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

Background: Human solid tumors undergo clonal evolution as they progress, but evidence for specific sequences of genetic changes that occur in individual tumors and are recapitulated in other tumors is difficult to obtain. Methods: Patterns of amplification of Her‐2/neu, c‐myc, and cyclin D1 were determined by fluorescence in situ hybridization (FISH) in relation to the presence of p53 dysfunction and ploidy in 60 primary human breast cancers. Results: We show that there are clusters of genophenotypic abnormalities that distinguish lobular breast cancers from nonlobular tumors; that cyclin D1 amplification occurs prior to the divergence of lobular breast cancers from nonlobular cancers; that p53 dysfunction, Her‐2/neu amplification, and c‐myc amplification are characteristic features of nonlobular breast cancers, but not of lobular breast cancers; and that the frequencies of amplification of all three oncogenes examined increase progressively with increasing aneuploidy, but that each gene exhibits a different profile of increasing amplification in relation to tumor progression. Early amplification of c‐myc appears to be an especially prominent feature of hypertetraploid/hypertetrasomic tumors. Conclusions: The data suggest that in tumors containing multiple abnormalities, these abnormalities often accumulate in the same cells within each tumor. Furthermore, the same patterns of accumulation of multiple genophenotypic abnormalities are recapitulated in different tumors. Cytometry (Comm. Clin. Cytometry) 46:136–149, 2001. © 2001 Wiley‐Liss, Inc.