PubMed · 8282917
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V A Muscarella. 1993. Angiosarcoma treated by Mohs micrographic surgery.. https://doi.org/10.1111/j.1524-4725.1993.tb02481.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.
The EMS1 gene, located at the chromosome 11q13 region, is the human homologue of p80/p85 cortactin, a chicken pp60(src) tyrosine kinase substrate. In cells derived from breast carcinomas and squamous carcinomas of the head and neck, DNA amplification of this region results in overexpression of cortactin. Overexpression is accompanied by a partial redistribution of cortactin from the cytoplasm into cell-matrix contact sites. To investigate whether overexpression only is sufficient for this redistribution, we performed biochemical analysis of human cortactin derived from carcinoma cell lines with either normal levels (UMSCC8) or with excessive levels of cortactin due to chromosome 11q13 amplification (UMSCC2). Pulse-chase experiments performed with UMSCC2 cells revealed that p85 originated from p80 by post-translational modifications. However, the conversion of p80 into p85 was hardly observed in UMSCC8 cells, indicating a different processing of the two isoforms in cells with a normal expression level of cortactin. Western blot analysis showed that treatment of UMSCC2 cells with cycloheximide, serum, epidermal growth factor, or vanadate resulted in the disappearance of the p80 form and conversion into p85. Conversion of p80 into p85 was accompanied by a redistribution of cortactin from cytoplasm to cell-matrix contact sites. In UMSCC8 cells, these treatments had no effect on the p80/p85 ratio, and cortactin remained in the cytoplasm. Conversion into p85 therefore is correlated with a relocalization of cortactin to the cell periphery. In addition, p85 from epidermal growth factor- or vanadate-treated UMSCC2 cells showed a significant enhancement in phosphorylation compared with p85 in UMSCC8 cells. Our findings demonstrate that in carcinoma cells with 11q13 amplification not only overexpression but also post-translational modifications of cortactin coincides with the redistribution from the cytoplasm into cell-matrix contact sites.
Human papillomavirus (HPV) infection has been widely implicated in cervical carcinogenesis, but it appears to be an early event, with other genetic abnormalities being required for biological transformation. In this study, interphase cytogenetic analysis of numerical abnormalities of chromosomes 11, 17 and X was performed on paraffin-embedded tissue sections from 25 invasive squamous-cell carcinomas of the cervix and compared with both histopathological features and the morphological distribution of HPV sequences as determined by in situ hybridisation. Numerical differences between chromosomes were identified in 76% of cases, with underrepresentation of chromosomes 11 and/or 17 relative to X in 64% of the total; 22 of 25 cases were HPV-positive, containing either HPV 16, 18 or 31. There was no relationship between the distribution of viral sequences and chromosomal pattern, suggesting that HPV infection precedes karyotypic changes. Our findings suggest that relative reduction in number of chromosomes 11 and 17 is important in the development of invasive cervical neoplasia and are consistent with the putative presence of relevant tumour-suppressor genes on these chromosomes.