RNA sequencing-based cell proliferation analysis across 19 cancers identifies a subset of proliferation-informative cancers with a common survival signature

Abstract

IMAGE CAPTION: A) Tumor proliferative index Cox regression negative log p-values are B) anti-correlated with the cancer’s median index. C) Heatmap of significant genes in at least 919 cancers. (Ramaker & Lasseigne, et al. Oncotarget. 2017.)

Despite advances in cancer diagnosis and treatment strategies, robust prognostic signatures remain elusive in most cancers. Cell proliferation has long been recognized as a prognostic marker in cancer, but the generation of comprehensive, publicly available datasets allows examination of the links between cell proliferation and cancer characteristics such as mutation rate, stage, and patient outcomes. Here we explore the role of cell proliferation across 19 cancers (n = 6,581 patients) by using tissue-based RNA sequencing data from The Cancer Genome Atlas Project and calculating a ‘proliferative index’ derived from gene expression associated with Proliferating Cell Nuclear Antigen (PCNA) levels. This proliferative index is significantly associated with patient survival (Cox, p-value < 0.05) in 7 of 19 cancers, which we have defined as proliferation-informative cancers (PICs). In PICs, the proliferative index is strongly correlated with tumor stage and nodal invasion, as well as patient survival. PICs demonstrate reduced baseline expression of proliferation machinery relative to non-PICs. Additionally, we find the proliferative index is significantly associated with gross somatic mutation burden (Spearman, p = 1.76 x 10-23) as well as with mutations in individual driver genes. This analysis provides a comprehensive characterization of tumor proliferation indices and their association with disease progression and prognosis in multiple cancer types and highlights specific cancers that may be particularly susceptible to improved targeting of this classic cancer hallmark. We also present an R package (ProliferativeIndex) for analysis.

Publication
Oncotarget
Date