PubMed · 10668674
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K T Pitman. Rationale for elective neck dissection.. https://doi.org/10.1016/s0196-0709(00)80121-0
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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.
Alterations in chromosomal number and structure are found in most solid malignancies including head and neck squamous cell carcinoma (HNSC), however, the presence of ongoing, chromosomal instability in HNSC and its relation to spindle assembly checkpoint defects has not been formally demonstrated. We investigated the status of chromosomal instability (CIN) in HNSC primary tumors and cell lines as well as spindle assembly checkpoint integrity in HNSC cell lines. Centromeric fluorescence in situ hybridization (FISH) was carried out on expanded single cell-derived colonies from HNSC cell lines and primary HNSC touch preparations. The deviation of chromosomes from the modal number in single cell derived colonies was 18.4-27% in 6 HNSC cell lines, and 2-3% in a control cell line, HCT116. Twelve primary tumors and 4 normal controls were also studied; all primary tumors demonstrated significant deviation from the modal chromosomal number (average 33.7%, range = 29.9-43.9%), compared to normal controls (average 4.6%, range = 3.6-5.6%). Additional characterization of the rate of chromosomal breakage was carried out by dual color FISH simultaneously using centromeric and telomeric probes for individual chromosomes on expanded singe cell-derived colonies and primary HNSC. Control HCT 116 colonies demonstrated a mean discordance between number of centromeric and telomeric hybridization signals in 21% (range = 19-23%) of cells, whereas HNSC cell line colonies demonstrated a mean discordance of 50% (range = 38-55%), with the majority of instances of discordant signal indicating telomeric loss. Similarly, touch preparations from primary HNSC demonstrated discordance in hybridization signal of centromeric vs. telomeric signal of 26.3% (range = 18.5-42%), with normal controls showing a rate of discordance of 6.4% (range = 4-8%). Finally, all 6 HNSC cell lines demonstrated partial impairment of mitotic arrest in response to nocodazole, indicating that impairment of the spindle assembly checkpoint may contribute to chromosomal instability in HNSC. Ongoing instability in chromosomal number and structure are consistent features of primary HNSC and cell lines. Spindle assembly checkpoint impairment occurs in HNSC cell lines and may contribute to chromosomal instability in HNSC.
Two-dimensional polyacrylamide gel electrophoresis (2-DE) profiles of human lung squamous carcinoma tissue and paired surrounding normal bronchial epithelial tissue were compared. Selected differential protein-spots were identified with peptide mass fingerprinting based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and database searching. Well-resolved and reproducible 2-DE patterns of both the tumor and the normal tissues were acquired. The average deviations of spot position were 0.873+/-0.125mm in IEF direction and 1.025+/-0.213mm in SDS-PAGE direction, respectively. For the tumor tissues, a total of 1349+/-67 spots were detected and 1235+/-48 spots were matched with an average matching rate of 91.5%. For the corresponding normal tissues, a total of 1297+/-73 spots were detected and 1183+/-56 spots were matched with an average matching rate of 91.2%. A total of 1069+/-45 spots were matched between the tumor and the normal tissues. Forty differential proteins between tumor and normal tissues were characterized. Some proteins were the products of oncogenes and others were involved in the regulation of cell cycle and signal transduction. These data are valuable for mass identification of differentially expressed proteins involved in lung carcinogenesis, establishing human lung cancer proteome database and screening molecular marker to further study human lung squamous carcinoma.