Microsatellite instability and methylation of the DNA mismatch repair genes in head and neck cancer

Demokan, Semra; Süoğlu, Yusufhan; Demir, Deniz; Gözeler, Mustafa Sıtkı; Dalay, Nejat

doi:10.1093/annonc/mdl048

Cited by 48 publications

(41 citation statements)

References 29 publications

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“…In other cancer types MSI has been identified but remains poorly defined, for instance in squamous cell carcinomas. Hypermethylation of MLH1 and MSH2 genes have been implicated as a potential cause of MSI in head and neck squamous cell carcinoma [11]. In ovarian cancer, alterations of homologous repair genes including BRCA1 have been associated with CD274 expression and tumor-infiltrating lymphocytes [12].…”

Section: Introductionmentioning

confidence: 99%

Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

et al. 2016

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Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PD-L1) expression.A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma.A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC.Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition.

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Section: Introductionmentioning

confidence: 99%

Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

et al. 2016

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“…Methylation of different genes acting in independent pathways have been analyzed in HNC (Sanchez-Caspedes et al, 2000;Rosas et al, 2001;Hasegawa et al, 2002;Ogi et al, 2002;Fan, 2004;Demokan et al, 2006). However, most of these studies have focused on a single or, at most, a few candidate genes; and the reported methylation frequencies and specificities of the methods vary widely between the studies.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Methylation Profiling of Tumor Suppressor Genes in Head and Neck Cancer

Yalnız

Demokan

Süoğlu

et al. 2011

DNA and Cell Biology

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Head and neck cancer (HNC) is a common cancer, and its prognosis has not changed during the last decades. Detection of the disease at an early stage is crucial for successful treatment, as early diagnosis can significantly increase the survival rate. Methylation of tumor suppressor genes is an early event in cancer responsible for incorrect gene silencing. Since methylation changes are reversible, they also provide a promising target for therapy. So far, only individual genes have been analyzed for aberrant methylation in HNC. In this study, we analyzed the methylation status of 24 tumor suppressor genes simultaneously by methylation-specific multiplex ligation-dependent probe amplification in matched tumor and normal tissue samples from patients with HNC. CHFR, RARβ, DAPK1, and RASFF1 genes were the most frequently methylated genes in tumor tissue. Eight genes were not methylated in any sample. The methylation frequencies for individual genes ranged from 0% to 19%. Our results indicate that methylation of tumor suppressor genes is not high as previously reported by methylation-specific polymerase chain reaction and is confined to a smaller but significant fraction of the tumors. Whether this group represents a unique entity in the disease spectrum warrants further studies.

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“…Approximately 80-90% of cases of HNSCC are attributed to prolonged tobacco and/or alcohol use (2). However, only a small fraction of those who consume tobacco or alcohol develop this disease, suggesting that genetic factors are also important in its pathogenesis (4)(5)(6). Fundamental to the genetic basis of all cancers is the overexpression of oncogenes and/or silencing of tumor suppressor genes.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Rab25 activates Akt1 in head and neck squamous cell carcinoma

et al. 2015

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Abstract. Several studies have suggested that Ras-associated binding 25 protein (Rab25) is involved in the pathogenesis of human cancer. Although it has been demonstrated that the development of head and neck squamous cell carcinoma (HNSCC) is the result of an accumulation of multiple sequential genetic and epigenetic alterations in key genes with important functions in cell growth and the cell cycle, recent studies have indicated that HNSCC is a complex and heterogenous disease. To the best of our knowledge, there is no data regarding the regulation of the Rab25 gene at the mRNA or protein level in HNSCC. Furthermore, available data on Rab25 expression in other types of cancer are conflicting. The aim of the present study was to investigate whether Rab25 is involved in the development and/or progression of HNSCC, and to analyze the mechanisms underlying its effects in this type of cancer. The expression of Rab25 mRNA in HNSCC tissues and adjacent non-tumor tissue samples was measured using reverse transcription-quantitative polymerase chain reaction, while the level of the Rab25, Akt1 and phosphorylated-Akt1 proteins was measured using western blotting. Expression of Rab25 mRNA and protein was downregulated in 69.1% and 56.1% of tumor tissue samples, respectively. This downregulation was associated with an increase in p-Akt1 expression, in the absence of a change in total Akt1 protein levels, in tumor tissues compared with normal tissues. The current findings suggest that Rab25 acts as a tumor suppressor in HNSCC.

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Microsatellite instability and methylation of the DNA mismatch repair genes in head and neck cancer

Abstract: Our results indicate that microsatellite instability and modifications in the hMLH1 and hMSH2 genes are implicated in a significant proportion of the patients with head and neck cancer.

Cited by 48 publications

References 29 publications

Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

Simultaneous Methylation Profiling of Tumor Suppressor Genes in Head and Neck Cancer

Downregulation of Rab25 activates Akt1 in head and neck squamous cell carcinoma

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