PubMed · 8604693
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S M Skoumal. 1996. False positives and malpractice risk.. https://doi.org/10.1093/ajcp%2F105.4.520
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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.
Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycle acting at the restriction point in late G1. Amplification of the cyclin D1 locus, located on chromosome 11q13, as well as cyclin D1 protein overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumorigenesis, using a combination of fluorescence in situ hybridization and immunohistochemistry techniques. From 29 selected patients presenting with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of amplification at the 11q13 band, we analysed 46 paraffin-embedded tissue specimens that demonstrated, besides the primary tumor, the presence of contiguous adjacent normal tissue and/or premalignant lesions. Of the 16 amplified cases, nine demonstrated a continuous progression from premalignant to invasive carcinoma and seven (77.7%) of these cases showed cyclin D1 gene amplification in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein expression was observed in all 16 amplified tumors and five of the 13 (38.4%) non-amplified tumors. Interestingly, dysregulated cyclin D1 expression was also found in the premalignant lesions adjacent to all 16 amplified tumors, and it appeared to precede cyclin D1 gene amplification. In contrast no dysregulated expression was detected in the premalignant lesions of the non-amplified tumors. In conclusion, these findings provide strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene amplification.
PURPOSE: A potential disadvantage of accelerated fractionation in radiotherapy is the lack of time for reoxygenation, so that hypoxia becomes a more potent cause of failure. Accordingly, we have combined nimorazole, the only hypoxic radiosensitizer shown to significantly improve local control in head and neck cancer, with continuous hyperfractionated accelerated radiation therapy (CHART). METHODS AND MATERIALS: Twenty-two patients with locally advanced (stage IV) squamous cell carcinoma of the head and neck were treated with escalating doses of nimorazole given concomitantly with CHART (three fractions of 1.5 Gy per day, spaced 5 1/2 hours apart, on 12 consecutive days). All patients received 1.2 g/m2 nimorazole 90 minutes before each first daily fraction. Seventeen patients received a further 0.6 g/m2 before each second daily fraction and six of these patients received an additional dose of 0.6 g/m2 before each third fraction. RESULTS: The three times daily schedule yielded mean plasma drug concentrations at the time of irradiation of 37.7 microg/ml with the morning fractions, 31.2 microg/ml with the afternoon fractions, and 30.4 microg/ml with the evening fractions. In view of these results the midday dose was increased to 0.9 microg/m2 in an ongoing Phase II study. Drug toxicity was limited to nausea and vomiting apart from two cases of mild paraesthesia at the highest dose level. CONCLUSIONS: Comparison with a historical group of patients, treated with the CHART regimen alone and matched for irradiation volume and technique, showed that nimorazole did not increase the severity of acute normal tissue radiation effects. Encouraging tumor responses have been seen in the patients receiving nimorazole with every radiotherapy fraction.