Distinctive patterns of Her-2/neu, c-myc, and cyclin D1 gene amplificationby fluorescence in situ hybridization in primary human breast cancers

Background: Human solid tumors undergo clonal evolution as they progress, b ut evidence for specific sequences of genetic changes that occur in individ ual tumors and are recapitulated in other tumors is difficult to obtain. Me thods: Patterns of amplification of Her-2/neu, c-myc, and cyclin D1 were de termined by fluorescence in situ hybridization (FISH) in relation to the pr esence of p53 dysfunction and ploidy in 60 primary human breast cancers. Re sults: We show that there are clusters of genophenotypic abnormalities that distinguish lobular breast cancers from nonlobular tumors; that cyclin Dt amplification occurs prior to the divergence of lobular breast cancers from nonlobular cancers; that p53 dysfunction, Her-2/neu amplification, and c-m yc amplification are characteristic features of nonlobular breast cancers, but not of lobular breast cancers; and that the frequencies of amplificatio n of all three oncogenes examined increase progressively with increasing an euploidy, but that each gene exhibits a different profile of increasing amp lification in relation to tumor progression. Early amplification of c-myc a ppears to be an especially prominent feature of hypertetraploid/hypertetras omic tumors. Conclusions: The data suggest that in tumors containing multip le abnormalities, these abnormalities often accumulate in the same cells wi thin each tumor. Furthermore, the same patterns of accumulation of multiple genophenotypic abnormalities are recapitulated in different tumors. (C) 20 01 Wiley-Liss, Inc.