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Multivariate Analysis of Chromosomal Imbalances in Breast Cancer Delineates Cytogenetic Pathways and Reveals Complex Relationships among Imbalances¹

Department of Clinical Genetics, University Hospital, SE-221 85 Lund [M. H., D. G., G. B. H., F. M.], and Department of Genetics, Lund University, SE-223 62 Lund [T. S.], Sweden

More than 550 breast adenocarcinomas with clonal chromosomal abnormalitieshave been reported. Although the aberration pattern is clearly nonrandom, no specific primary or secondary karyotypic abnormality has been identified, and furthermore the chronological order in which the aberrations appear during disease progression is not well known. The high degree of karyotypic complexity in epithelial tumors such as breast cancer is one reason why our understanding of the sequential order of cytogenetic evolution is unclear. To overcome some of these difficulties, we have used several statistical methods that allow identification and interpretation of karyotypic pathways. These methods were applied on 538 breast cancer karyotypes. The distribution of the number of imbalances/tumor showed a monomodal appearance, indicating that one single mode of karyotypic evolution is operating in this tumor type. We show that there exists a temporal order with respect to the appearance of chromosomal imbalances. The imbalances +1pq, 1q-, 3p-, and +7 appear earlier than expected from random events, and two cytogenetic pathways, one initiated by +1q and followed by 11q- and -22, the other initiated by either 3p- or 1q- and followed by 1p-, 3q-, and 6q-, can be discerned. We also show that +7 and +8q behave independently of the other imbalances and cannot, by simple means, be incorporated in the identified pathway scheme. Although the cytogenetic pathways are well separated at earlier stages, they later converge and include a common set of late imbalances.

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