Molecular karyotype (amplotype) of metastatic colorectal cancer by unbiased arbitrarily primed PCR DNA fingerprinting.

Genomic instability characterizes the aneuploid cancer cell. Losses of genetic material are critical in cancer by exposing recessive mutations in tumor suppressor genes. Gains of genetic material also may lead to overexpression of genes contributing to tumor progression either in the presence or absence of mutation. However, the detection of moderate gains (such as tri-tetraploidy) has been a challenge in cancer research. Unbiased DNA fingerprinting by the arbitrarily primed PCR allows the detection of moderate gains (in addition to losses) of DNA sequences of known chromosomal localization. We have generated in this manner a molecular karyotype of metastatic colon cancer. This amplotype shows that sequences from several chromosomes undergo both losses (1, 4, 9, 14, and 18) and gains (6, 7, 12, and 20) in over half of the tumors. Moreover, gains of sequences from chromosomes 8 and 13 occurred in most tumors, indicating the existence in these chromosomes of positive regulators of cell growth or survival that are under strong positive selection during tumor progression. We conclude that overrepresentation of these chromosomal regions is a critical step for metastatic colorectal cancer. Comparative amplotype analysis from primary and metastatic tumors suggest the existence in chromosome 4 of gene(s) whose loss is specifically selected in cells that reach the metastatic stage.