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
Figure 4
Cancer risk in KT recipients.
