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

Mathias Seviiri,Matthew H Law,Jue Sheng Ong,Puya Gharahkhani,Dale R Nyholt,Peter Hopkins,Daniel Chambers,Scott Campbell,Nicole M Isbel,H Peter Soyer,Catherine M Olsen,Jonathan J Ellis,David C Whiteman,Adele C Green,Stuart Macgregor

doi:10.1016/j.jid.2021.03.034

Abstract

Solid organ transplant recipients (SOTRs) have elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), especially in high UVR environments. We assessed whether polygenic risk scores can improve the prediction of BCC and SCC risks and multiplicity over and above the traditional risk factors in SOTRs in a high UV setting. We built polygenic risk scores for BCC (n= 594,881) and SCC (n= 581,431) using UK Biobank and 23andMe datasets, validated them in the Australian QSkin Sun and Health Study cohort (n > 6,300), and applied them in SOTRs in the skin tumor in allograft recipients cohort from Queensland, Australia, a high UV environment. About half of the SOTRs with a high genetic risk developed BCC (absolute risk= 45.45%, 95% confidence interval= 33.14-58.19%) and SCC (absolute risk= 44.12%, 95% confidence interval= 32.08-56.68%). For both cancers, SOTRs in the top quintile were at >3-fold increased risk relative to those in the bottom quintile. The respective polygenic risk scores improved risk predictions by 2% for BCC (area under the curve= 0.77 vs. 0.75, P= 0.0691) and SCC (area under the curve= 0.84 vs. 0.82, P= 0.0260), over and above the established risk factors, and 19.03% (for BCC) and 18.10% (for SCC) of the SOTRs were reclassified in a high/medium/low risk scenario. The polygenic risk scores also added predictive accuracy for tumor multiplicity (BCC R2= 0.21 vs. 0.19, P= 3.2× 10-3; SCC R2= 0.30 vs. 0.27, P= 4.6× 10-4).

Highlights

Solid organ transplant recipients (OTRs) (SOTRs) have significantly elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (Garrett et al, 2017; Menzies et al, 2019; Park et al, 2019)
polygenic risk score (PRS) models for UK Biobank D 23andMe versus UK Biobank only for BCC and SCC Comparing the PRS derived from the UK Biobank (UKB) þ 23andMe versus that derived from only UKB, we found that the area under the curve (AUC) was very slightly higher for SCC for the UKB þ 23andMe scenario but that the reverse was true for BCC (Supplementary Table S2)
This study evaluated whether a PRS generated from the general population can be used to stratify the risk of BCC and SCC among solid organ transplant recipient (SOTR) with chronic immunosuppression in a high UV environment

Summary

Introduction

Solid organ transplant recipients (OTRs) (SOTRs) have significantly elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (Garrett et al, 2017; Menzies et al, 2019; Park et al, 2019). This is primarily attributed to chronic immunosuppression in SOTRs (Agraharkar et al, 2004; Yanik et al, 2017). GWASs have identified germline host risk factors for KC cancers (Chahal et al, 2016a, 2016b; Liyanage et al, 2019; Sarin et al, 2020) Prevention of these KC cancers among SOTRs should include screening, risk stratification, and prediction. These should employ a comprehensive approach that uses both external and host factors

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