Appraising non-linear association between pre-diagnostic platelet counts and cancer survival outcomes: observational and genetic analysis

Abstract

Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 10⁹/L) and inferior OS (HR: 1.07; 95% CI: 1.04–1.10; p < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (p < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998–1.001; p = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.

Plain Language Summary

What is the context?

• Previous studies have reported inconsistent associations between platelet counts (PLTs) and cancer survival. However, it is unclear whether there is a linear causal effect, as most studies measured PLTs at the time of cancer diagnosis, which could be influenced by the cancer itself.

• This study aimed to investigate the association and potential causality between pre-diagnostic PLTs and cancer survival outcomes using a large prospective cohort and genetic analysis.

What is new?

• The observational cohort study found a significant association between elevated pre-diagnostic PLTs and poorer overall and cancer-specific survival. We also identified a U-shaped relationship between PLTs and cancer survival, suggesting that both high and low PLTs may be detrimental.

• The Mendelian randomization analysis did not support a causal effect of PLTs on overall cancer survival, although it hinted at potential non-linear effects at lower PLT ranges.

• The study also identified several genes (TPM4, PDIA5, PSMD13, TMCC2, ZFPM2, BAZ2A, CDKN2A, GP1BA, TAOK1, CABLES1, and THPO) related to PLTs that were associated with cancer survival.

What is the impact?

• The findings suggest that early detection of elevated PLTs may indicate occult cancer development and poorer subsequent survival outcomes. However, PLTs are less likely to be a promising therapeutic target for improving cancer survival, as the observed associations could be influenced by confounding factors.

• The study highlights the need for further research into the complex relationship between PLTs and cancer prognosis, as well as the exploration of other platelet-related traits as potential drug targets.

Keywords:

• Cancer survival
• cohort study
• Mendelian randomization
• platelet counts

Acknowledgments

We acknowledge the UK Biobank, The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project for their efforts on human health and the sharing of scientific data.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

CL, JC, XC, YZ, and YH are the guarantors of integrity of the entire study. CL, JC, YZ, and YZ were responsible for study concepts and design. CL carried out the literature research. CL, JC, DH, CS, JH, LW, HL, and QW were responsible for the statistical analysis. CL prepared the manuscript. CL, JC, DH, CS, JH, LW, HL, QW, XC, YH, and YZ edited the manuscript. All authors drafted or revised the manuscript and approved the final version.

Data availability statement

Individual data from the UK Biobank could be accessed via application. Access to public datasets is described in article. All R source codes for analysis are available at https://github.com/lict99/PLT_Cancer_Survival.

Ethics approval statement

The UK Biobank was approved by the North West-Haydock Research Ethics Committee (21/NW/0157).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/09537104.2024.2379815

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant no. 82103918 to Y.H.]; and Natural Science Foundation of Sichuan [grant no. 2022NSFSC1314 to Y.H.]. The funding sources did not play a role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.