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

Abstract

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 to 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 post-transplant cSCC cases (71 kidney and 17 heart) and 300 white post-transplant controls (265 kidney and 35 heart) using a DNA biobank linked with de-identified 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 genome wide analysis. Results Age (OR 1.08 [1.05–1.11], p<0.001) and azathioprine exposure (OR 8.64 [3.92–19.03], p<0.001) were significantly associated while gender, smoking tobacco use, dialysis duration and immunosuppression duration were not. Ten candidate SNPs previously associated with non-melanoma skin cancer in the general population were significantly associated with cSCC in transplant recipients. Genome wide association analysis implicated SNPs in genes previously associated with malignancy, CSMD1 (OR 3.14 [1.90–5.20]) and CACNA1D (OR 2.67 [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.

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort

“…1,2 As a result of this success, malignancy is a common transplant complication, with non-melanoma skin cancers (NMSC) accounting for 95% of posttransplant malignancies. 5 A number of studies have evaluated clinical predictors of NMSC posttransplant [6][7][8] and robust predictors include age, sex, and type of immunosuppressive treatment. 5 A number of studies have evaluated clinical predictors of NMSC posttransplant [6][7][8] and robust predictors include age, sex, and type of immunosuppressive treatment.…”

“…9 For example, it has been suggested that azathioprine exposure when combined with UV light induces DNA damage, which can lead to tumorigenesis. 7 Studying SCC in a kidney and heart transplant population, the authors highlighted increased age and azathioprine exposure as risk factors for skin cancer, but no genomewide significant genetic predictors were detected. 10 Despite the increased risk of skin cancer, only one study has tested for germline genetic associations with skin cancer posttransplant on a genomic scale.…”

“…9 Conversely, mammalian target of rapamycin (mTOR) inhibitors, which is also used as an immunosuppressant in solid organ transplants, were reported to reduce skin cancer incidence posttransplant. 7 This study had limited power (n = 388) compared to genome-wide association studies (GWAS) of SCC and BCC in nontransplant populations (n = 8058+) where robust genetic risk factors for NMSC were identified. 7 Studying SCC in a kidney and heart transplant population, the authors highlighted increased age and azathioprine exposure as risk factors for skin cancer, but no genomewide significant genetic predictors were detected.…”

Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis

“…Eleven studies assessed the relationship between azathioprine exposure and SCC in OTRs (3,17,20,21,36,40,41,47,48, 50, 54) ( Table 1) and 10 of the 11 were eligible for inclusion in the meta-analysis (50) ( Table S3). Two studies were population-based casecontrol studies (17,48) whilst the remainder were cohort studies.…”

Cutaneous squamous cell cancer (cSCC) risk and the human leukocyte antigen (HLA) system

“…geography), methodology (i.e. composition of the control group), immunosuppression protocols (azathioprine has been reported to increase cSCC risk), or other unidentified factors [60,61]. Here we outline future work to address some of these limitations.…”