Abstract
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. 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 × 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.
Highlights
A fundamental characteristic of cancer cells is their ability to maintain the capacity to proliferate, bypassing the homeostatic signaling network controlling cell division in normal tissue
We compared tumor proliferative index (PI) to previously compiled scores of tumor purity describing the proportion of non-cancerous cells within a sample across The Cancer Genome Atlas (TCGA) samples [29] as well as hematoxylin and eosin staining provided in clinical files associated with each sample
This was true when comparing tumor tissue collected by TCGA to normal tissue collected from the same organs by the Genotype-Tissue Expression (GTEx) Consortium (n = 9), demonstrating tumorigenesis is accompanied by a characteristic increase in proliferation-related gene expression (Figure 1B)
Summary
A fundamental characteristic of cancer cells is their ability to maintain the capacity to proliferate, bypassing the homeostatic signaling network controlling cell division in normal tissue. Proliferation is a clear hallmark of cancer, tumor evolutionary tradeoffs may exist in certain tumor types or stages that prioritize resources for other processes promoting survival like metastasis [3, 4], angiogenesis [5,6,7], immune system evasion [8, 9], drug efflux [10, 11], DNA repair [12, 13], drug resistance [14], or reactive oxygen species (ROS) regulation [15]. A majority of cytotoxic chemotherapies preferentially target the increased proliferation rate of cancer cells by damaging DNA in dividing cells or impairing vital replication machinery [25, 26]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
