An Epigenetically Derived Monoclonal Origin for Recurrent Respiratory Papillomatosis

Stephen, Josena K.; Vaught, L; Chen, Kang Mei; Shah, Veena; Schweitzer, Vanessa G.; Gardner, Glendon M.; Benninger, Michael S.; Worsham, Maria J.

doi:10.1001/archotol.133.7.684

Cited by 21 publications

(38 citation statements)

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“…Briefly, concurrently present tumor (severe dysplasia, carcinoma in situ, tumor) and nontumor (normal, mild/moderate dysplasia) lesions in the same paraffin-embedded formalin fixed tissue block were marked by the pathologist and individual lesions were microdissected from 5 micron sections mounted on glass slides using a single-use disposable scalpel blade under a dissecting microscope. This procedure minimizes mixing of normal and tumor subpopulations and yields lesion and tumor samples estimated to be at least 90% free from contamination with normal cells [3, 4]. …”

Section: Methodsmentioning

confidence: 99%

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Malignant and Nonmalignant Gene Signatures in Squamous Head and Neck Cancer

Worsham

Lü

Chen

et al. 2012

Journal of Oncology

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Genetic events specific to the pathogenesis of malignancy can offer clues to the tumorigenesis process. The objective of this study was to identify gene alterations that differentiate tumor and nontumor lesions in squamous head and neck cancer (HNSCC). DNA from 220 primary HNSCC with concurrently present tumor and nontumor lesions from the same patient was interrogated for genomic alterations of loss or gain of copy. Conditional logistic regression dealt with tumor and non-tumor records within a patient. Of 113 genes, 53 had univariate effects (P < 0.01), of which 16 genes remained in the multivariable model with P < 0.01. The model had a C-index (ROC) of 0.93. Loss of CDKN2B and gain of BCL6, FGF3, and PTP4A3 predicted tumor. Loss of BAK1 and CCND1 and gain of STCH predicted nontumor. This highly powered model assigned alterations in 16 genes specific for malignant versus nonmalignant lesions, supporting their contribution to the pathogenesis of HNSCC as well as their potential utility as relevant targets for further evaluation as markers of early detection and progression.

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Section: Methodsmentioning

confidence: 99%

“…The relative amounts of PCR product obtained reflect the relative amounts of ligated probes at the start of the PCR reaction. Amplification products are analyzed on a DNA sequencer (Applied Biosystems, Foster City, Ca), quantified and interpreted as previously described [1, 3, 4, 6–8]. …”

Section: Methodsmentioning

confidence: 99%

Malignant and Nonmalignant Gene Signatures in Squamous Head and Neck Cancer

Worsham

Lü

Chen

et al. 2012

Journal of Oncology

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“…In squamous head and neck cancer (HNSCC), recent comprehensive high-throughput methods have underscored the contribution of both genetic (19, 20) and epigenetic events (21, 22), often working together (23), in the development and progression of HNSCC. Previous studies from our group (24, 25) have demonstrated that epigenetic events of DNA hypermethylation underlie the pathogenesis of benign sinonasal and recurrent laryngeal papillomas, establishing a monoclonal origin for recurrent respiratory papillomatosis (RRP) as well support a monoclonal progression for malignant transformation to LSCC in some RRP cases…”

Section: Introductionmentioning

confidence: 80%

Molecular characterization of late stomal recurrence following total laryngectomy

et al. 2011

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The goal was to determine recurrent or second primary status for late stomal malignancies, 16 and 17 years post-total laryngectomy in two laryngeal squamous cell carcinoma (LSCC) patients, based on DNA methylation signatures and HPV typing. Adopting a literature review based definition of late stomal recurrences as new primaries at the site of the stoma or neopharynx occurring more than 5 years after total laryngectomy, we employed a multi-gene candidate approach to examine promoter methylation in 24 tumor suppressor genes and PCR-based assays for HPV status offered additional insights into whether the late stomal tumors post total laryngectomy were related or not. The primary tumor for Patient 1 was negative for HPV but had aberrant hypermethylation of APC, MLH1, and BRCA1. The stomal biopsy 17-years later showed presence of HPV-16 without any methylated genes. In Patient 2, HPV-11 and promoter methylation of APC identified in the primary tumor was also observed in the stomal malignancy 16 years post total laryngectomy. Additional information provided by molecular typing for HPV and methylation markers underscored Patient 1’s and 2’s late stomal presentation as most likely a second primary and recurrence, respectively. DNA methylation markers are particularly advantageous because DNA methylation is an early event in tumorigenesis, and the epigenetic modification, 5-methylcytosine, is a stable marker. Molecular marks to discern genetic heterogeneity or relatedness of stomal malignancies several years post-total laryngectomy can provide clues to their status as either second primaries or likely recurrences. Our results support the hypothesis that a subset of stomal recurrences after total laryngectomy represents second primary tumors.

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“…The microdissected lesions were mounted on glass slides using a single-use-disposable scalpel blade under a dissecting microscope. This procedure minimizes mixing of normal and tumor subpopulations, and yields lesion and tumor samples estimated to be at least 90% free from contamination with normal cells [11,12]. …”

Section: Methodsmentioning

confidence: 99%

Distinct Gene Profiles for Tumor and Non-Tumor Tissue in the Head and Neck: An Analytical Approach

Lü

Stephen²,

Chen³

et al. 2012

J Cancer Sci Ther

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In a study of genetic alterations, the Multiplex Ligation-dependent Probe Amplification (MLPA) assay was used to measure gain or loss of 113 gene-probes in tumor and non-tumor tissue samples collected from each of the 220 patients with squamous head and neck cancer (HNSCC). Conditional and marginal models were available; both models account for correlated data but have different aspects. The conditional logistic regression model was proposed to estimate the subject-specific risk of tumor based on the paired tumor and non-tumor data collection, which was in contrast with the marginal model to estimate population-average risk. The modeling process included rigorous variable selection, an initial multivariable model, a final model selection, and model validation. Genes with individual effect (p<0.01) were considered as candidates for the initial multivariable model for tumor. The final model included gene-probes with p<0.01 and estimations of odds ratios (OR) 95% Confidence Intervals (CIs) and the model’s predictive ability, measured by the receiver operating characteristic curve (ROC). A 10-fold cross-validation was performed to validate the model. Of 113 gene-probes, using the conditional approach, 16 genes in 7 chromosomes, remained in the final multivariable model with p<0.01 and an ROC score of 0.94. The cross-validation showed ROC mean (SD) score of 0.96(0.04). The marginal model, in contrast, ended with 8 gene-probes and had an observed ROC of 0.81. Conclusion The conditional approach appears to be the model of choice when assessing gene-probe risks of subjects with paired data collection and fewer missing covariates, compared to the marginal approach. This multiple gene model demonstrated excellent ability to discriminate tumor from non-tumor, and supports its contribution to the pathogenesis of HNSCC as well as their potential utility for further markers of early tumor detection.

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An Epigenetically Derived Monoclonal Origin for Recurrent Respiratory Papillomatosis

Cited by 21 publications

References 50 publications

Malignant and Nonmalignant Gene Signatures in Squamous Head and Neck Cancer

Malignant and Nonmalignant Gene Signatures in Squamous Head and Neck Cancer

Molecular characterization of late stomal recurrence following total laryngectomy

Distinct Gene Profiles for Tumor and Non-Tumor Tissue in the Head and Neck: An Analytical Approach

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