PubMed · 8536193
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D W Lewis. 1995. Diagnostic tests.. https://pubmed.ncbi.nlm.nih.gov/8536193/
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We previously reported a novel association between CDKN2A nonpromoter methylation and transcription (ARF/INK4a) in human papillomavirus associated oropharyngeal tumors. In this study we assessed whether nonpromoter CDKN2A methylation in laryngeal squamous cell carcinomas (LXSCC) conferred a similar association with transcription that predicted patient outcome. We compared DNA methylation and ARF/INK4a RNA expression levels for the CDKN2A locus using the Illumina HumanMethylation27 beadchip and RT-PCR in 43 LXSCC tumor samples collected from a prospective study of head and neck cancer patients treated at Montefiore Medical Center (MMC). Validation was performed using RNAseq data on 111 LXSCC tumor samples from the Cancer Genome Atlas (TCGA). The clinical relevance of combined nonpromoter CDKN2A methylation and transcription was assessed by multivariate Cox regression for locoregional recurrence on a subset of 69 LXSCC patients with complete clinicopathologic data from the MMC and TCGA cohorts. We found evidence of CDKN2A nonpromoter hypermethylation in a third of LXSCC from our MMC cohort, which was significantly associated with increased ARF and INK4a RNA expression (Wilcoxon rank-sum, P = 0.007 and 0.003, respectively). A similar association was confirmed in TCGA samples (Wilcoxon rank-sum test P < 0.0001 for ARF and INK4a). Patients with CDKN2A hypermethylation or high ARF/INK4a expression were significantly less likely to develop a locoregional recurrence compared to those with neither of the features, independent of other clinicopatholgic risk factors (adjusted hazard ratio=0.21, 95% confidence interval:0.05-0.81). These results support the conclusion that CDKN2A nonpromoter methylation is associated with increased ARF and INK4a RNA expression, and improved locoregional control in LXSCC.
Lichen sclerosis is a chronic inflammatory skin disease that causes substantial discomfort and morbidity, most commonly in adult women, but also in men and children. Any skin site may be affected (and, rarely, the oral mucosa) but lichen sclerosus is most common in the anogenital area, where it causes intractable itching and soreness. In children, the disorder may be confused with changes seen in sexual abuse. Progression to destructive scarring is common. There is increased risk of developing vulval cancer, and there are links with penile cancer. Patients should be kept under long-term review. Lichen sclerosus can occur without symptoms, and the exact prevalence is uncertain. It occurs most commonly in women at times of low sex hormone output. The underlying cause is unknown, but there seems to be a genetic susceptibility and a link with autoimmune mechanisms. The wart virus and the spirochaete borrelia have been suggested but not substantiated as infective triggers. The Koebner phenomenon is known to occur (lichen sclerosus occurs in skin already scarred or damaged), so trauma, injury, and sexual abuse have been suggested as possible triggers of symptoms in genetically predisposed people. The treatment of choice for anogenital lichen sclerosus is potent topical corticosteroid ointment for a limited time. Circumcision may be indicated in men, and surgery may be considered in women, to relieve effects of scarring or to treat coexisting carcinoma. Current research aims to identify a treatable cause of lichen sclerosus, to identify patients at risk of scarring and of malignant disorders, and to find target pathways for therapeutic intervention.
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