Polygenic Risk Scores Stratify Keratinocyte Cancer Risk among Solid Organ Transplant Recipients with Chronic Immunosuppression in a High Ultraviolet Radiation Environment

Abstract

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Re-weightingMC1R, ASIPandIRF4risk variants optimises polygenic risk scores for keratinocyte cancer stratification in solid organ transplant recipients

“…We and others have shown that a KC PRS derived from the general population is able to predict risk in both high UV and low UV settings [11][12][13] . In this paper we explored if there are differences in the magnitude of risk conferred by known germline genetic risk factors for OTRs vs general population in the UKB.…”

“…375 participants including 30 liver, 93 lung and 252 kidney transplant recipients had their DNA extracted and genotyped using an Illumina Global Screening Array. Based on genetic data, individuals were excluded based on high genotype missingness (> 3%), relatedness (identity by descent pihat > 0.2), ancestry diversity from European samples in the HapMap phase 3 (> 6 standard deviations from the European mean of PC1 and PC2), and sex-mismatch 13 . In addition, SNPs were removed based on a low call rate (< 95%), low MAF (< 1%), and Hardy-Weinberg equilibrium P < 1 × 10 -6 13 .…”

“…To date no studies have assessed whether genetic risk variants have the same impact on risk in immunosuppressed individuals as they do in the general population. SCC and BCC polygenic risk scores (PRSs) derived from GWASs in the general non-transplantee population have effectively stratified the SCC and BCC risk following immunosuppression in SOTRs [11][12][13][14] . Ideally, a PRS for use in SOTRs would be derived from a SOTR training set but in practice the sample sizes of SOTRs will always be too small to allow derivation of accurate PRS weights, especially for single nucleotide polymorphism (SNPs) of moderate or small effect.…”

Interventions After First Post-Transplant Cutaneous Squamous Cell Carcinoma: A Proposed Decision Framework

“…However, circulating immunological markers have been of interest as neoantigens that may drive immunological responses are common (especially in premalignancy) due to the high mutational burden in CSCC and the possible association with HPV (65). Other markers, including polygenic risk scores (66,67), polymorphisms identified through genome-wide association studies (67)(68)(69)(70)(71), circulating (and tumoral) microRNA (72) and tumoral gene expression (73,74) have been investigated for prognostic value in either OTR or ICP. Only a subset have been validated externally and/or for stratification of further CSCC risk (66,67,75,76,77).…”

“…Other markers, including polygenic risk scores (66,67), polymorphisms identified through genome-wide association studies (67)(68)(69)(70)(71), circulating (and tumoral) microRNA (72) and tumoral gene expression (73,74) have been investigated for prognostic value in either OTR or ICP. Only a subset have been validated externally and/or for stratification of further CSCC risk (66,67,75,76,77). Synchronous stratification for rejection risk would reassure both practitioners and patients regarding immunosuppression reduction.…”