Methylation of Multiple Genes as Diagnostic and Therapeutic Markers in Primary Head and Neck Squamous Cell Carcinoma

Chen, Kangmei; Sawhney, Raja; Khan, Mohammad Javed; Benninger, Michael S.; Hou, Zizheng; Sethi, Seema; Stephen, Josena K.; Worsham, Maria J.

doi:10.1001/archotol.133.11.1131

Cited by 70 publications

(81 citation statements)

References 36 publications

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“…CHFR promoter hypermethylation of primary OSCC was 34.7% in our study. In primary head and neck squamous cell carcinomas, the frequency of CHFR methylation has been reported to bẽ 30% (25) and 25% (26). These results were consistent with our data.…”

Section: Discussionsupporting

confidence: 93%

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Aberrant promoter hypermethylation of the CHFR gene in oral squamous cell carcinomas

Baba

Hara²,

Kato³

et al. 2009

Oncol Rep

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Abstract. Recent studies have shown that promoter hypermethylation of tumor suppressor genes is an important factor in carcinogenesis of several human organs. The purpose of this study was to examine the methylation status of CHFR, a novel cell cycle regulatory gene, in both primary oral cancer tumors and the adjacent normal mucosa, and to clarify the relation between the methylation status and expression of the CHFR-related chromosomal passenger protein Aurora-A. The methylation status of the CHFR gene was examined by the methylation-specific PCR (MSP) in 49 primary oral squamous cell carcinomas (OSCC) and 6 OSCC cell lines. In 13 cases, the adjacent normal oral mucosal tissues were also examined. Normal oral mucosa from 18 healthy volunteers was used as the control. The mRNA level of Aurora-A and CHFR in OSCC cell lines was investigated by real-time RT PCR and the protein expression of Aurora-A in certain tumor samples was confirmed by immunohistochemistry. Aberrant promoter methylation of the CHFR gene was detected in 34.7% (17 of 49) of OSCC cases. As for the 13 OSCC cases with paired cancerous and adjacent normal tissues, promoter hypermethylation of the CHFR gene was detected in 46.1% (6 of 13) of the cancerous tissues. In contrast, promoter hypermethylation of the CHFR gene was recognized in only 7.7% (1 of 13) of the surrounding normal mucosa.

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Section: Discussionsupporting

confidence: 93%

“…Thus, our results imply that the OSCCs in advanced stage have more frequent methylation in the promoter region of CHFR. It was also reported that the methylation of CHFR is seen only in the stage IV case of head and neck cancer (26). Therefore, when the cancer progresses, CHFR methylation occurs with high frequency.…”

Section: Discussionmentioning

confidence: 92%

Aberrant promoter hypermethylation of the CHFR gene in oral squamous cell carcinomas

Baba

Hara²,

Kato³

et al. 2009

Oncol Rep

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“…Several studies have reported an association between aberrant DNA methylation and carcinogenesis (39)(40)(41). However, the association between epigenetic changes and cancer etiology needs to be elucidated.…”

Section: Results Of Immunostainingmentioning

confidence: 99%

High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer

Koike

Kasamatsu

Iyoda

et al. 2012

International Journal of Oncology

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Abstract.The four and a half LIM domains 1 (FHL1) gene has been related to carcinogenesis. However, the expression status of FHL1 in human oral squamous cell carcinoma (OSCC) remains unclear and the detailed mechanism of gene silencing is poorly understood. The aim of this study was to examine the FHL1 expression level and its regulatory mechanism in OSCCs. Quantitative reverse-transcriptase-polymerase chain reaction (PCR) and western blotting showed significant downregulation of FHL1 in all OSCC-derived cell lines (Sa3, HSC-2, HSC-3, HSC-4, HO-1-u-1, HO-1-N-1, KON and Ca9-22) compared to human normal oral keratinocytes. We also found that FHL1 mRNA expression was frequently downregulated (P<0.01) in 51 (86.4%) of 59 primary OSCCs compared with the corresponding normal oral tissues, while there was no significant difference between the status of the FHL1 protein expression in OSCCs and the clinicopathological features. Using methylationspecific PCR, we detected methylated FHL1 in all cell lines and treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine restored the FHL1 expression. However, no significant restoration of FHL1 expression was observed using sodium butyrate, an inhibitor of histone deacetylase and chromatin immunoprecipitation showed that histone H3 lysine 9 in the FHL1 promoter region was significantly acetylated. In addition, no mutation in the entire coding region of the FHL1 gene was found. Therefore, our data suggested that inactivation of the FHL1 gene is a frequent event during oral carcinogenesis and that the mechanism of FHL1 downregulation in OSCCs is through DNA methylation of the promoter region rather than histone deacetylation or mutation. IntroductionHead and neck squamous cell carcinoma (HNSCC) is one of the most frequently occurring malignancies and a major cause of morbidity and mortality (1,2). Oral cancer is the most common among the HNSCCs and the most frequently occurring oral cancer is squamous cell carcinoma (OSCC), which accounts for more than 90% of all oral malignancies (3). The number of OSCC cases that occur worldwide annually exceeds 300,000 (4). The mechanisms behind tumor progression of OSCC are known to a limited extent, indicating a clear need for comprehensive knowledge that can lead to more specific and effective molecular target.Microarray technology facilitates simultaneous evaluation of thousands of genes in a specimen. The results of microarray analysis provide researchers with high throughput screening to study the roles played by specific genes in cancer development and progression. We previously reported gene expression profiling of OSCC to identify cancer-related genes (5,6).The four and a half LIM domains (FHL) family of genes is characterized by LIM domains, a term derived from the first letters of three transcription factors: Lin-11, Isl-1 and Mec-3. Because the LIM domains provide protein-protein binding interfaces, the FHL genes play an important role in cellular events such as focal adhesion and differentiation by repressing or ac...

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“…17 Quantitative methylation-specific PCR detects the presence of neoplastic DNA with a sensitivity of 1 cell in 1000. 20 This PCR approach is more sensitive than conventional PCR and more specific due to the use of an internally binding, fluorogenic hybridization probe.…”

Section: Hpv16 Detection By Means Of Quantitative Polymerase Chain Rementioning

confidence: 99%

IGSF4Methylation as an Independent Marker of Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma

Chen

Stephen

Havard

et al. 2015

JAMA Otolaryngol Head Neck Surg

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Methylation of Multiple Genes as Diagnostic and Therapeutic Markers in Primary Head and Neck Squamous Cell Carcinoma

Cited by 70 publications

References 36 publications

Aberrant promoter hypermethylation of the CHFR gene in oral squamous cell carcinomas

Aberrant promoter hypermethylation of the CHFR gene in oral squamous cell carcinomas

High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer

IGSF4Methylation as an Independent Marker of Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma

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