CDH13

Gene Summary

Gene:CDH13; cadherin 13
Aliases: CDHH, P105
Location:16q23.3
Summary:This gene encodes a member of the cadherin superfamily. The encoded protein is localized to the surface of the cell membrane and is anchored by a GPI moiety, rather than by a transmembrane domain. The protein lacks the cytoplasmic domain characteristic of other cadherins, and so is not thought to be a cell-cell adhesion glycoprotein. This protein acts as a negative regulator of axon growth during neural differentiation. It also protects vascular endothelial cells from apoptosis due to oxidative stress, and is associated with resistance to atherosclerosis. The gene is hypermethylated in many types of cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cadherin-13
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: CDH13 (cancer-related)

Ye M, Huang T, Li J, et al.
Role of CDH13 promoter methylation in the carcinogenesis, progression, and prognosis of colorectal cancer: A systematic meta-analysis under PRISMA guidelines.
Medicine (Baltimore). 2017; 96(4):e5956 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: H-cadherin (CDH13) is commonly downregulated through promoter methylation in various cancers. However, the role of CDH13 promoter methylation status in patients with colorectal cancer (CRC) remains to be clarified.
METHODS: Eligible articles were identified from online electronic database based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria. The pooled odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated and analyzed.
RESULTS: Eventually, a total of nine studies were included in this meta-analysis, including 488 CRC, 298 adjacent, 144 normal, 68 premalignant tissues. The results demonstrated that CDH13 promoter methylation was notably higher in CRC than in normal, adjacent, and premalignant tissues (cancer tissues vs normal tissues: OR = 16.94, P < 0.001; cancer tissues vs adjacent tissues: OR = 20.06, P < 0.001; cancer tissues vs premalignant tissues: OR = 2.23, P = 0.038). CDH13 promoter methylation had a significantly increased risk for poorly differentiated CRC (OR = 4.07, P = 0.001). CDH13 promoter methylation was not associated with sex status, tumor stage, and lymph node status (all P > 0.05). One study with 85 CRC patients reported that CDH13 promoter methylation was correlated with poor prognosis in overall survival (OS).
CONCLUSIONS: CDH13 promoter methylation may play an important role in the initiation and progression of CRC, and may be correlated with OS of patients with CRC. Additional studies with large sample sizes are needed to further confirm our findings in the future.

Jin X, Liu X, Li X, Guan Y
Integrated Analysis of DNA Methylation and mRNA Expression Profiles Data to Identify Key Genes in Lung Adenocarcinoma.
Biomed Res Int. 2016; 2016:4369431 [PubMed] Free Access to Full Article Related Publications
Introduction. Lung adenocarcinoma (LAC) is the most frequent type of lung cancer and has a high metastatic rate at an early stage. This study is aimed at identifying LAC-associated genes. Materials and Methods. GSE62950 downloaded from Gene Expression Omnibus included a DNA methylation dataset and an mRNA expression profiles dataset, both of which included 28 LAC tissue samples and 28 adjacent normal tissue samples. The differentially expressed genes (DEGs) were screened by Limma package in R, and their functions were predicted by enrichment analysis using TargetMine online tool. Then, protein-protein interaction (PPI) network was constructed using STRING and Cytoscape. Finally, LAC-associated methylation sites were identified by CpGassoc package in R and mapped to the DEGs to obtain LAC-associated DEGs. Results. Total 913 DEGs were identified in LAC tissues. In the PPI networks, MAD2L1, AURKB, CCNB2, CDC20, and WNT3A had higher degrees, and the first four genes might be involved in LAC through interaction. Total 8856 LAC-associated methylation sites were identified and mapped to the DEGs. And there were 29 LAC-associated methylation sites located in 27 DEGs (e.g., SH3GL2, BAI3, CDH13, JAM2, MT1A, LHX6, and IGFBP3). Conclusions. These key genes might play a role in pathogenesis of LAC.

Chen F, Huang T, Ren Y, et al.
Clinical significance of CDH13 promoter methylation as a biomarker for bladder cancer: a meta-analysis.
BMC Urol. 2016; 16(1):52 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Methylation of the tumor suppressor gene H-cadherin (CDH13) has been reported in many cancers. However, the clinical effect of the CDH13 methylation status of patients with bladder cancer remains to be clarified.
METHODS: A systematic literature search was performed to identify eligible studies in the PubMed, Embase, EBSCO, CKNI and Wanfang databases. The pooled odds ratio (OR) and the corresponding 95 % confidence interval (95 % CI) was calculated and summarized.
RESULTS: Nine eligible studies were included in the present meta-analysis consisting of a total of 1017 bladder cancer patients and 265 non-tumor controls. A significant association was found between CDH13 methylation levels and bladder cancer (OR = 21.71, P < 0.001). The results of subgroup analyses based on sample type suggested that CDH13 methylation was significantly associated with bladder cancer risk in both the tissue and the urine (OR = 53.94, P < 0.001; OR = 7.71, P < 0.001; respectively). A subgroup analysis based on ethnic population showed that the OR value of methylated CDH13 was higher in Asians than in Caucasians (OR = 35.18, P < 0.001; OR = 8.86, P < 0.001; respectively). The relationships between CDH13 methylation and clinicopathological features were also analyzed. A significant association was not observed between CDH13 methylation status and gender (P = 0.053). Our results revealed that CDH13 methylation was significantly associated with high-grade bladder cancer, multiple bladder cancer and muscle invasive bladder cancer (OR = 2.22, P < 0.001; OR = 1.45, P = 0.032; OR = 3.42, P < 0.001; respectively).
CONCLUSION: Our study indicates that CDH13 methylation may play an important role in the carcinogenesis, development and progression of bladder cancer. In addition, CDH13 methylation has the potential to be a useful biomarker for bladder cancer screening in urine samples and to be a prognostic biomarker in the clinic.

Chmelařová M, Sirák I, Mžik M, et al.
Importance of Tumour Suppressor Gene Methylation in Sinonasal Carcinomas.
Folia Biol (Praha). 2016; 62(3):110-9 [PubMed] Related Publications
Epigenetic changes are considered to be a frequent event during tumour development. Hypermethylation of promoter CpG islands represents an alternative mechanism for inactivation of tumour suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. The aim of this study was to investigate promoter methylation of specific genes in samples of sinonasal carcinoma by comparison with normal sinonasal tissue. To search for epigenetic events we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to compare the methylation status of 64 tissue samples of sinonasal carcinomas with 19 control samples. We also compared the human papilloma virus (HPV) status with DNA methylation. Using a 20% cut-off for methylation, we observed significantly higher methylation in RASSF1, CDH13, ESR1 and TP73 genes in the sinonasal cancer group compared with the control group. HPV positivity was found in 15/64 (23.4 %) of all samples in the carcinoma group and in no sample in the control group. No correlation was found between DNA methylation and HPV status. In conclusion, our study showed that there are significant differences in promoter methylation in the RASSF1, ESR 1, TP73 and CDH13 genes between sinonasal carcinoma and normal sinonasal tissue, suggesting the importance of epigenetic changes in these genes in carcinogenesis of the sinonasal area. These findings could be used as prognostic factors and may have implications for future individualised therapies based on epigenetic changes.

Altenburg A, Abdel-Naser MB, Nikolakis G, et al.
CD40/CD40 ligand interactions and TNFα treatment reduce activity of P105 promoter of the human papilloma virus-18 in vitro.
Exp Oncol. 2016; 38(1):22-5 [PubMed] Related Publications
BACKGROUND: Cervical carcinoma cells including those infected with the oncogenic human papilloma virus (HPV) and several cervical carcinoma cell lines show a strong expression of the CD40 receptor, unlike benign cervical epithelial cells infected with HPV. The functional relevance of this up-regulated expression in the tumor is not fully understood. Nevertheless, it might offer a unique possibility to target those malignant cells due to the antiviral and antitumoral effects of the CD40/CD40 ligand (CD40L) interactions.
AIM: In vitro assessment of the effect of CD40L on HPV 18-P105 promoter activity and the subsequent release of IL-6 by the promoter transfected HeLa(CD40) cells, which express CD40 constitutively.
MATERIAL AND METHODS: Transfection of HeLa(CD40) cells was achieved by electroporation after optimizing the parameters by the pCMV-β-Gal vector and β-Gal stain. Transfected HeLa(CD40) cells were challenged with BHK(CD40L) and TNFα, in addition to BHK(wt) and medium alone as controls. HPV18-P105 promoter activity was demonstrated by luciferase reporter gene assay while IL-6 was assessed by ELISA.
RESULTS: CD40/CD40L interactions and TNFα treatment significantly reduced HPV18-P105 promoter activity (56.0 ± 10.2% and 64.1 ± 9.1% vs. control, respectively; p < 0.001). Likewise, IL-6, which is a sensitive cytokine of CD40 activation, was significantly increased in HeLa(CD40) cells in the same experiments (2.7 fold after stimulation with BHK(CD40L) and 5.2 fold after stimulation with TNFα vs. control; p < 0.01 and p < 0.001, respectively).
CONCLUSION: It is likely that the CD40/CD40L interactions and TNFα are effective against cervical carcinomas by repressing transcriptional activity of HPV promoter. This can result in new adjuvant treatments.

de Oliveira KA, Kaergel E, Heinig M, et al.
A roadmap of constitutive NF-κB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses.
Genome Med. 2016; 8(1):28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NF-κB is widely involved in lymphoid malignancies; however, the functional roles and specific transcriptomes of NF-κB dimers with distinct subunit compositions have been unclear.
METHODS: Using combined ChIP-sequencing and microarray analyses, we determined the cistromes and target gene signatures of canonical and non-canonical NF-κB species in Hodgkin lymphoma (HL) cells.
RESULTS: We found that the various NF-κB subunits are recruited to regions with redundant κB motifs in a large number of genes. Yet canonical and non-canonical NF-κB dimers up- and downregulate gene sets that are both distinct and overlapping, and are associated with diverse biological functions. p50 and p52 are formed through NIK-dependent p105 and p100 precursor processing in HL cells and are the predominant DNA binding subunits. Logistic regression analyses of combinations of the p50, p52, RelA, and RelB subunits in binding regions that have been assigned to genes they regulate reveal a cross-contribution of p52 and p50 to canonical and non-canonical transcriptomes. These analyses also indicate that the subunit occupancy pattern of NF-κB binding regions and their distance from the genes they regulate are determinants of gene activation versus repression. The pathway-specific signatures of activated and repressed genes distinguish HL from other NF-κB-associated lymphoid malignancies and inversely correlate with gene expression patterns in normal germinal center B cells, which are presumed to be the precursors of HL cells.
CONCLUSIONS: We provide insights that are relevant for lymphomas with constitutive NF-κB activation and generally for the decoding of the mechanisms of differential gene regulation through canonical and non-canonical NF-κB signaling.

Huang T, Li J, Zhang C, et al.
Distinguishing Lung Adenocarcinoma from Lung Squamous Cell Carcinoma by Two Hypomethylated and Three Hypermethylated Genes: A Meta-Analysis.
PLoS One. 2016; 11(2):e0149088 [PubMed] Free Access to Full Article Related Publications
Significant differences in the aberrant methylation of genes exist among various histological types of non-small cell lung cancer (NSCLC), which includes adenocarcinoma (AC) and squamous cell carcinoma (SCC). Different chemotherapeutic regimens should be administered to the two NSCLC subtypes due to their unique genetic and epigenetic profiles. The purpose of this meta-analysis was to generate a list of differentially methylated genes between AC and SCC. Our meta-analysis encompassed 151 studies on 108 genes among 12946 AC and 10243 SCC patients. Our results showed two hypomethylated genes (CDKN2A and MGMT) and three hypermethylated genes (CDH13, RUNX3 and APC) in ACs compared with SCCs. In addition, our results showed that the pooled specificity and sensitivity values of CDH13 and APC were higher than those of CDKN2A, MGMT and RUNX3. Our findings might provide an alternative method to distinguish between the two NSCLC subtypes.

Scarpa M, Scarpa M, Castagliuolo I, et al.
Aberrant gene methylation in non-neoplastic mucosa as a predictive marker of ulcerative colitis-associated CRC.
Oncotarget. 2016; 7(9):10322-31 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: BACKGROUND PROMOTER: hypermethylation plays a major role in cancer through transcriptional silencing of critical genes. The aim of our study is to evaluate the methylation status of these genes in the colonic mucosa without dysplasia or adenocarcinoma at the different steps of sporadic and UC-related carcinogenesis and to investigate the possible role of genomic methylation as a marker of CRC.
RESULTS: The expression of Dnmts 1 and 3A was significantly increased in UC-related carcinogenesis compared to non inflammatory colorectal carcinogenesis. In non-neoplastic colonic mucosa, the number of methylated genes resulted significantly higher in patients with CRC and in those with UC-related CRC compared to the HC and UC patients and patients with dysplastic lesion of the colon. The number of methylated genes in non-neoplastic colonic mucosa predicted the presence of CRC with good accuracy either in non inflammatory and inflammatory related CRC.
METHODS: Colonic mucosal samples were collected from healthy subjects (HC) (n = 30) and from patients with ulcerative colitis (UC) (n = 29), UC and dysplasia (n = 14), UC and cancer (n = 10), dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, -3a, -3b, mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR.
CONCLUSIONS: Methylation status of APC, CDH13, MGMT, MLH1 and RUNX3 in the non-neoplastic mucosa may be used as a marker of CRC: these preliminary results could allow for the adjustment of a patient's surveillance interval and to select UC patients who should undergo intensive surveillance.

Sheng Y, Wang H, Liu D, et al.
Methylation of tumor suppressor gene CDH13 and SHP1 promoters and their epigenetic regulation by the UHRF1/PRMT5 complex in endometrial carcinoma.
Gynecol Oncol. 2016; 140(1):145-51 [PubMed] Related Publications
OBJECTIVE: Epigenetic changes in cancer and precancerous lesions could be utilized as biomarkers for cancer early detection. This study aims to investigate the novel biomarkers in endometrial carcinoma, and explore their epigenetic regulation.
METHODS: Methylation of six tumor suppressor genes (CDH13, SHP1, HIN1, DKK3, CTNNA1 and PCDH8) was evaluated in 155 endometrium samples. Changes of methylation and mRNA expression after treatment with 5-Aza-2'-deoxycytidine (5-Aza-CdR) or/and trichostatin A (TSA) were investigated by MSP and qRT-PCR respectively. Co-immunoprecipitation was used to detect the interactions between UHRF1 and PRMT5 proteins.
RESULTS: CDH13 and SHP1 promoters were highly methylated (81.36% and 86.44%, respectively) in endometrial carcinoma, while CDH13 promoter methylation was also present in complex hyperplasia and atypical hyperplasia (51.72% and 50.00%, respectively). Methylation of CDH13 and SHP1 promoters was associated with age and tumor differentiation or muscular infiltration depth. CDH13 and SHP1 promoters were completely methylated in endometrial carcinoma cell lines and were partially reversed by 5-Aza-CdR or TSA to induce mRNA levels (P<0.01). After combined treatment with these two agents, methylation of CDH13 and SHP1 promoters was completely reversed and expression of their mRNA was significantly increased (P<0.01). Moreover, PRMT5 could bind to UHRF1 and down-regulated by 5-Aza-CdR and/or TSA treatment (P<0.05).
CONCLUSIONS: Our data demonstrate for the first time that SHP1 methylation has high specificity for diagnosis of endometrial carcinoma, while CDH13 promoter methylation plays a role in the earlier stage. Furthermore, UHRF1 could form a complex with PRMT5 to contribute to the endometrial carcinogenesis.

Yin J, Wang H, Vogel U, et al.
Association and interaction of NFKB1 rs28362491 insertion/deletion ATTG polymorphism and PPP1R13L and CD3EAP related to lung cancer risk in a Chinese population.
Tumour Biol. 2016; 37(4):5467-73 [PubMed] Related Publications
The nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NFKB1) gene encodes p105 and p50 kD which are both subunits of the transcription factor NF-kB, involved in a wide variety of diseases and pathological states associated with inflammation, immunity, and tumorigenesis. The NFKB1 rs28362491 polymorphism in the promoter region (-94 insertion/deletion ATTG) has been associated with risk of various cancers. Our study aims were to evaluate the associations of NFKB1 rs28362491 polymorphism and interactions of this single-nucleotide polymorphism (SNP) and PPP1R13L and CD3EAP and smoking duration in relation to lung cancer risk in a Chinese population. The study population consisted of 544 Chinese lung cancer cases and 550 cancer-free matched (age, sex, and ethnicity) controls. No associations were found between NFKB1 rs28362491 and lung cancer risk. CD3EAP rs967591 was associated with increased lung cancer risk in the dominant model [OR (95 % CI) = 1.38 (1.05-1.80), P = 0.018]. The common haplotype containing PPP1R13L rs1970764(G), CD3EAP rs967591(A), and CD3EAP rs735482(C) was associated with lung cancer [adjusted OR (95 % CI) = 1.29 (1.03-1.62), P = 0.028]. Multifactor dimensionality reduction (MDR) analysis revealed two-way and three-way interactions between CD3EAP rs735482 and smoking and between NFKB1 rs28362491, PPP1R13L rs1970764, and smoking. In conclusion, we were able to reproduce previously found associations between PPP1R13L and CD3EAP polymorphisms and lung cancer risk in an increased study group, and we found interactions between NFKB1 rs28362491-PPP1R13L rs1970764 and smoking duration and between CD3EAP rs735482 and smoking duration. These results suggest that these genes and smoking are part of the same biological pathway leading to smoking-induced lung cancer.

Lu Y, Xiao L, Liu Y, et al.
MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation.
Autophagy. 2015; 11(12):2213-32 [PubMed] Free Access to Full Article Related Publications
The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53(+/+) and TP53(-/-) HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

Huang KT, Mikeska T, Li J, et al.
Assessment of DNA methylation profiling and copy number variation as indications of clonal relationship in ipsilateral and contralateral breast cancers to distinguish recurrent breast cancer from a second primary tumour.
BMC Cancer. 2015; 15:669 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with breast cancer have an increased risk of developing subsequent breast cancers. It is important to distinguish whether these tumours are de novo or recurrences of the primary tumour in order to guide the appropriate therapy. Our aim was to investigate the use of DNA methylation profiling and array comparative genomic hybridization (aCGH) to determine whether the second tumour is clonally related to the first tumour.
METHODS: Methylation-sensitive high-resolution melting was used to screen promoter methylation in a panel of 13 genes reported as methylated in breast cancer (RASSF1A, TWIST1, APC, WIF1, MGMT, MAL, CDH13, RARβ, BRCA1, CDH1, CDKN2A, TP73, and GSTP1) in 29 tumour pairs (16 ipsilateral and 13 contralateral). Using the methylation profile of these genes, we employed a Bayesian and an empirical statistical approach to estimate clonal relationship. Copy number alterations were analysed using aCGH on the same set of tumour pairs.
RESULTS: There is a higher probability of the second tumour being recurrent in ipsilateral tumours compared with contralateral tumours (38 % versus 8 %; p <0.05) based on the methylation profile. Using previously reported recurrence rates as Bayesian prior probabilities, we classified 69 % of ipsilateral and 15 % of contralateral tumours as recurrent. The inferred clonal relationship results of the tumour pairs were generally concordant between methylation profiling and aCGH.
CONCLUSION: Our results show that DNA methylation profiling as well as aCGH have potential as diagnostic tools in improving the clinical decisions to differentiate recurrences from a second de novo tumour.

Nakatsuji M, Minami M, Seno H, et al.
EP4 Receptor-Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis.
PLoS Genet. 2015; 11(10):e1005542 [PubMed] Free Access to Full Article Related Publications
Prostaglandin E2 plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4-associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP-deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis.

Sud A, Cooke R, Swerdlow AJ, Houlston RS
Genome-wide homozygosity signature and risk of Hodgkin lymphoma.
Sci Rep. 2015; 5:14315 [PubMed] Free Access to Full Article Related Publications
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing Hodgkin lymphoma (HL) we analysed 589 HL cases and 5,199 controls genotyped for 484,072 tag single nucleotide polymorphisms (SNPs). Across the genome the cumulative distribution of ROH was not significantly different between cases and controls. Seven ROH at 4q22.3, 4q32.2, 7p12.3-14.1, 7p22.2, 10p11.22-23, 19q13.12-2 and 19p13.2 were associated with HL risk at P < 0.01. Intriguingly 4q22.3 harbours an ROH to which the nuclear factor NF-kappa-B p105 subunit (NFKB1) maps (P = 0.002). The ROH at 19q13.12-2 has previously been implicated in B-cell precursor acute lymphoblastic leukaemia. Aside from these observations which require validation, it is unlikely that levels of measured homozygosity caused by autozygosity, uniparental isodisomy or hemizygosity play a major role in defining HL risk in predominantly outbred populations.

Park J, Kim I, Jung KJ, et al.
Gene-gene interaction analysis identifies a new genetic risk factor for colorectal cancer.
J Biomed Sci. 2015; 22:73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adiponectin levels have been shown to be associated with colorectal cancer (CRC). Furthermore, a newly identified adiponectin receptor, T-cadherin, has been associated with plasma adiponectin levels. Therefore, we investigated the potential for a genetic association between T-cadherin and CRC risk.
RESULT: We conducted a case-control study using the Korean Cancer Prevention study-II cohort, which is composed of 325 CRC patients and 977 normal individuals. Study results revealed that rs3865188 in the 5' flanking region of the T-cadherin gene (CDH13) was significantly associated with CRC (p = 0.0474). The odds ratio (OR) for the TT genotype as compared to the TA + AA genotype was 1.577 (p = 0.0144). In addition, the interaction between CDH13 and the adiponectin gene (APN) for CRC risk was investigated using a logistic regression analysis. Among six APN single nucleotide polymorphisms (rs182052, rs17366568, rs2241767, rs3821799, rs3774261, and rs6773957), an interaction with the rs3865188 was found for four (rs2241767, rs3821799, rs3774261, and rs6773957). The group with combined genotypes of TT for rs3865188 and GG for rs377426 displayed the highest risk for CRC development as compared to those with the other genotype combinations. The OR for the TT/GG genotype as compared to the AA/AA genotype was 4.108 (p = 0.004). Furthermore, the plasma adiponectin level showed a correlation with the gene-gene interaction, and the group with the highest risk for CRC had the lowest adiponectin level (median, 4.8 μg/mL for the TT/GG genotype vs.7.835 μg/mL for the AA/AA genotype, p = 0.0017).
CONCLUSIONS: The present study identified a new genetic factor for CRC risk and an interaction between CDH13 and APN in CRC risk. These genetic factors may be useful for predicting CRC risk.

Pon JR, Wong J, Saberi S, et al.
MEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation.
Nat Commun. 2015; 6:7953 [PubMed] Free Access to Full Article Related Publications
Myocyte enhancer factor 2B (MEF2B) is a transcription factor with mutation hotspots at K4, Y69 and D83 in diffuse large B-cell lymphoma (DLBCL). To provide insight into the regulatory network of MEF2B, in this study, we analyse global gene expression and DNA-binding patterns. We find that candidate MEF2B direct target genes include RHOB, RHOD, CDH13, ITGA5 and CAV1, and that indirect target genes of MEF2B include MYC, TGFB1, CARD11, MEF2C, NDRG1 and FN1. MEF2B overexpression increases HEK293A cell migration and epithelial-mesenchymal transition, and decreases DLBCL cell chemotaxis. K4E, Y69H and D83V MEF2B mutations decrease the capacity of MEF2B to activate transcription and decrease its' effects on cell migration. The K4E and D83V mutations decrease MEF2B DNA binding. In conclusion, our map of the MEF2B regulome connects MEF2B to drivers of oncogenesis.

Millares L, Serra M, Andreo F, et al.
Assessment of methylation status of locoregional lymph nodes in lung cancer using EBUS-NA.
Clin Exp Metastasis. 2015; 32(7):637-46 [PubMed] Related Publications
Hypermethylation of the promoter region of tumor suppressor genes is associated with carcinogenesis in lung cancer (LC). Endobronchial ultrasound with needle aspiration (EBUS-NA) is a semi-invasive method for obtaining cell blocks from lymph nodes, which can be used for epigenetic analyses. To establish the relationship between methylation status of p16, DAPK, RASSF1a, APC and CDH13 genes in lymph nodes sampled by EBUS-NA, tumor staging and prognosis. Methylation status of DAPK, p16, RASSF1a, APC and CDH13 genes was assessed in EBUS-NA cell blocks from LC patients and related to stage and survival. Eighty-five consecutive patients [mean age 67 (SD 8)] were included. Methylation of ≥1 gene was found in 43 malignant nodes (67 %). A higher prevalence of RASSF1a methylation was observed in small cell lung cancer patients [9/10 (90 %) vs. 15/53 (28 %); p < 0.001 χ(2) test]. Methylation of APC and/or p16 was related to advanced staging in non-small cell lung cancer (NSCLC) [15/29 (52 %) vs. 6/24 (25 %), p = 0.048, χ(2) test]. Patients with NSCLC showing methylation of APC and/or p16 had also lower 6-month survival (p = 0.019, log rank test), which persisted after adjustment for age and subtyping (HR = 6, 95 % CI [1.8-19.5], p = 0.003, Cox regression). Epigenetic analyses are feasible in EBUS-NA cell blocks and may identify methylation patterns associated with worse prognosis. Methylation of p16 and APC genes in NSCLC patients was associated with advanced staging and lower 6-month survival.

Kravtsova-Ivantsiv Y, Shomer I, Cohen-Kaplan V, et al.
KPC1-mediated ubiquitination and proteasomal processing of NF-κB1 p105 to p50 restricts tumor growth.
Cell. 2015; 161(2):333-47 [PubMed] Related Publications
NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. Also, overabundance of p50 downregulates p65, suggesting that a p50-p50 homodimer may modulate transcription in place of the tumorigenic p50-p65. Transcript analysis reveals increased expression of genes associated with tumor-suppressive signals. Overall, KPC1 regulation of NF-κB1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.

Hagiwara K, Kunishima S, Iida H, et al.
The synergistic effect of BCR signaling inhibitors combined with an HDAC inhibitor on cell death in a mantle cell lymphoma cell line.
Apoptosis. 2015; 20(7):975-85 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is a B cell malignancy characterized by aberrant expression of cyclin D1 due to a t(11;14) translocation. MCL is refractory to conventional chemotherapy, and treatment remains challenging. We investigated the efficacy of the histone deacetylase (HDAC) inhibitor vorinostat combined with one of several B-cell receptor (BCR) signaling inhibitors on MCL cell death and the underlying mechanisms, using MCL cell lines. The Bruton's tyrosine kinase inhibitor PCI-32765 and the spleen tyrosine kinase inhibitor R406 showed synergistic effects with vorinostat on growth inhibition. Treatment with PCI-32765 or R406 alone induced 27.3 ± 2.1 or 25.1 ± 3.2% apoptosis. When combined with vorinostat, these apoptotic fractions significantly increased to 50.8 ± 4.9 and 63.1 ± 5.0%, respectively. Activation of caspase-3 and poly-(ADP-ribose) polymerase cleavage were markedly increased. We performed gene expression profiling following treatment with the combination of vorinostat and individual BCR signaling inhibitors using a microarray, and differentially expressed genes were identified. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the nuclear factor (NF)-κB signaling pathway was significantly enriched following treatment with the combination of vorinostat and R406. Protein expression analysis confirmed the down-regulation of NF-κB1/p105 and cyclin D1, suggesting inhibition of the NF-κB pathway. Taken together, the combination of an HDAC inhibitor and a BCR signaling inhibitor may be a novel therapeutic strategy for MCL.

Siegel EM, Riggs BM, Delmas AL, et al.
Quantitative DNA methylation analysis of candidate genes in cervical cancer.
PLoS One. 2015; 10(3):e0122495 [PubMed] Free Access to Full Article Related Publications
Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated.

Zhong YH, Peng H, Cheng HZ, Wang P
Quantitative assessment of the diagnostic role of CDH13 promoter methylation in lung cancer.
Asian Pac J Cancer Prev. 2015; 16(3):1139-43 [PubMed] Related Publications
In order to explore the association between cadherin 13 (CDH13) gene promoter methylation and lung carcinoma (LC) risk, we carried out a meta-analysis with searching of PubMed, Web of Science. Ultimately, 17 articles were identified and analysised by STATA 12.0 software. Overall, we found a significant relationship between CDH13 promoter methylation and LC risk (odds ratio=6.98, 95% confidence interval: 4.21-11.56, p<0.001). Subgroup analyses further revealed that LC risk was increased for individuals carrying the methylated CDH13 compared with those with unmethylated CDH13. Hence, our study identified a strong association between CDH13 gene promoter methylation and LC and highlighted a promising potential for CDH13 methylation in LC risk prediction.

Hafez MM, Al-Shabanah OA, Al-Rejaie SS, et al.
Increased hypermethylation of glutathione S-transferase P1, DNA-binding protein inhibitor, death associated protein kinase and paired box protein-5 genes in triple-negative breast cancer Saudi females.
Asian Pac J Cancer Prev. 2015; 16(2):541-9 [PubMed] Related Publications
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with higher metastatic rate and both local and systemic recurrence compared to non-TNBC. The generation of reactive oxygen species (ROS) secondary to oxidative stress is associated with DNA damage, chromosomal degradation and alterations of both hypermethylation and hypomethylation of DNA. This study concerns differential methylation of promoter regions in specific groups of genes in TNBC and non-TNBC Saudi females in an effort to understand whether epigenetic events might be involved in breast carcinogenesis, and whether they might be used as markers for Saudi BCs. Methylation of glutathione S-transferase P1 (GSTP1), T-cadherin (CDH13), Paired box protein 5 (PAX5), death associated protein kinase (DAPK), twist-related protein (TWIST), DNA-binding protein inhibitor (ID4), High In Normal-1 (HIN-1), cyclin-dependent kinase inhibitor 2A (p16), cyclin D2 and retinoic acid receptor-β (RARβ1) genes was analyzed by methylation specific polymerase chain reaction (MSP) in 200 archival formalin- fixed paraffin embedded BC tissues divided into 3 groups; benign breast tissues (20), TNBC (80) and non-TNBC (100). The relationships between methylation status, and clinical and pathological characteristics of patients and tumors were assessed. Higher frequencies of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 hypermethylation were found in TNBC than in non-TNBC. Hypermethylation of GSTP1, CDH13, ID4, DAPK, HIN-1 and PAX5 increased with tumor grade increasing. Other statistically significant correlations were identified with studied genes. Data from this study suggest that increased hypermethylation of GSTP1, ID4, TWIST, DAPK, PAX5 and HIN-1 genes in TNBC than in non-TNBC can act as useful biomarker for BCs in the Saudi population. The higher frequency of specific hypermethylated genes paralleling tumor grade, size and lymph node involvement suggests contributions to breast cancer initiation and progression.

Bakkum-Gamez JN, Wentzensen N, Maurer MJ, et al.
Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons.
Gynecol Oncol. 2015; 137(1):14-22 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing.
METHODS: Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC).
RESULTS: Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p<0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC.
CONCLUSION: DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC.

Monsó E, Montuenga LM, Sánchez de Cos J, et al.
Biological Marker Analysis as Part of the CIBERES-RTIC Cancer-SEPAR Strategic Project on Lung Cancer.
Arch Bronconeumol. 2015; 51(9):462-7 [PubMed] Related Publications
The aim of the Clinical and Molecular Staging of Stage I-IIp Lung Cancer Project is to identify molecular variables that improve the prognostic and predictive accuracy of TMN classification in stage I/IIp non-small cell lung cancer (NSCLC). Clinical data and lung tissue, tumor and blood samples will be collected from 3 patient cohorts created for this purpose. The prognostic protein signature will be validated from these samples, and micro-RNA, ALK, Ros1, Pdl-1, and TKT, TKTL1 y G6PD expression will be analyzed. Tissue inflammatory markers and stromal cell markers will also be analyzed. Methylation of p16, DAPK, RASSF1a, APC and CDH13 genes in the tissue samples will be determined, and inflammatory markers in peripheral blood will also be analyzed. Variables that improve the prognostic and predictive accuracy of TNM in NSCLC by molecular staging may be identified from this extensive analytical panel.

Li L, Jiang M, Feng Q, et al.
Aberrant Methylation Changes Detected in Cutaneous Squamous Cell Carcinoma of Immunocompetent Individuals.
Cell Biochem Biophys. 2015; 72(2):599-604 [PubMed] Related Publications
In order to elucidate the role of epigenetic alterations in the development of cutaneous squamous cell carcinoma (SCC), we analyzed both gene-specific promoter hypermethylation and repetitive sequence hypomethylation in cutaneous SCC as well as normal skin tissue samples. We showed that methylation of DAPK1 and CDH13 was associated with cutaneous SCC. While methylation frequency of DAPK1 was increased from sun-protected normal skin, sun-exposed normal skin, perilesional to lesional tissues, methylation of CDH13 was almost exclusively detected in cutaneous SCC tissues. Further, methylation of DAPK1 and CDH13 was neither correlated with the presence of HPV nor with the presence of p53 mutations in lesional skin tissues. Finally, we detected trend of reduced methylation level of repetitive sequences from sun-protected, sun-exposed normal skin samples to perilesional, and lesional tissues from SCC patients. We conclude that both gene-specific hypermethylation and repetitive sequence hypomethylation are present in cutaneous SCC tissue samples; these epigenetic changes might represent an independent pathway in the development of cutaneous SCC.

Anbalagan D, Yap G, Yuan Y, et al.
Annexin-A1 regulates microRNA-26b* and microRNA-562 to directly target NF-κB and angiogenesis in breast cancer cells.
PLoS One. 2014; 9(12):e114507 [PubMed] Free Access to Full Article Related Publications
Annexin 1 (ANXA1) is an endogenous anti-inflammatory protein implicated in cancer. ANXA1 was previously shown to be regulated by hsa-miR-196a. However, whether ANXA1 itself regulates microRNA (miR) expression is unknown. Therefore, we investigated the regulation of miR by ANXA1 in MCF7 breast cancer cells. MCF7-EV (Empty vector) and MCF7-V5 (ANXA1-V5 expressing cells) were subjected to a miR microarray. Microarray analysis revealed a number of miRNAs which were dysregulated in MCF7-V5 cells. 2 novel miRNAs (miR562 and miR26b*) were validated, cloned and functionally characterized. As ANXA1 constitutively activates NF-κB activity to modulate breast cancer metastasis, we found that miR26b* and miR562 directly targeted the canonical NF-κB pathway by targeting the 3' UTR and inhibiting expression of Rel A (p65) and NF-κB1 (p105) respectively. MiR562 inhibited wound healing, which was reversed when ANXA1 was overexpressed. Overexpression of either miR562 or miR26b* in MCF-7 cells enhanced endothelial tube formation when cocultured with human umbilical cord endothelial cells while conversely, treatment of MCF7 cells with either anti-miR562 or anti-miR26b* inhibited endothelial tube formation after co-culture. Further analysis of miR562 revealed that miR562-transfected cell conditioned media enhances endothelial cell tube formation, indicating that miR562 increased angiogenic secreted factors from MCF-7 breast tumor cells. TNFα was increased upon overexpression of miR562, which was reversed when ANXA1 was co-transfected In conclusion, this data suggests that ANXA1-regulated miR26b* and miR562 may play a role in wound healing and tumor-induced endothelial cell tube formation by targeting NF-κB expression and point towards a potential therapeutic target for breast cancer.

Pang JM, Deb S, Takano EA, et al.
Methylation profiling of ductal carcinoma in situ and its relationship to histopathological features.
Breast Cancer Res. 2014; 16(5):423 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: DNA methylation is a well-studied biomarker in invasive breast cancer, but its role in ductal carcinoma in situ (DCIS) is less well characterized. The aims of this study are to assess the methylation profile in DCIS for a panel of well-characterized genes that are frequently methylated in breast cancer, to investigate the relationship of methylation with pathological features, and to perform a proof-of-principle study to evaluate the practicality of methylation as a biomarker in diagnostic DCIS material.
METHODS: Promoter CpG island methylation for a panel of 11 breast cancer-related genes was performed by methylation-sensitive high resolution melting (MS-HRM). Formalin-fixed, paraffin-embedded (FFPE) biopsies from 72 samples of pure DCIS (DCIS occurring in the absence of synchronous invasive carcinoma), 10 samples of mixed DCIS (DCIS adjacent to invasive carcinoma), and 18 samples of normal breast epithelium adjacent to a DCIS lesion were micro-dissected prior to DNA extraction.
RESULTS: Methylation was seen for all the tested genes except BRCA1. RASSF1A was the most frequently methylated gene (90% of DCIS samples) and its methylation was associated with comedo necrosis (p = 0.018). Cluster analysis based on the methylation profile revealed four groups, the highly methylated cluster being significantly associated with high nuclear grade, HER2 amplification, negative estrogen receptor (ER) α status, and negative progesterone receptor (PgR) status, (p = 0.038, p = 0.018, p <0.001, p = 0.001, respectively). Methylation of APC (p = 0.017), CDH13 (p = 0.017), and RARβ (p <0.001) was associated with negative ERα status. Methylation of CDH13 (p <0.001), and RARβ (p = 0.001) was associated with negative PgR status. Methylation of APC (p = 0.013) and CDH13 (p = 0.026) was associated with high nuclear grade. Methylation of CDH13 (p = 0.009), and RARβ (p = 0.042) was associated with HER2-amplification.
CONCLUSIONS: DNA methylation can be assessed in FFPE-derived samples using suitable methodologies. Methylation of a panel of genes that are known to be methylated in invasive breast cancer was able to classify DCIS into distinct groups and was differentially associated with phenotypic features in DCIS.

Lin YL, Xie PG, Ma JG
Aberrant methylation of CDH13 is a potential biomarker for predicting the recurrence and progression of non muscle invasive bladder cancer.
Med Sci Monit. 2014; 20:1572-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: CDH13 is a novel tumor suppressor gene often inactivated by aberrant promoter methylation in human cancers. Previous studies have shown that CDH13 methylation correlated with advanced disease and poor prognosis in non-muscle invasive bladder cancer (NMIBC). The aim of the current study was to investigate the correlations between CDH13 methylation and disease recurrence as well as progression of NMIBC.
MATERIAL AND METHODS: The methylation status of CDH13 in 178 NMIBC samples and 38 normal bladder epithelial tissues was examined by methylation-specific PCR (MSP), and then correlated with clinicopathological features.
RESULTS: We found that CDH13 methylation occurs frequently in NMIBC, and significantly correlates with high grade, advanced stage, larger tumor size, and tumor recurrence and progression. Moreover, patients with methylated CDH13 exhibited significantly shorter recurrence-free survival (P<0.0001) and progression-free survival (P=0.0060) than patients with unmethylated CDH13. In addition, a multivariate Cox proportional hazard model analysis suggests that CDH13 methylation is an independent predictor for the recurrence (P=0.0043) and progression (P=0.0016) of NMIBC after initial transurethral resection.
CONCLUSIONS: Our findings demonstrate that CDH13 methylation is a frequent event in NMIBC, and is associated with unfavorable tumor features. It should be used as an independent predictor for the recurrence and progression of NMIBC, and may be useful for the design of individualized therapeutic modalities.

Noorlag R, van Kempen PM, Moelans CB, et al.
Promoter hypermethylation using 24-gene array in early head and neck cancer: better outcome in oral than in oropharyngeal cancer.
Epigenetics. 2014; 9(9):1220-7 [PubMed] Free Access to Full Article Related Publications
Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis and a potential target for personalized cancer treatment. In head and neck cancer, little is known about the role of promoter hypermethylation in survival. Using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) we investigated the role of promoter hypermethylation of 24 well-described genes (some of which are classic TSGs), which are frequently methylated in different cancer types, in 166 HPV-negative early oral squamous cell carcinomas (OSCC), and 51 HPV-negative early oropharyngeal squamous cell carcinomas (OPSCC) in relation to clinicopathological features and survival. Early OSCC showed frequent promoter hypermethylation in RARB (31% of cases), CHFR (20%), CDH13 (13%), DAPK1 (12%), and APC (10%). More hypermethylation (≥ 2 genes) independently correlated with improved disease specific survival (hazard ratio 0.17, P = 0.014) in early OSCC and could therefore be used as prognostic biomarker. Early OPSCCs showed more hypermethylation of CDH13 (58%), TP73 (14%), and total hypermethylated genes. Hypermethylation of two or more genes has a significantly different effect on survival in OPSCC compared with OSCC, with a trend toward worse instead of better survival. This could have a biological explanation, which deserves further investigation and could possibly lead to more stratified treatment in the future.

Drilon A, Sugita H, Sima CS, et al.
A prospective study of tumor suppressor gene methylation as a prognostic biomarker in surgically resected stage I to IIIA non-small-cell lung cancers.
J Thorac Oncol. 2014; 9(9):1272-7 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: While retrospective analyses support an association between early tumor recurrence and tumor suppressor gene promoter methylation in early-stage non-small-cell lung cancers (NSCLCs), few studies have investigated this question prospectively.
METHODS: Primary tumor tissue from patients with resected pathologic stage I to IIIA NSCLCs was collected at the time of surgery and analyzed for promoter methylation via methylation-specific reverse transcriptase polymerase chain reaction (MethyLight). The primary objective was to determine an association between promoter methylation of 10 individual tumor suppressor genes (CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, SOCS3, and ADAMTS8) and recurrence-free survival (RFS), with the secondary objectives of determining association with overall survival (OS), and relation to clinical or pathologic features.
RESULTS: A total of 107 patients had sufficient tumor tissue for successful promoter methylation analysis. Majority of patients were former/current smokers (88%) with lung adenocarcinoma (78%) and pathologic stage I disease (62%). Median follow-up was 4 years. When controlled for pathologic stage, promoter methylation of the individual genes CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, and ADAMTS8 was not associated with RFS. Promoter methylation of the same genes was not associated with OS except for DAPK1 which was associated with improved OS (p = 0.03). The total number of genes with methylated promoters did not correlate with RFS (p = 0.89) or OS (p = 0.55).
CONCLUSION: Contrary to data established by previous retrospective series, tumor suppressor gene promoter methylation (CDKN2A, CDH13, RASSF1, APC, MGMT, GSTP1, DAPK1, WIF1, and ADAMTS8) was not prognostic for early tumor recurrence in this prospective study of resected NSCLCs.

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