Prognostic value of CA20, a score based on centrosome amplification-associated genes, in breast tumors

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.

Pan-cancer association of a centrosome amplification gene expression signature with genomic alterations and clinical outcome

“…To estimate relative CA levels in human samples, we used CA20, a score based on the expression of 20 genes experimentally associated with CA [ 23 ], as a surrogate. We quantified CA20 across the transcriptomes (profiled by RNA-seq) of 9,721 tumour and 725 matched-normal samples spanning 32 cancer types from TCGA ( Fig 1a , S1 Table ).…”

“…Breast cancer is one of the best studied cancer types, with large cohorts of clinically annotated tumour samples available [ 27 , 28 ], and where the CA20 score was developed [ 23 ]. In addition, CA has been frequently correlated with aggressive features in breast cancer [ 6 , 25 , 26 , 29 ].…”

“…To at least partially circumvent those challenges, we propose the estimation of CA based on the expression levels of CA-associated genes. Recently, proof-of-principle gene-expression-based CA signatures have been developed [ 20 – 23 ], the most comprehensive one being CA20, based on the expression of TUBG1 , which encodes the most abundant centrosomal protein, and 19 other genes whose overexpression has been experimentally shown to induce CA [ 23 ]. This signature was proposed to reflect CA levels in tumour samples and shown to have a prognostic value in two independent breast cancer cohorts [ 23 ].…”

Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma

“…There are two scores to determine CA in clinical samples that have previously been reported: the centrosome index (CI) (34,35) and the centrosome amplification 20 (CA20) (36). Both of these scores are calculated from mRNA expression values of certain genes required for centriole duplication.…”

Panoptic View of Prognostic Models for Personalized Breast Cancer Management

“…Ogden et al identified and validated CA20, a 20 gene CA transcriptomic signature (consisting of centrosome structural genes and genes involved in inducing CA), in breast tumors. CA20 is an independent predictor of poor survival and a high score is indicative of high chromosomal instability (CIN) and tumor aggressiveness [148]. Later, Almeida et al in their pan-cancer computational analysis (from The Cancer Genome Atlas [TCGA] cohort) confirmed the association of CA20 with clinical and molecular features of BC as well as with CIN.…”