Demethylation of the TSDR Is a Marker of Squamous Cell Carcinoma in Transplant Recipients

• Published in: American journal of transplantation Vol. 14; no. 11; pp. 2617 - 2622
• Main Authors: Sherston, S. N., Vogt, K., Schlickeiser, S., Sawitzki, B., Harden, P. N., Wood, K. J.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01.11.2014; Wiley Subscription Services, Inc; John Wiley & Sons, Ltd
• Subjects: Adult; Aged; Aged, 80 and over; Basic (laboratory) research/science; Biological and medical sciences; biomarker; Biomarkers, Tumor - blood; Brief Communications; Cancer; cancer/malignancy/neoplasia: skin; Carcinoma, Squamous Cell - blood; Dermatology; DNA Methylation; Female; flow cytometry; Health risk assessment; Humans; immune regulation; immunobiology; Immunosuppressive Agents - administration & dosage; kidney transplantation/nephrology; Male; Medical sciences; Middle Aged; monitoring: immune; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); nonmelanoma; organ transplantation in general; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; translational research/science; Transplantation - adverse effects; Transplants & implants; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Skin disease; Squamous cell carcinoma; Basal cell carcinoma; Biological marker; Transplantation; Malignant tumor; Metabolism; Homotransplantation; Demethylation; Treatment; Surgery; Graft; Pharmacokinetics; Cancer; translational research/science; organ transplantation in general; kidney transplantation/nephrology; Basic (laboratory) research/science; flow cytometry; immunobiology; monitoring: immune; cancer/malignancy/neoplasia: skin; biomarker; immune regulation; nonmelanoma
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12899

Malignancy is an important cause of death in transplant recipients. Cutaneous squamous cell carcinoma (cSCC) causes significant morbidity and mortality as 30% of transplant recipients will develop cSCC within 10 years of transplantation. Previously we have shown that high numbers of regulatory T cells (Tregs) are associated with the development of cSCC in kidney transplant recipients (KTRs). Demethylation analysis of the Treg‐specific demethylated region (TSDR) provides a more accurate association with cSCC risk after transplantation. Age, gender and duration of immunosuppression matched KTRs with (n = 32) and without (n = 27) cSCC, were re‐analyzed for putative clinical and immunological markers of cancer risk. The proportion of FOXP3+ CD4+ cells was higher in the population with a previous SCC. Major T cell subsets remained stable over time; although B cell, CD8 and CD4 subpopulations demonstrated age‐related changes. TSDR methylation analysis allowed clarification of Treg numbers, enhancing the association of high Treg levels in KTRs with cSCC compared to the cSCC‐free cohort. These data validate and expand on previous findings in long‐term KTRs, and show that immune markers remain stable over time. TSDR demethylation analysis provides a more accurate biomarker of cancer posttransplantation. This study demonstrates that the proportion of naturally occurring regulatory T cells, identified by a specific demethylated region in the forkhead box P3 locus, is associated with increased cutaneous squamous cell carcinoma in kidney transplant recipients and is a useful biomarker of cancer risk.