Clinical and Genetic Factors Associated with Cutaneous Squamous Cell Carcinoma in Kidney and Heart Transplant Recipients

Background. Cutaneous squamous cell carcinoma (cSCC) occurs with higher frequency and recurrence rates, increased morbidity and mortality, and more aggressive metastasis in kidney and heart transplant recipients compared to the general population but all transplant recipients do not develop cSCC. In addition, the phenotypic expression of cSCC among transplant recipients can vary between mild disease and extensive recurrent metastatic disease. These clinically observed differences in occurrence and severity of cSCC among transplant recipients suggest the possibility that an underlying genetic component might modify risk. Methods. We identified 88 white posttransplant cSCC cases (71 kidney and 17 heart) and 300 white posttransplant controls (265 kidney and 35 heart) using a DNA biobank linked with deidentified electronic medical records. Logistic regression was used to determine adjusted odds ratios (OR) for clinical characteristics and single nucleotide polymorphisms (SNP) associated with cSCC in both a candidate SNP and genomewide analysis. Results. Age (OR, 1.08; 95% confidence interval [95% CI], 1.05-1.11; P < 0.001) and azathioprine exposure (OR, 8.64; 95% CI, 3.92-19.03; P < 0.001) were significantly associated, whereas sex, smoking tobacco use, dialysis duration, and immunosuppression duration were not. Ten candidate SNPs previously associated with nonmelanoma skin cancer in the general population were significantly associated with cSCC in transplant recipients. Genomewide association analysis implicated SNPs in genes previously associated with malignancy, CSMD1 (OR, 3.14; 95% CI, 1.90-5.20) and CACNA1D (OR, 2.67; 95% CI, 1.73-4.10]). Conclusions. This study shows an association of increasing age and azathioprine exposure with cSCC and confirms a genetic contribution for cSCC development in kidney and heart transplant recipients.