PubMed · 5499908
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F W Van de Water. 1970. Partial laryngectomy.. https://pubmed.ncbi.nlm.nih.gov/5499908/
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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.
A review of the DAHANCA-group's projects concerning cancer of the head and neck over 20 years is presented. Apart from the first, all projects were randomized trials. Two projects with neoadjuvant chemotherapy have not shown any notable tumour control or better survival. More than 1800 patients suffering from cancer of the head and neck treated in the five oncological centres of the country were included in the three projects concerning radiosensitizers and radiotherapy. The radiation has been accelerated during the years making it more effective. Each of the three projects has improved the local control rate by 11-15% and the survival is enhanced by 11-13% for each project. Cooperation between our five oncological centres has given good results and increased the survival for patients with head and neck cancer. It is now routine to give the radiosensitizer tablets Nimorazol 1 1/2 hours before radiation and to give six fractions weekly to patients with squamous cell cancer in the supraglottic region, pharynx and oral cavity.
Two hundred eight primary squamous cell carcinomas of the head and neck have been analyzed with respect to the presence of the retinoblastoma tumor suppressor protein, pRb. Of these, 23 tumors (11%) that preferentially localized to the tonsils revealed complete absence or dramatic reduction in the amount of pRb. Other cell cycle components, cyclin D1 and p16INK4A, which are intimately related to pRb through an autoregulatory loop, were also dramatically decreased or overexpressed, respectively, in these pRb-defective tumors. On the other hand, the majority of the pRb-defective tumors contained the wild-type p53 gene. No evidence was found for genetic defects at the Rb locus in these tumors. Very significantly, in 11 of 12 pRb-defective tonsillar tumors, but in none of 9 pRb-positive tonsillar tumors (P < 10[-7]), DNA of oncogenic human papillomavirus types was identified, providing a strong indication for a human papillomavirus-associated etiology of these tumors and suggesting the functional inactivation of the pRb protein by the viral E7 gene product. In comparison to all head and neck squamous cell carcinomas studied, the pRb-defective tonsillar tumors were in general more poorly differentiated (P = 0.0059), and they were all metastatic at the time of resection. Of particular clinical interest, despite these adverse histopathological factors, the clinical outcome for these patients was relatively favorable, strongly implying that the pRb-defective tumors responded uniformly well toward postoperative radiation therapy.