chi 2 = 12.135). Furthermore, tumors showing highly malignant phenotypes had accumulated more genetic changes at the loci studied than those having less malignant phenotypes on the basis of histopathological classification, lymph node metastasis, and tumor size. These results suggested that accumulation of genetic alterations, including loss of function of tumor suppressor genes on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, may contribute to tumor development and/or progression in primary breast cancer.