PubMed · 8147770
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J P Shah. 1994. Neck dissection: which and when?. https://doi.org/10.1111/j.1445-2197.1994.tb02188.x
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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.
Previous molecular genetic studies revealed that allelic loss of chromosome arm 3p is a frequent event in upper aerodigestive tract squamous cell carcinoma (UADT SCC). Recently, the Von-Hippel Lindau (VHL) tumor suppressor gene was identified at chromosome band 3p25-26. To determine if the VHL locus is altered in these tumors, a paired series of 26 tumors and blood from patients with UADT SCC that were previously shown to exhibit allelic loss of 3p were tested for LOH surrounding the VHL locus using four different polymorphic markers. All of the samples (100%) exhibited LOH for at least 1 marker. However, no LOH was detected using a polymorphism within exon 1 of the VHL gene which was informative for 18 of the 26 cases. Furthermore, mutations of the VHL gene could not be identified by single-strand conformation polymorphism, dideoxyfingerprint or direct DNA sequence analysis. In addition, the VHL gene was not inactivated by hypermethylation in any of the 26 tumor samples studied. These findings demonstrate that allelic loss of chromosome arm 3p in UADT SCC involves regions surrounding the VHL locus but does not include the VHL gene. The VHL gene, therefore, does not appear to be involved in the pathogenesis of UADT SCC.
PURPOSE: This study was done to determine the outcome in patients with oropharyngeal carcinoma treated at the University of Florida with radiotherapy alone to the primary site, for comparison with reported results of other types of treatment. METHODS AND MATERIALS: Of a consecutive cohort of 785 patients with biopsy-proven, previously untreated, invasive squamous cell carcinoma of the oropharynx, this report is based on the 490 patients who had continuous-course irradiation with curative intent at the University of Florida between October 1964 and January 1991. All patients had a minimum 2-year follow-up. Forty-eight percent had Stage T3 or T4 disease, and 64% had clinically apparent neck node metastases. The median radiation dose was 68 Gy for once-a-day treatment and 76.8 Gy for twice-a-day treatment. Patients with advanced neck node disease had planned neck dissection(s) after radiotherapy. RESULTS: The overall local control rate after radiotherapy alone was 73%. The ultimate local control rate (including surgical salvage) was 78%. At 5 years, the probability of control of neck disease was 85%; control above the clavicles, 67%; absolute survival, 44%; cause-specific survival, 77%; distant metastasis (as the first or only site of failure), 11%. Thirteen patients (2.6%) experienced severe treatment complications. CONCLUSION: Radiotherapy results in tumor control and survival rates comparable with rates achieved with combined irradiation and surgery, with less morbidity.