Differentially Methylated Regions in T Cells Identify Kidney Transplant Patients at Risk for De Novo Skin Cancer

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Abstract

Introduction

Cutaneous squamous cell carcinoma (cSCC) occurs 65-200 times more in organ transplant recipients than in the general population. T cells, which are targeted by immunosuppressive drugs, are involved in anti-tumour immune surveillance and their function is regulated by DNA methylation. We aim to discover differentially methylated regions (DMRs) in T cells involved in de novo cSCC development after kidney transplantation. Genome-wide DNA methylation of T cells was studied at time of transplantation (pre-Tx cohort) and prior to the clinical presentation of the first cSCC after kidney transplantation (post-Tx cohort).

Methods

Kidney transplant recipients with a future post-transplant cSCC (post-Tx n=19; pre-Tx n=27) were matched to recipients without cSCC (post-Tx n=19; pre-Tx n=27). Pure T cells were isolated by cell sorting from PMBCs and genome-wide DNA methylation was measured using Illumina’s Infinium 450K arrays. Linear mixed modelling was applied to adjust for confounders followed by comb-p to find DMRs. Pyrosequencing was used as a technical validation of the array results.

Results

Post-transplantation 7 DMRs were found between recipients with a future cSCC and those without cSCC. The top results include an intragenic region of SERPINB9, which was located in an actively transcribed gene in T cells, and a known tumour suppressor microRNA VTRNA2-1. Prior to transplantation 16 DMRs were found. Twelve of these 16 DMRs were located in genomic regions that are actively transcribed or enhancer regions. That includes the DMR annotated to FLOT1, a protein involved in T-cell migration.

Results

Methylation values obtained with the array were successfully validated with pyrosequencing.

Conclusion

Our results demonstrate that the T cells of kidney transplant recipients with a future post-transplant cSCC have different DNA methylation profiles compared to the T cells of kidney transplant recipients without cSCC, before the clinical presentation of a de novo cSCC and also before transplantation.

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