PDCD1 (PD-1) promoter methylation predicts outcome in head and neck squamous cell carcinoma patients

Abstract

BackgroundBiomarkers that facilitate the prediction of disease recurrence in head and neck squamous cell carcinoma (HNSCC) may enable physicians to personalize treatment. In the current study, DNA promoter methylation of programmed cell death 1 (PDCD1, PD-1) was evaluated as a prognostic biomarker in HNSCC patients.ResultsHigh PDCD1 methylation (mPDCD1) was associated with a significantly shorter overall survival after surgical resection in both the discovery (HR = 2.24 [95%CI: 1.08–4.64], p = 0.029) and the validation cohort (HR = 1.54 [95%CI: 1.08–2.21], p = 0.017). In multivariate Cox proportional hazards analysis, PDCD1 methylation remained a significant prognostic factor for HNSCC (HR = 2.14 [95%CI: 1.19–3.84], p = 0.011). Further, mPDCD1 was strongly associated with the human papilloma virus (HPV) status.Materials and MethodsmPDCD1 was assessed retrospectively in a discovery cohort of 120 HNSCC patients treated at the University Hospital of Bonn and a validation cohort of 527 HNSCC cases analyzed by The Cancer Genome Atlas Research Network.ConclusionsPDCD1methylation might aid the identification of HNSCC patients potentially benefitting from a radical or alternative treatment, particularly in the context of immunotherapies targeting PD-1/PD-L1.

LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

“…37 38 DNA methylation status is a particular promising biomarker for immunotherapies as demonstrated in previous reports. [12][13][14][15][16] Results of the present study suggest that LAG3 gene expression in KIRC is strongly regulated epigenetically, that is, LAG3 methylation correlates with LAG3 mRNA expression. In particular, hypomethylation of the promoter region negatively correlates with enhanced mRNA expression in the KIRC TCGA cohort whereas two methylation sites, one in the body of the LAG3 gene, and one downstream within a putative binding site of the transcriptional repressor CTCF, positively correlate with mRNA expression.…”

“…Shown is chromosome 12, position 6 771 404-6 779 853, including the LAG3 gene, its transcripts and regulatory elements (promoter, promoter flank, and CCCTCbinding factor (CTCF) binding site), and the investigated loci. The LAG3 methylation target sites of the HumanMethylation450 BeadChip beads (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) and qMSP assays (4 and 8) are based on Genome Reference Consortium Human Build 38 patch release 13 (GRCh38.p13). The illustration (modified) was exported from www.ensemble.org (release 98).…”

“…The illustration (modified) was exported from www.ensemble.org (release 98). 50 Beads are numbered as follows: cg26956535 (1), cg22777668 (2), cg16352928 (3), cg02695343 (4), cg10500147 (5), cg17213699 (6), cg19872463 (7), cg04671742 (8), cg01820374 (9), cg19421125 (10), cg10191002 (11), cg20652042 (12), cg06157570 (13), cg14292870 (14), cg11429292 (15), and cg15828668 (16). LAG3, lymphocyte activating 3; qMSP, quantitative methylation-specific PCR.…”

“…Methylation has been shown to regulate expression of PD-1 and PD-L1 in various malignancies. [12][13][14][15][16] We therefore hypothesized that LAG3 expression might also be regulated epigenetically via DNA methylation. Understanding the epigenetic regulation of LAG3 expression is of major interest, as it could be useful for the stratification of patients who may benefit from immunotherapeutic LAG3 inhibition.…”

miR‐134 targets PDCD7 to reduce E‐cadherin expression and enhance oral cancer progression

“…Among these proteins, PDCD1, PDCD4 and PDCD5 have been implicated in HNSCC oncogenesis. Promoter methylation of PDCD1, also known as PD‐1 in therapeutic targeting, is associated with shorter survival times in patients with HNSCC . PDCD4 tumor suppressor was shown to be targeted by miR‐21 in numerous types of malignancies, including HNSCC .…”