Background:
Transplant patients are at extreme risk of multiple invasive skin cancers. Chemopreventive medication can reduce this risk by ∼50%, but clinicians are unable to identify high-risk patients before cancer onset.

Objective:
To assess the efficacy of a genetic test for skin cancer to identify ultra-high risk transplant patients who might benefit from chemoprevention or develop skin cancers with poor prognostic features.

Methods:
We developed a polygenic risk test for skin cancer using data from 1.2 million people using a Bayesian approach that models genetic information from the whole genome. We applied the genetic test to a cohort of transplant patients (STAR n=357) from a high UV environment in Australia to assess whether it could predict ultra-high risk individuals suitable for chemoprevention.

Results:
In the STAR cohort, higher genetic risk patients were more likely to: develop skin cancer (OR=2.04, 95%CI=1.54-2.71, P=8.72e-07), be treated with cancer-preventive medication (e.g. acitretin: OR=2.55, 95%CI=1.31 - 4.95, P=5.62e-03), have skin cancers with poor prognostic features, have poorly differentiated tumors (OR=2.29, 95%CI=1.39-3.77, P=1.18e-03), have tumors with unclear margins (OR=2.09, 95%CI =1.03-4.25, P=0.041), have large tumors >2cm (OR=4.09, 95%CI=1.88-8.90, P=3.92e-04), and have highly invasive disease (OR=1.95, 95%CI=1.18-3.23, P=9.06e-03). We are now conducting a comparative analysis in a large cohort (QSkin) of non-transplantees.

Conclusion:
Our genetic test for skin cancer has the potential to identify ultra-high risk transplant patients who should be prioritized by clinicians for personalized early chemoprevention.