DOI: 10.6084/m9.figshare.26395877.v1
title: Appraising non-linear association between pre-diagnostic platelet counts and cancer survival outcomes: observational and genetic analysis

description: 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 × 10<sup>9</sup>/L) and inferior OS (HR: 1.07; 95% CI: 1.04–1.10; <i>p</i> &lt; .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (<i>p</i> &lt; .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; <i>p</i> = .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. <b>What is the context?</b>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. 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. <b>What is new?</b>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 (<i>TPM4</i>, <i>PDIA5</i>, <i>PSMD13</i>, <i>TMCC2</i>, <i>ZFPM2</i>, <i>BAZ2A</i>, <i>CDKN2A</i>, <i>GP1BA</i>, <i>TAOK1</i>, <i>CABLES1</i>, and <i>THPO</i>) related to PLTs that were associated with cancer survival. 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 (<i>TPM4</i>, <i>PDIA5</i>, <i>PSMD13</i>, <i>TMCC2</i>, <i>ZFPM2</i>, <i>BAZ2A</i>, <i>CDKN2A</i>, <i>GP1BA</i>, <i>TAOK1</i>, <i>CABLES1</i>, and <i>THPO</i>) related to PLTs that were associated with cancer survival. <b>What is the impact?</b>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. 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.