Genomic instability and the development of metastatic lymph node tumors

Background: Although recent data suggest that cells with metastatic potential disseminate from the primary breast tumor early in tumor development, the mechanism by which disseminated breast cancer cells proliferate within foreign tissues is not well understood. Here, we examined levels and patterns of allelic imbalance (AI) in metastatic lymph node (LN) tumors to identify molecular signals that promote the survival and growth of disseminated breast tumor cells. Methods: DNA from 106 metastatic LN tumors from 25 patients was isolated after laser microdissection of pure tumor cell populations. AI was assessed at 26 chromosomal regions frequently altered in breast cancer. Tumor burden was calculated by dividing the area of the metastatic tumor in the node by the area of the entire LN. Results: Metastatic tumor burden ranged from focal to complete replacement of the LN with tumor. Grouping the nodes as <25% tumor, 25-50% tumor, 50-75% tumor, and ≥75% tumor replacement revealed the average frequency of AI ranged from 0.13 (±0.11) in the <25% group to 0.17 (±0.13) in LNs with ≥75% tumor burden. The range of AI in both the <25% and >75% replacement group was 0.00-0.48. Allelic losses at chromosomal regions 1p36.1-36.2, 5q21.1-21.3, 6q15, 10q23.31-23.33, and 17p13.1 were significantly higher in metastatic LNs with >75% compared with <25% tumor burden. Conclusions: In metastatic LNs, levels of AI were not associated with tumor burden, suggesting that accumulation of genetic changes is not coincidental with tumor growth; rather the accumulation of specific genetic changes is a prerequisite to the transformation of disseminated breast cells into metastatic LN tumors.