Pan-cancer polygenic risk score associates with cancer susceptibility following kidney transplantation
Jarmo Ritari, Kati Hyvärinen, Kirsi Jahnukainen, FinnGen Consortium, Jukka Partanen, Ilkka Helanterä, Timo Jahnukainen
Jarmo Ritari, Kati Hyvärinen, Kirsi Jahnukainen, FinnGen Consortium, Jukka Partanen, Ilkka Helanterä, Timo Jahnukainen
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Clinical Research and Public Health Nephrology Oncology

Pan-cancer polygenic risk score associates with cancer susceptibility following kidney transplantation

Abstract

BACKGROUND Cancer accounts for over 20% of late posttransplant mortality, yet the contribution of genetic susceptibility to posttransplant cancer risk remains unclear. This study investigates germline genetic risk factors for posttransplant cancer in the Finnish population using data from the FinnGen cohort.METHODS A pan-cancer polygenic risk score (PRS) was constructed using genetic variants identified in UK and US populations to assess the influence of common germline variants on time to first cancer diagnosis in 1,802 Finnish kidney transplant recipients (KTRs), of whom 317 developed posttransplant cancer. The PRS was first validated in the FinnGen non-transplantation cohort and subsequently applied to KTRs, with replication in lung and liver transplant recipients (n = 476). Functional relevance was explored by assessing associations between the PRS and expression levels of 2,923 plasma proteins in the UK Biobank (n = 53,013).RESULTS Compared with a matched non-transplantation cohort (n = 68,294), KTRs exhibited earlier cancer onset. The PRS was significantly associated with time to first cancer diagnosis in the non-transplantation population (HR 1.04, 95% CI 1.038–1.056, P = 3.75 × 10–25). Among KTRs younger than 40 years, higher PRS was associated with earlier cancer onset (HR 1.08, 95% CI 1.01–1.17, P = 0.036), indicating a stronger genetic effect at younger ages. The PRS significantly (Bonferroni < 0.05) altered the regulation of 87 plasma proteins, several of which were known cancer-related markers.CONCLUSION Inherited genetic predisposition, captured by pan-cancer PRS, may contribute to individual susceptibility to cancer after solid organ transplantation, particularly at younger ages.FUNDING State research funding (Helsinki and Uusimaa Health District), the Foundation for Pediatric Research, and the Sigrid Jusèlius Foundation.

Authors

Jarmo Ritari, Kati Hyvärinen, Kirsi Jahnukainen, FinnGen Consortium, Jukka Partanen, Ilkka Helanterä, Timo Jahnukainen

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Figure 2

Validation of the pan-cancer polygenic risk score (PRS) in non-transplantation FinnGen cohort.

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Validation of the pan-cancer polygenic risk score (PRS) in non-transplan...
(A) Hazard ratios for overall cancer risk of the various cancer-type-specific risk scores and the 4 pan-cancer PRS candidates (sum, max, min, and pos; see Methods for details) obtained from multivariate Cox proportional hazards (coxph) survival models. The coxph models analyze the time to the first cancer diagnosis with and without adjusting for BMI and smoking along with other model covariates such as sampling age and population stratification (see Methods). (B) Continuous population distribution of the best performing score (“sum”) that is used as the pan-cancer PRS of choice in the follow-up analyses. The x-axis unit is the standard deviation of the mean (SD). The distribution tails, which are colored according to protective (green) and risk (red) PRS directions, are most relevant for cancer risk analysis and stratification. (C) PRS distribution in the FinnGen non-transplantation cohort categorized into 2 classes according to SD (binary PRS) and analyzed with coxph survival models. The distribution tails behave as expected by increasing or lowering the risk according to the distanced from the PRS mean. In A and C, the error bars represent 95% CIs. Survival analyses in A were performed with multivariable coxph regression.