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Identification of Kidney Transplant Patients at Risk for Skin Cancer by Differentially Methylated Regions in T Cells

Peters, Fleur1; Peeters, Annemiek MA1; Mandaviya, Pooja R.2; van de Wetering, Jacqueline1; Betjes, Michiel GH1; Baan, Carla C.1; Boer, Karin1

doi: 10.1097/

1Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands; 2Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, Netherlands.

Introduction: Skin cancer, specifically cutaneous squamous cell carcinoma (cSCC), is the most often occurring malignancy in patients after organ transplantation with an incidence of 100–200 times more than in the general population. Biomarkers to predict post-transplant cSCC are unavailable. We hypothesized that individuals at increased risk for post-transplant cSCC could be identified by epigenetic alterations in T cells, which are crucial in tumour immune surveillance. Therefore, we studied genome-wide DNA methylation in T cells at time of transplantation and prior to the clinical onset of cSCC in kidney transplant (KTx) patients.

Methods: Pure T cells were isolated by FACS sorting from PMBCs of KTx patients with (n = 46) and without cSCC after transplantation (n = 46). Patients with post-transplant cSCC were matched to patients without cSCC. Genome-wide DNA methylation was measured using Illumina’s Infinium 450 K array. To find differentially methylated regions (DMRs), we applied linear mixed modelling to adjust for confounders followed by comb-p to find the regions.

Results: The results showed 16 DMRs at time of transplantation between patients with post-transplant cSCC and those without post-transplant cSCC. The majority (11/16) of these DMRs were hypomethylated in patients with post-transplant cSCC and 13 of these 16 DMRs were located within the promoter region of a gene. After transplantation but prior to the clinical onset of cSCC, 7 DMRs were found. These results include an intragenic region of SERPINB9, an actively transcribed gene in T cells, and a known tumour suppressor microRNA. No overlap was found so far between the two groups.

Conclusion: These findings support the hypothesis that differentially methylated regions can potentially serve as a predictive tool for the development of post-transplant cSCC, both at time of transplantation and prior to the clinical onset of cSCC.

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