Abstract
Centrosome amplification (CA) is a hallmark of cancer, observable in ≥75% of breast tumors. CA drives aggressive cellular phenotypes such as chromosomal instability (CIN) and invasiveness. Thus, assessment of CA may offer insights into the prognosis of breast cancer and identify patients who might benefit from centrosome declustering agents. However, it remains unclear whether CA is correlated with clinical outcomes after adjusting for confounding factors. To gain insights, we developed a signature, “CA20”, comprising centrosome structural genes and genes whose dysregulation is implicated in inducing CA. We found that CA20 was a significant independent predictor of worse survival in two large independent datasets after adjusting for potentially confounding factors. In multivariable analyses including both CA20 and CIN25 (a gene expression-based score that correlates with aneuploidy and has prognostic value in many types of cancer), only CA20 was significant, suggesting CA20 captures the risk-predictive information of CIN25 and offers information beyond it. CA20 correlated strongly with CIN25, so a high CA20 score may reflect tumors with high CIN and potentially other aggressive features that may require more aggressive treatment. Finally, we identified processes and pathways differing between CA20-low and high groups that may be valuable therapeutic targets.
Highlights
Centrosome amplification (CA) is a hallmark of cancer observable in ≥75% of breast tumors[1] that promotes invasive behavior[2] and enhanced migratory ability[3] in cancer cells
Stratification was conducted according to average CA20 and CIN25 scores found in the discovery set as well as optimal cutpoints in CA20 and CIN25 scores found in the discovery set based on the log-rank test
In Kaplan-Meier plots, stratification into high- and low-breast cancer-specific survival (BCSS) groups based on the average and optimal cutpoints in CA20 and CIN25 scores was significant in both the discovery and validation sets (p < 10−6 for all, Fig. 1; see Tables 1 and 2 for descriptive statistics of study datasets). When both CA20 and CIN25 were entered as covariates in full multivariable models using discovery set data, only CA20 appeared in the final model, and it was a significant predictor of BCSS (Hazard Ratio [HR] = 2.88, p < 0.001; Table 3)
Summary
CA is a hallmark of cancer observable in ≥75% of breast tumors[1] that promotes invasive behavior[2] and enhanced migratory ability[3] in cancer cells. Our lab previously developed a four-gene signature, which includes two genes for centrosome structural proteins and two genes whose overexpression induces CA, called the Centrosome Amplification Index (CAI), which we found stratifies breast cancer patients into two groups with significantly different overall survival (OS) in Kaplan-Meier analysis[3]. Because CA causes CIN, we were interested in comparing the prognostic value of CA20 with that of the CIN score “CIN25”, which correlates with total functional aneuploidy and predicts worse outcomes in a variety of cancers[12], determining which of these two scores has the most significant impact on outcomes when included together in multivariable models of survival, and comparing processes, pathways, and oncogenic signatures that are enriched in tumors with high CA20 and CIN25 scores
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