Polygenic Risk Scores Allow Risk Stratification for Keratinocyte Cancer in Organ-Transplant Recipients

Abstract

Organ-transplant recipients have an elevated risk of keratinocyte cancers: basal cell carcinoma (BCC) and squamous cell carcinoma. We assessed whether polygenic risk scores (PRSs) generated in nontransplantees from the UK Biobank and 23andMe (13,981 squamous cell carcinoma, 33,736 BCC, and >560,000 controls) can predict keratinocyte cancer risk in an independent organ-transplant recipient cohort. After adjusting for traditional risk factors, compared with the bottom 20%, organ-transplant recipients in the top 20% PRS had an increased risk of BCC (OR ¼ 3.25, 95% confidence interval ¼ 1.44e7.31, P ¼ 4.4 Â 10-3) and squamous cell carcinoma (OR ¼ 2.11, 95% confidence interval ¼ 0.98e4.53, P ¼ 0.055). For BCC, the top 20% PRS individuals had an absolute risk of 23%, whereas the risk in the bottom 20% was similar to that in the general nontransplantee population. Adding PRS to a model containing traditional skin cancer risk factors yielded a 3% increase in the area under the curve for receiver operating characteristic curve for BCC (0.73 vs. 0.70); adding the PRS did not significantly increase the area under the curve for receiver operating characteristic curve for squamous cell carcinoma. Organ-transplant recipients in the highest genetic risk quintile could benefit from more intense keratinocyte cancer screening and preventive strategies compared with their counterparts. The BCC PRS improves prediction over and above the traditional skin cancer risk factors by 3%.

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

“…About half of the patients in the top quintile developed BCC and SCC within the relatively short three-year follow up period. In contrast, as we reported previously, only about 23% of SOTRs in the top quintile in the UK (a low UV setting), had developed BCC and SCC by late middle age (Seviiri et al 2021). Third, as opposed to follow-up of patients immediately after receiving their organ transplant, this study assessed SOTRs with a mean (SD) duration of 9.61 (8.50) years after transplantation and thus with chronic immunosuppression, another key risk factor for KC in SOTRs.…”

“…top PRS quintile) have a substantially higher risk of developing BCC or SCC compared to their counterparts with a low genetic risk (e.g. bottom quintile), and that the PRS improves BCC and SCC risk prediction over and above the established clinical and skin cancer risk factors (Seviiri et al 2021;Stapleton et al 2019). Our study differs from other previous studies in a number of ways.…”

“…Our study differs from other previous studies in a number of ways. First, we used LDpred (Vilhjálmsson et al 2015), a method which considers a large number of genetic markers at the PRS generation stage in contrast to the LD clump method used in the previous studies (Roberts et al 2020;Seviiri et al 2021;Stapleton et al 2020;Stapleton et al 2019). BCC and SCC have strong signals in high LD regions like HLA which might lead to inefficient harnessing of the available information.…”

“…Second, it has assessed the performance of a PRS in a high UV environment, where environmental factors greatly increase background BCC or SCC incidence. Previous studies have evaluated the PRS in environments with typically lower UV such as the United Kingdom and USA (Roberts et al 2020;Seviiri et al 2021; J o u r n a l P r e -p r o o f Stapleton et al 2020;Stapleton et al 2019). About half of the patients in the top quintile developed BCC and SCC within the relatively short three-year follow up period.…”

“…To date, KC prevention has relied upon assessment of traditional risk factors but new approaches harnessing genetic information via polygenic risk scores (PRSs) have shown recently to have good potential for improving risk stratification. We have previously reported that in a low UV setting such as in the United Kingdom; a) PRSs derived from the general population enable effective risk stratification for KC among SOTRs, b) transplant recipients with a high genetic risk (PRS) have 3.3-fold and 2.1-fold increased risk per 1 standard deviation increase in BCC or SCC PRS respectively, and c) the PRS improves BCC predictions over and above traditional risk factors with a 3% increase in the prediction accuracy (area under the receiver operating characteristic curve) (Seviiri et al 2021). Other studies have also shown that PRSs generated from the non-transplant general population can predict the risk of BCC and SCC among SOTRs in low UV settings (Stapleton et al 2020;Stapleton et al 2019).…”