PubMed · 2505026
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V Sivanesaratnam. 1989-09-04. Mitomycin-C cardiotoxicity.. https://doi.org/10.5694/j.1326-5377.1989.tb101205.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.
We have shown previously that microsatellite alterations in serum DNA was predictive of distant metastasis in a study with 21 primary head and neck squamous cell carcinoma patients. To further investigate serum microsatellite alterations as a prognostic tool, we carried out microsatellite analysis of serum DNA with 10 markers on 152 patients with head and neck cancer. Forty-five percent (68/152) of patients had microsatellite alterations of serum DNA identical to corresponding tumor DNA. In 16 patients that had distant metastasis, 11 patients had a positive serum test (microsatellite alterations detectable in their serum DNA with one or more markers). The difference in distant metastasis rates between the negative and positive serum tests (6.0% [5/84] vs. 16.2% [11/68], RR = 2.7) was clinically significant and almost reached statistical significance (p = 0.06). When the analysis was restricted to patients with recurrent disease, a positive serum test correlated with those who developed distant metastasis (p = 0.04). Other parameters, such as development of recurrence, stage of the cancer, disease-free survival and overall survival, were not associated with a positive serum test. Detecting tumor DNA in serum by microsatellite analysis may help identify patients at risk for distant metastasis. Therefore, circulating tumor cells may contribute to the presence of tumor DNA in the serum. In the future if a serum test is positive, therapeutic approaches may by intensified, such as platinum-based chemoradiation, to reduce distant failures.
Antineoplastic properties of cyclopentenone 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) involve peroxisome proliferator-activated receptor gamma (PPARgamma) dependent and independent mechanisms. We recently reported that 15d-PGJ2 inhibits cell growth and induces apoptosis in human oral squamous cell carcinoma (SCC) partly independent of PPARgamma activation. Given the importance of epidermal growth factor receptor (EGFR) as a therapeutic target in head and neck SCC, we addressed the effects of 15d-PGJ2 on EGFR expression. 15d-PGJ2, but not other PPARgamma ligands, abrogated EGFR protein expression in oral SCC cells. 15d-PGJ2 also decreased EGFR mRNA, indicating downmodulation at the transcriptional level. Moreover, treatment with 9,10-dihydro-15d-PGJ2, a 15d-PGJ2 analog lacking the reactive carbonyl group, failed to effect EGFR expression. These findings provide evidence for EGFR downregulation in oral SCC cells through a novel anticancer effect of 15d-PGJ2 that is attributed to the reactive cyclopentenone ring system.