Status of reduced expression and hypermethylation of the APC tumor suppressor gene in human oral squamous cell carcinoma

Uesugi, Hisako; Uzawa, Katsuhiro; Kawasaki, Keishi; Shimada, Ken; Moriya, Tsuneo; Tada, Akio; Shiiba, Masashi; Tanzawa, Hideki

doi:10.3892/ijmm.15.4.597

Cited by 22 publications

(27 citation statements)

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“…Genetic and epigenetic alterations in APC (adenomatosis polyposis coli), a tumor suppressor gene originally implicated in colon cancer have been reported in other malignancies including oral squamous cell carcinomas, gastric cancers and esophageal adenocarcinomas. Uesugi et al(49) previously reported APC as being mutated and/or deleted in primary oral squamous cell carcinoma (OSCC) tissues and suggested that loss of APC function contributes to carcinogenesis in the oral region. Promoter hypermethylation is also an important mechanism of APC inactivation in oral cancers occurring in 25% of OSCC cell(49).…”

Section: Discussionmentioning

confidence: 99%

DNA Hypermethylation Profiles in Squamous Cell Carcinoma of the Vulva

Stephen

Chen

Raitanen

et al. 2009

International Journal of Gynecological Pathology

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Gene silencing through promoter hypermethylation is a growing concept in the development of human cancers. In this study, we examined the contribution of aberrant methylation of promoter regions in methylation-prone tumor suppressors to the pathogenesis of vulvar cancer. Thirteen cell lines from 12 patients with squamous cell carcinoma of the vulva (SCV) were evaluated for aberrant methylation status and gene copy number alterations, concomitantly, using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay. Of the 22 tumor suppressor genes examined, aberrant methylation was observed for 9 genes: TP73, FHIT, VHL, APC, ESR1, CDKN2B, DAPK1, GSTP1 andI GSF4. The most frequently methylated genes included TP73 in 9 of 13 cell lines, and IGSF4, DAPK1 and FHIT in 3 of 13 cell lines. Methylation specific polymerase chain reaction (MSP) was performed for TP73 and FHIT to confirm aberrant methylation by MS-MLPA. In the context of gene copy number and methylation status, both copies of the TP73 gene were hypermethylated. Loss or decreased mRNA expression of TP73 and IGSF4 by RT-PCR confirmed aberrant methylation. Frequent genetic alterations of loss and gain ofgene copy number included gain of GSTP1 and MEN1, and loss of MFHAS1 and IGSF4 in over 50% of the SCV cell lines. These findings underscore the contribution of both genetic and epigenetic events to the underlying pathogenesis of squamous cell carcinoma of the vulva.

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Section: Discussionmentioning

confidence: 99%

DNA Hypermethylation Profiles in Squamous Cell Carcinoma of the Vulva

Stephen

Chen

Raitanen

et al. 2009

International Journal of Gynecological Pathology

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“…Therefore, by analyzing for DNA methylation, we can turn a negative biological event into a positive clinical test. Previous studies analyzing promoter hypermethylation have looked at a panel of 2 to 20 genes to establish the sensitivity of detection of head and neck cancer (3)(4)(5)(6)(7)(8)(9). In these studies, genes have been chosen based on their known role in head and neck carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Methylation Array Analysis of Preoperative and Postoperative Saliva DNA in Oral Cancer Patients

Viet

Schmidt

2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Purpose: To perform methylation array analysis of 807 cancer-associated genes using tissue and saliva of oral squamous cell carcinoma (OSCC) patients with the objective of identifying highly methylated gene loci that hold diagnostic and predictive value as a biomarker. Experimental Design: We did the methylation array on DNA extracted from preoperative saliva, postoperative saliva, and tissue of 13 patients with OSCC, and saliva of 10 normal subjects. We identified sites that were highly methylated in the tissue and preoperative saliva samples but not methylated in the postoperative saliva samples or in normal subjects.Results: High quality DNA was obtained and the methylation array was successfully run on all samples. We identified significant differences in methylation patterns between the preoperative and postoperative saliva from cancer patients. We established a gene classifier consisting of 41 gene loci from 34 genes that showed methylation in preoperative saliva and tissue but were not methylated in postoperative saliva or normal subjects. Gene panels of 4 to 10 genes were constructed from genes in the classifier. The panels had a sensitivity of 62% to 77% and a specificity of 83% to 100% for OSCC. Conclusions: We report methylation array analysis of 807 cancer-associated genes in the saliva of oral cancer patients before and after oral cancer resection. Our methylation biomarker approach shows the proof of principle that methylation array analysis of saliva can produce a set of cancer-related genes that are specific and can be used as a composite biomarker for the early detection of oral cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3603 -11)

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“…Genetic and epigenetic alterations in this gene have since been recognized in other malignancies including oral squamous cell carcinoma (OSCC), gastric cancers and esophageal adenocarcinomas. Uesugi et al (42) previously reported mutations and/or deletions of APC in primary OSCC and suggested that loss of APC function contributes to carcinogenesis in the oral region. APC inactivation as a result of promoter hypermethylation occurred in 25% of OSCC cell (42).…”

Section: Discussionmentioning

confidence: 99%

“…Uesugi et al (42) previously reported mutations and/or deletions of APC in primary OSCC and suggested that loss of APC function contributes to carcinogenesis in the oral region. APC inactivation as a result of promoter hypermethylation occurred in 25% of OSCC cell (42). In a primary LSCC cohort of 79 patients, aberrant methylation of APC occurred in 16% of the tumors (43).…”

Section: Discussionmentioning

confidence: 99%

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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Status of reduced expression and hypermethylation of the APC tumor suppressor gene in human oral squamous cell carcinoma

Cited by 22 publications

References 0 publications

DNA Hypermethylation Profiles in Squamous Cell Carcinoma of the Vulva

DNA Hypermethylation Profiles in Squamous Cell Carcinoma of the Vulva

Methylation Array Analysis of Preoperative and Postoperative Saliva DNA in Oral Cancer Patients

Molecular characterization of late stomal recurrence following total laryngectomy

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