(Authors 1, 3, 4, 5, 8): UCSF Cancer Center, UCSF
(Author 2): UCSF Cancer Center, UCSF, and Geraldine Brush Cancer Center, California Pacific Medical Center
(Author 6): Dept. Pathology, Northwestern University
(Author 7): Dept. Pathology, and UCSF Cancer Center, UCSF
Tumor progression is thought to occur through multiple genetic events, presumably by a process of tumor evolution occurring through selection of individual tumor clones. We have used comparative genomic hybridization to study clonal evolution in solid tumors. CGH-identified chromosomal alterations in any one tumor sample defines a "signature" for each tumor sample. We have used this approach to define the clonal relationships between different stages of an individual tumor presenting synchronously (preinvasive vs. invasive, or primary vs. metastasis), or metachronously (primary tumors and their "recurrences"). A statistical approach was developed which defined the likelihood of two samples being related clonally.
Primary tumors and their lymph node or distant metastases showed a high degree of concordance (mean 75%, n=33 pairs). Similarly, a strong concordance was seen in CGH alterations when comparing a focus of (breast or bladder) in situ carcinoma presenting synchronously with a tumor primary. There was no evidence that specific genetic regions were altered more frequently in the progressed sample. The high frequency of tumor sample pairs showing high concordance suggests that the rate of genetic divergence may slow in advanced tumors. Tumor clonality was also useful in defining the relationship between primary tumors and their metachronous recurrences in superficial bladder cancers and in breast ductal carcinomas in situ.. Our statistical model showed that similarities in the alterations in a primary and its recurrence were clearly greater than any random similarities in samples between patients, although rare recurrences were interpreted as independent tumor clones (new primaries).