Cell cycle correlated genes dictate the prognostic power of breast cancer gene lists

BACKGROUND: Numerous gene lists or "classifiers" have been derived from global gene expression data that assign breast cancers to good and poor prognosis groups. A remarkable feature of these molecular signatures is that they have few genes in common, prompting speculation that they may use distinct genes to measure the same pathophysiological process(es), such as proliferation. However, this supposition has not been rigorously tested. If gene-based classifiers function by measuring a minimal number of cellular processes, we hypothesized that the informative genes for these processes could be identified and the data sets could be adjusted for the predictive contributions of those genes. Such adjustment would then attenuate the predictive function of any signature measuring that same process. RESULTS: We tested this hypothesis directly using a novel iterative-subtractive approach. We evaluated five gene expression data sets that sample a broad range of breast cancer subtypes. In all data sets, the dominant cluster capable of predicting metastasis was heavily populated by genes that fluctuate in concert with the cell cycle. When six well-characterized classifiers were examined, all contained a higher than expected proportion of genes that correlate with this cluster. Furthermore, when the data sets were globally adjusted for the cell cycle cluster, each classifier lost its ability to assign tumors to appropriate high and low risk groups. In contrast, adjusting for other predictive gene clusters did not impact their performance. CONCLUSION: These data indicate that the discriminative ability of breast cancer classifiers is dependent upon genes that correlate with cell cycle progression.