PubMed · 7373118
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B Bell. 1980. Hypercalcemia in malignancy.. https://pubmed.ncbi.nlm.nih.gov/7373118/
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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.
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BACKGROUND: Inhibition of apoptosis, or programmed cell death, may be critical both in the development of cancer and in determining response to therapy. The authors examined the expression of two related apoptotic inhibitors, Bcl-2 and Bcl-xL, in pretreatment biopsies from a series of 42 patients with squamous cell carcinoma of the head and neck. The observed pattern of apoptotic inhibitor expression was compared with that of the p53 gene product, another factor implicated in carcinogenesis and therapeutic responsiveness. METHODS: Formalin fixed, paraffin embedded tumor biopsies from 42 patients with locally advanced squamous cell carcinoma of the head and neck were analyzed by immunohistochemistry using antibodies specific for Bcl-xL, Bcl-2, and p53. Measures of clinical outcome, including disease specific survival and overall survival, were compared among the groups. RESULTS: The majority of the tumors demonstrated enhanced expression of either Bcl-2 or Bcl-xL compared with surrounding normal epithelium. Fifty-two percent of the tumors had up-regulated Bcl-xL, and 17% had up-regulated Bcl-2. There was no overlap between these groups. Expression of Bcl-2, but not Bcl-xL, was correlated with improved disease specific survival. Immunohistochemically detectable p53 expression (48% of tumors) was not found to correlate with expression of either Bcl-xL or Bcl-2 and, in this series, was not a predictor of clinical outcome. CONCLUSIONS: These results suggest that disruption of apoptotic control pathways is an important event in the evolution of squamous cell carcinoma of the head and neck. A common mechanism for this disruption involves overexpression of Bcl-xL, Patients whose tumors demonstrate Bcl-2 positivity, even with locoregionally advanced disease, appear to have a high likelihood of cure with aggressive combined modality therapy and may be treated successfully with less toxic therapy.