Chromosome Instability Predicts Cancer Outcome

Using data on gene expression (activity) from 18 previous studies of cancer, representing six cancer types, the scientists found that this genetic profile, or signature, predicted poor clinical outcome in 12 of the populations studied.

"Chromosomal instability is one of the key mechanisms that keeps malignant cell proliferation going,” said Zoltan Szallasi, M.D., of the Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology (CHIP, Boston, MA, USA), and the study's senior investigator. "We have achieved a relatively easy way to measure the level of chromosomal instability in a given tumor sample.” With further development, the team's work could also form the basis of a diagnostic tool that could be used in the clinic.

The human genome is at constant risk for mutations due to environmental insults, errors in gene replication, and other factors that can cause chromosomes to break and bits of DNA to be lost, duplicated, or reshuffled to the wrong chromosomes. Cells have repair mechanisms that constantly fix this damage, but when the repair process breaks down, chromosomes become unstable and cancers are more likely to develop.

Chromosomal instability leads to a condition known as aneuploidy, in which chunks of DNA are either missing or duplicated. The technique developed by Dr. Szallasi's team indirectly measures the degree of aneuploidy--and thus the degree of chromosomal instability--by looking for abnormal expression levels of genes at the different chromosomal locations.

The team identified 25 genes whose activity most strongly predicted chromosomal instability itself. This 25-gene signature was a significant predictor of clinical outcomes in a variety of cancers (breast, lung, medulloblastoma, glioma, mesothelioma, and lymphoma). It could also differentiate between primary tumors and tumor metastases, and distinguish the more aggressive cancers in grade 1 and grade 2 breast cancer.



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