DLEC1; deleted in lung and esophageal cancer 1 (3p21.3)

Gene Summary

Gene:DLEC1; deleted in lung and esophageal cancer 1
Aliases: F56, DLC1, CFAP81
Summary:This gene contains 37 exons, spans approximately 59-kb, and is located in the 3p22-p21.3 chromosomal segment that is commonly deleted in various carcinomas. Several alternatively spliced transcripts have been observed that contain disrupted coding regions and likely encode nonfunctional proteins. Aberrant transcription of this gene may be involved in carcinogenesis of the lung, esophagus, and kidney. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:deleted in lung and esophageal cancer protein 1
Updated:14 December, 2014


What does this gene/protein do?
DLEC1 is implicated in:
- cytoplasm
- molecular_function
- negative regulation of cell proliferation
Data from Gene Ontology via CGAP

Cancer Overview

Deletions of chromosome 3p are frequent in many different types of cancer. Researchers in Tokyo (Daigo, 1999) isolated a novel gene by large-scale sequencing of genomic DNA at 3p21.3. Using RT-PCR they found non-functional RNA transcripts in 11/30 primary non-small cell lung cancers, 3/10 primary esophageal squamous cell carcinomas, 4/14 esophageal cancer cell lines and 2/2 renal cancer cell lines. However, no alterations of the gene itself were identified. They originally designated this candidate tumour supressor gene DLC1 (NOTE: the symbol DLC1 was later assigned to the gene Deleted in Liver Cancer 1 at 8p22)

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (7)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lung CancerDLEC1 and Lung Cancer View Publications6
Lung Cancer, Non-Small CellDLEC1 and Non-Small Cell Lung Cancer View Publications4
Nasopharyngeal CancerDLEC1 and Nasopharyngeal Cancer View Publications4
Liver CancerDLEC1 and Liver Cancer View Publications3
Breast CancerDLEC1 and Breast Cancer View Publications3
Uterine SarcomaDLEC1 and Uterine Cancer View Publications2
Bladder CancerDLEC1 and Bladder Cancer View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: DLEC1 (cancer-related)

Ashoor H, Hérault A, Kamoun A, et al.
HMCan: a method for detecting chromatin modifications in cancer samples using ChIP-seq data.
Bioinformatics. 2013; 29(23):2979-86 [PubMed] Free Access to Full Article Related Publications
MOTIVATION: Cancer cells are often characterized by epigenetic changes, which include aberrant histone modifications. In particular, local or regional epigenetic silencing is a common mechanism in cancer for silencing expression of tumor suppressor genes. Though several tools have been created to enable detection of histone marks in ChIP-seq data from normal samples, it is unclear whether these tools can be efficiently applied to ChIP-seq data generated from cancer samples. Indeed, cancer genomes are often characterized by frequent copy number alterations: gains and losses of large regions of chromosomal material. Copy number alterations may create a substantial statistical bias in the evaluation of histone mark signal enrichment and result in underdetection of the signal in the regions of loss and overdetection of the signal in the regions of gain.
RESULTS: We present HMCan (Histone modifications in cancer), a tool specially designed to analyze histone modification ChIP-seq data produced from cancer genomes. HMCan corrects for the GC-content and copy number bias and then applies Hidden Markov Models to detect the signal from the corrected data. On simulated data, HMCan outperformed several commonly used tools developed to analyze histone modification data produced from genomes without copy number alterations. HMCan also showed superior results on a ChIP-seq dataset generated for the repressive histone mark H3K27me3 in a bladder cancer cell line. HMCan predictions matched well with experimental data (qPCR validated regions) and included, for example, the previously detected H3K27me3 mark in the promoter of the DLEC1 gene, missed by other tools we tested.

Related: Bladder Cancer Bladder Cancer - Molecular Biology

Tian F, Yip SP, Kwong DL, et al.
Promoter hypermethylation of tumor suppressor genes in serum as potential biomarker for the diagnosis of nasopharyngeal carcinoma.
Cancer Epidemiol. 2013; 37(5):708-13 [PubMed] Related Publications
PURPOSE: Promoter hypermethylation of tumor suppressor genes may serve as a promising biomarker for the diagnosis of cancer. Cell-free circulating DNA (cf-DNA) shares hypermethylation status with primary tumors. This study investigated promoter hypermethylation of five tumor suppressor genes as markers in the detection of nasopharyngeal carcinoma (NPC) in serum samples.
METHODS: cf-DNA was extracted from serum collected from 40 NPC patients and 41 age- and sex-matched healthy subjects. The promoter hypermethylation status of the five genes (RASSF1, CDKN2A, DLEC1, DAPK1 and UCHL1) was assessed by methylation-specific PCR after sodium bisulfite conversion. Differences in the methylation status of these five genes between NPC patients and healthy subjects were compared.
RESULTS: The concentration of cf-DNA in the serum of NPC patients was significantly higher than that in normal controls. The five tumor suppressor genes - RASSF1, CDKN2A, DLEC1, DAPK1 and UCHL1 - were found to be methylated in 17.5%, 22.5%, 25.0%, 51.4% and 64.9% of patients, respectively. The combination of four-gene marker - CDKN2A, DLEC1, DAPK1 and UCHL1 - had the highest sensitivity and specificity in predicting NPC.
CONCLUSION: Screening DNA hypermethylation of tumor suppressor genes in serum was a promising approach for the diagnosis of NPC.

Related: CDKN2A Nasopharyngeal Cancer RASSF1

Nikolaev SI, Santoni F, Vannier A, et al.
Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome.
Blood. 2013; 122(4):554-61 [PubMed] Related Publications
Some neonates with Down syndrome (DS) are diagnosed with self-regressing transient myeloproliferative disorder (TMD), and 20% to 30% of those progress to acute megakaryoblastic leukemia (AMKL). We performed exome sequencing in 7 TMD/AMKL cases and copy-number analysis in these and 10 additional cases. All TMD/AMKL samples contained GATA1 mutations. No exome-sequenced TMD/AMKL sample had other recurrently mutated genes. However, 2 of 5 TMD cases, and all AMKL cases, showed mutations/deletions other than GATA1, in genes proven as transformation drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3). One patient at the TMD stage revealed 2 clonal expansions with different GATA1 mutations, of which 1 clone had an additional driver mutation. Interestingly, it was the other clone that gave rise to AMKL after accumulating mutations in 7 other genes. Data suggest that GATA1 mutations alone are sufficient for clonal expansions, and additional driver mutations at the TMD stage do not necessarily predict AMKL progression. Later in infancy, leukemic progression requires "third-hit driver" mutations/somatic copy-number alterations found in non-DS leukemias. Putative driver mutations affecting WNT (wingless-related integration site), JAK-STAT (Janus kinase/signal transducer and activator of transcription), or MAPK/PI3K (mitogen-activated kinase/phosphatidylinositol-3 kinase) pathways were found in all cases, aberrant activation of which converges on overexpression of MYC.

Rinner B, Weinhaeusel A, Lohberger B, et al.
Chordoma characterization of significant changes of the DNA methylation pattern.
PLoS One. 2013; 8(3):e56609 [PubMed] Free Access to Full Article Related Publications
Chordomas are rare mesenchymal tumors occurring exclusively in the midline from clivus to sacrum. Early tumor detection is extremely important as these tumors are resistant to chemotherapy and irradiation. Despite continuous research efforts surgical excision remains the main treatment option. Because of the often challenging anatomic location early detection is important to enable complete tumor resection and to reduce the high incidence of local recurrences. The aim of this study was to explore whether DNA methylation, a well known epigenetic marker, may play a role in chordoma development and if hypermethylation of specific CpG islands may serve as potential biomarkers correlated with SNP analyses in chordoma. The study was performed on tumor samples from ten chordoma patients. We found significant genomic instability by Affymetrix 6.0. It was interesting to see that all chordomas showed a loss of 3q26.32 (PIK 3CA) and 3q27.3 (BCL6) thus underlining the potential importance of the PI3K pathway in chordoma development. By using the AITCpG360 methylation assay we elucidated 20 genes which were hyper/hypomethylated compared to normal blood. The most promising candidates were nine hyper/hypomethylated genes C3, XIST, TACSTD2, FMR1, HIC1, RARB, DLEC1, KL, and RASSF1. In summary, we have shown that chordomas are characterized by a significant genomic instability and furthermore we demonstrated a characteristic DNA methylation pattern. These findings add new insights into chordoma development, diagnosis and potential new treatment options.

Related: RASSF1 TACSTD2 (GA733) RARB

Wang Z, Li L, Su X, et al.
Epigenetic silencing of the 3p22 tumor suppressor DLEC1 by promoter CpG methylation in non-Hodgkin and Hodgkin lymphomas.
J Transl Med. 2012; 10:209 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inactivaion of tumor suppressor genes (TSGs) by promoter CpG methylation frequently occurs in tumorigenesis, even in the early stages, contributing to the initiation and progression of human cancers. Deleted in lung and esophageal cancer 1 (DLEC1), located at the 3p22-21.3 TSG cluster, has been identified frequently silenced by promoter CpG methylation in multiple carcinomas, however, no study has been performed for lymphomas yet.
METHODS: We examined the expression of DLEC1 by semi-quantitative reverse transcription (RT)-PCR, and evaluated the promoter methylation of DLEC1 by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS) in common lymphoma cell lines and tumors.
RESULTS: Here we report that DLEC1 is readily expressed in normal lymphoid tissues including lymph nodes and PBMCs, but reduced or silenced in 70% (16/23) of non-Hodgkin and Hodgkin lymphoma cell lines, including 2/6 diffuse large B-cell (DLBCL), 1/2 peripheral T cell lymphomas, 5/5 Burkitt, 6/7 Hodgkin and 2/3 nasal killer (NK)/T-cell lymphoma cell lines. Promoter CpG methylation was frequently detected in 80% (20/25) of lymphoma cell lines and correlated with DLEC1 downregulation/silencing. Pharmacologic demethylation reversed DLEC1 expression in lymphoma cell lines along with concomitant promoter demethylation. DLEC1 methylation was also frequently detected in 32 out of 58 (55%) different types of lymphoma tissues, but not in normal lymph nodes. Furthermore, DLEC1 was specifically methylated in the sera of 3/13 (23%) Hodgkin lymphoma patients.
CONCLUSIONS: Thus, methylation-mediated silencing of DLEC1 plays an important role in multiple lymphomagenesis, and may serve as a non-invasive tumor marker for lymphoma diagnosis.

Related: Chromosome 3 Hodgkin's Lymphoma Non Hodgkin's Lymphoma

Fonseca AL, Kugelberg J, Starker LF, et al.
Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors.
Genes Chromosomes Cancer. 2012; 51(10):949-60 [PubMed] Related Publications
The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2'-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development.

Related: Adrenocortical Cancer Adrenocortical Carcinoma - Molecular Biology Azacitidine

Chang PH, Huang CC, Lee TJ, et al.
Downregulation of DLEC1 in sinonasal inverted papilloma and squamous cell carcinoma.
J Otolaryngol Head Neck Surg. 2012; 41(2):94-101 [PubMed] Related Publications
OBJECTIVE: Inverted papilloma is associated with sinonasal squamous cell carcinoma. This study aimed to investigate the epigenetic regulation of the tumour suppressor gene DLEC1 in inverted papilloma and sinonasal squamous cell carcinoma.
METHODS: DLEC1 gene expression was investigated by quantitative real-time polymerase chain reaction (QRT-PCR) in normal mucosa, inverted papilloma, and squamous cell carcinoma tissues. Methylation-specific PCR and subsequent autosequencing were also used to examine the methylation status of DLEC1 promoter and the involved mechanism. DLEC1 expression in a large validation set was evaluated by immunohistochemistry (n  =  25 in each group).
RESULTS: DLEC1 was downregulated in inverted papilloma and squamous cell carcinoma tissues compared to normal mucosa (p < .01 in QRT-PCR and immunohistochemistry), with squamous cell carcinoma more repressed (p < .05 in QRT-PCR and immunohistochemistry) than inverted papilloma tissues. DLEC1 promoter hypermethylation was found in squamous cell carcinoma tissues.
CONCLUSION: Repression of DLEC1 in squamous cell carcinoma tissues is associated with promoter hypermethylation. DLEC1 is downregulated in sinonasal squamous cell carcinoma and inverted papilloma and has a distinct mechanism.

Ricketts CJ, Morris MR, Gentle D, et al.
Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma.
Epigenetics. 2012; 7(3):278-90 [PubMed] Free Access to Full Article Related Publications
In order to identify novel candidate tumor suppressor genes (TSGs) implicated in renal cell carcinoma (RCC), we performed genome-wide methylation profiling of RCC using the HumanMethylation27 BeadChips to assess methylation at > 14,000 genes. Two hundred and twenty hypermethylated probes representing 205 loci/genes were identified in genomic CpG islands. A subset of TSGs investigated in detail exhibited frequent tumor methylation, promoter methylation associated transcriptional silencing and reactivation after demethylation in RCC cell lines and down-regulation of expression in tumor tissue (e.g., SLC34A2 specifically methylated in 63% of RCC, OVOL1 in 40%, DLEC1 in 20%, TMPRSS2 in 26%, SST in 31% and BMP4 in 35%). As OVOL1, a putative regulator of c-Myc transcription, and SST (somatostatin) had not previously been linked to cancer and RCC, respectively, we (1) investigated their potential relevance to tumor growth by RNAi knockdown and found significantly increased anchorage-independent growth and (2) demonstrated that OVOL1 knockdown increased c-Myc mRNA levels.

Related: Kidney Cancer

Navarro A, Yin P, Monsivais D, et al.
Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma.
PLoS One. 2012; 7(3):e33284 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown.
PRINCIPAL FINDINGS: We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels.
CONCLUSIONS: These results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women.

Related: USA

Montavon C, Gloss BS, Warton K, et al.
Prognostic and diagnostic significance of DNA methylation patterns in high grade serous ovarian cancer.
Gynecol Oncol. 2012; 124(3):582-8 [PubMed] Related Publications
OBJECTIVE: Altered DNA methylation patterns hold promise as cancer biomarkers. In this study we selected a panel of genes which are commonly methylated in a variety of cancers to evaluate their potential application as biomarkers for prognosis and diagnosis in high grade serous ovarian carcinoma (HGSOC); the most common and lethal subtype of ovarian cancer.
METHODS: The methylation patterns of 10 genes (BRCA1, EN1, DLEC1, HOXA9, RASSF1A, GATA4, GATA5, HSULF1, CDH1, SFN) were examined and compared in a cohort of 80 primary HGSOC and 12 benign ovarian surface epithelium (OSE) samples using methylation-specific headloop suppression PCR.
RESULTS: The genes were variably methylated in primary HGSOC, with HOXA9 methylation observed in 95% of cases. Most genes were rarely methylated in benign OSE, with the exception of SFN which was methylated in all HGSOC and benign OSE samples examined. Methylation of DLEC1 was associated with disease recurrence, independent of tumor stage and suboptimal surgical debulking (HR 3.5 (95% CI:1.10-11.07), p=0.033). A combination of the methylation status of HOXA9 and EN1 could discriminate HGSOC from benign OSE with a sensitivity of 98.8% and a specificity of 91.7%, which increased to 100% sensitivity with no loss of specificity when pre-operative CA125 levels were also incorporated.
CONCLUSIONS: This study provides further evidence to support the feasibility of detecting altered DNA methylation patterns as a potential diagnostic and prognostic approach for HGSOC.

Related: Ovarian Cancer HOXA9 gene

Park SY, Kwon HJ, Choi Y, et al.
Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes.
Mod Pathol. 2012; 25(2):185-96 [PubMed] Related Publications
Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44+/CD24- and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44+/CD24- and ALDH1+ putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44+/CD24-cell (+) tumors than in CD44+/CD24-cell (-) tumors, even within the basal-like subtype. ALDH1 (+) tumors were also less methylated than ALDH1 (-) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.

Related: Breast Cancer

Wang Z, Yuan X, Jiao N, et al.
CDH13 and FLBN3 gene methylation are associated with poor prognosis in colorectal cancer.
Pathol Oncol Res. 2012; 18(2):263-70 [PubMed] Related Publications
The aim of this study was to identify potential epigenetic prognostic biomarkers for colorectal cancer (CRC) in the Chinese population. The methylation status of five tumor suppressor genes (CDH13, DLEC1, FBLN3, hMHL1 and RUNX3) was determined using manual microdissection followed by methylation-specific PCR in 85 paired CRC specimens and adjacent normal tissue. The results showed that methylation frequencies in cancerous tissues were 31.8% for CDH13, 37.6% for DLEC1, 38.8% for FBLN3, 22.4% for hMHL1 and 27.1% for RUNX3, all of which were significantly higher than in corresponding normal tissue. Furthermore, CDH13 methylation was associated with poor differentiation (P = 0.019) and tended to be predominant in advanced stages (P = 0.084); FBLN3 methylation was associated with advanced stages (P = 0.027) and lymph node metastasis (P = 0.029). Accordingly, the methylation status of CDH13 (P = 0.022), FBLN3 (P = 0.008), CDH13 and/or FBLN3 (P = 0.001) predicted adverse overall survival in CRC, while hMHL1 methylation showed a protective role in survival (P = 0.046). Cox proportional hazard models further indicated that CDH13 and/or FBLN3 methylation, but not that of hMHL1, was an independent prognostic factor for CRC. In conclusion, we found CDH13 and FBLN3 gene methylation are potential biomarkers for poor prognosis in CRC.

Related: Colorectal (Bowel) Cancer

Chung JH, Lee HJ, Kim BH, et al.
DNA methylation profile during multistage progression of pulmonary adenocarcinomas.
Virchows Arch. 2011; 459(2):201-11 [PubMed] Related Publications
Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to invasive ADC. To determine the potential role of promoter methylation during ADC development of the lung, we examined methylation status in 20 normal, 20 AAH, 30 AIS, and 60 ADC lung tissues and compared methylation status among the lesions. The MethyLight assay was used to determine the methylation status of 18 CpG island loci, which were hypermethylated in ADC compared to noncancerous lung tissues. The mean number of methylated CpG island loci was significantly higher in ADC than in AAH and AIS, (p < 0.003 between ADC and AAH, p < 0.005 between ADC and AIS). Aberrant methylation of HOXA1, TMEFF2, and RARB was frequently observed in preinvasive lesions, including AAH and AIS. Furthermore, methylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was significantly more frequent in invasive ADC than AAH or AIS. Our results indicate that epigenetic alterations are involved in the multistep progression of pulmonary ADC development, and aberrant CpG island methylation accumulates during multistep carcinogenesis. In addition, aberrant methylation of HOXA1, TMEFF2, and RARB occurred in preinvasive lesions, which indicates that epigenetic alterations of these genes are involved in the early stages of pulmonary ADC development. In contrast, hypermethylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was more frequent in invasive ADC than in preinvasive lesions, which indicates that methylation of these genes occurs later during tumor invasion in the AAH-AIS-ADC sequence.

Related: Lung Cancer

Zhang Y, Ye X, Geng J, Chen L
Epigenetic inactivation of deleted in lung and esophageal cancer 1 gene by promoter methylation in gastric and colorectal adenocarcinoma.
Hepatogastroenterology. 2010 Nov-Dec; 57(104):1614-9 [PubMed] Related Publications
BACKGROUND/AIM: Deleted in Lung and Esophageal Cancer 1 (DLEC1) gene was a new candidate tumor suppressor gene, we evaluated the diagnostic role of DLEC1 methylation in gastric adenocarcinoma (GAC) and colorectal adenocarcinoma (CRAC).
METHODOLOGY: Methylation-specific polymerase chain reaction (MSP) was used to determine the promoter methylation status of DLEC1 gene in tissue and serum DNA. DLEC1 gene expression was determined by immunohistochemistry.
RESULTS: DLEC1 methylation was detected in 38.5% (25/65) of GAC and 45.1% (32/71) of CRAC tissues, while seldom in the adjacent normal tissues of stomach (8.0%, 4/50) and colorectum (7.1%, 4/56) (p < 0.001). The hypermethylation status of DLEC1 was associated with low or absent of DLEC1 protein expression both in tumor and pre-malignant lesions (p < 0.001), but not correlated with patients' clinicopathological features and elevated CEA/CA19-9 levels. Moreover, 33.8% (22/65) of GAC and 39.4% (28/71) of CRAC serums had DLEC1 methylation, which was higher than that in the serums of cancer-free controls (p < 0.001), and the concordance of DLEC1 methylation in tumor tissues and corresponding serum samples was well.
CONCLUSION: Epigenetic inactivation of DLEC1 was crucial in gastric and colorectal carcinogenesis. DLEC1 methylation in serum may be a promise biomarker for GAC and CRAC early diagnosis.

Related: Colorectal (Bowel) Cancer Stomach Cancer Gastric Cancer

Song H, Yi J, Zhang Y, et al.
[DNA methylation of tumor suppressor genes located on chromosome 3p in non-small cell lung cancer].
Zhongguo Fei Ai Za Zhi. 2011; 14(3):233-8 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: DNA methylation is one of the mechanisms of epigenetics. Allelic loss located on chromosome 3p happen frequently and early in non-small cell lung cancer (NSCLC). The aim of this study is to detect the promoter methylation status of tumor suppressor genes (TSGs) located on chromosome 3p in NSCLC and to evaluate its correlation with clinicopathological features.
METHODS: A total of 78 paired NSCLC specimens and their adjacent normal tissues were collected in the study. Promoter methylation status was determined by methylation-specific polymerase chain reaction (MSP). DLEC1 gene expression was determined by RT-PCR and immunohistochemistry.
RESULTS: Aberrant methylation frequency of DLEC1, RASSF1A, hMLH1, RARβ and FHIT genes detected in 78 NSCLC tissues were 41.03%, 39.74%, 30.77% and 16.67%, respectively, which were all significantly higher than that in adjacent normal tissues. However, FHIT gene was not detected methylation in both cancerous and non-cancerous tissues. DLEC1 hypermethylation was associated with advanced stage (P=0.011) and lymph metastasis (P=0.019), while RASSF1A, RARβ, hMLH1 and mean methylation index (MI) were not correlated with any clinicopathological parameters. Moreover, DLEC1 gene downregulation was detected in 56.41% (44/78) NSCLC tissues and correlated with promoter hypermethylation.
CONCLUSIONS: Frequent hypermethylation of TSGs located on chromosome 3p was a common event contributing to NSCLC pathogenesis and DLEC1 methylation was closely correlated with loss of expression.

Related: Non-Small Cell Lung Cancer Chromosome 3 Lung Cancer

Zhang Y, Wang R, Song H, et al.
Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer.
Cancer Lett. 2011; 303(1):21-8 [PubMed] Related Publications
Aberrant DNA methylation is a common phenomenon in human cancer. The aims of this study were to investigate the methylation profiles of non-small cell lung cancer (NSCLC) in the Chinese population. Twenty tumor suppressor genes (TSGs) were determined of the methylation status using methylation-specific PCR in 78 paired NSCLC specimens and adjacent normal tissues, as well as in 110 Stage I/II NSCLC and 50 cancer-free plasmas. The results showed that, nine genes (APC, CDH13, KLK10, DLEC1, RASSF1A, EFEMP1, SFRP1, RARβ and p16(INK4A)) demonstrated a significantly higher frequency of methylation in NSCLC compared with the normal tissues (P≤0.001), while the others (RUNX3, hMLH1, DAPK, BRCA1, p14(ARF), MGMT, NORE1A, FHIT, CMTM3, LSAMP and OPCML) showed relatively low sensitivity or specificity. Furthermore, methylation of multiple genes was more frequentin cancerous tissue, CpG island methylator phenotype positive (CIMP+) cases were detected in 65.38% of (51/78) NSCLC while only in 1.28% (1/78) of adjacent normal tissues (P<0.001), and CIMP+ was associated with advanced stage (P=0.017), lymphatic metastasis (P=0.001) and adverse 2-year progression-free survival (P=0.027). The nine genes validated in tissues also showed a significantly higher frequency of tumor-specific hypermethylation in NSCLC plasma, as compared with the cancer-free plasmas, and a 5-gene set (APC, RASSF1A, CDH13, KLK10 and DLEC1) achieved a sensitivity of 83.64% and a specificity of 74.0% for cancer diagnosis. Thus, the results indicated that methylated alteration of multiple genes plays an important role in NSCLC pathogenesis and a panel of candidate epigenetic biomarkers for NSCLC detection in the Chinese population was identified.

Related: Non-Small Cell Lung Cancer Lung Cancer

Park SY, Kwon HJ, Lee HE, et al.
Promoter CpG island hypermethylation during breast cancer progression.
Virchows Arch. 2011; 458(1):73-84 [PubMed] Related Publications
This study was designed to evaluate the changes in promoter CpG islands hypermethylation during breast cancer progression from pre-invasive lesions [flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS)] to invasive ductal carcinoma (IDC). We performed MethyLight analysis for the methylation status of 57 promoter CpG island loci in 20 IDCs and their paired normal breast tissues. After selecting 15 CpG island loci showing breast cancer-specific DNA methylation, another set of normal breast tissue (n = 10), ADH/FEA (n = 30), DCIS (n = 35), and IDC (n = 30) of the breast were analyzed for these loci. We found six new methylation markers of breast cancer, namely DLEC1, GRIN2B, HOXA1, MT1G, SFRP4, and TMEFF2, in addition to APC, GSTP1, HOXA10, IGF2, RARB, RASSF1A, RUNX3, SCGB3A1 (HIN-1), and SFRP1. The number of methylated genes increased stepwise from normal breast to ADH/FEA and DCIS, while IDC did not differ from DCIS. Methylation levels and frequencies of APC, DLEC1, HOXA1, and RASSF1A promoter CpG islands were significantly higher in ADH/FEA than in normal breast tissue. GRIN2B, GSTP1, HOXA1, RARB, RUNX3, SFRP1, and TMEFF2 showed higher methylation levels and frequencies in DCIS than in ADH/FEA. DICS and IDC did not differ in the methylation levels or frequencies for most CpG island loci except SFRP1 and HOXA10. Our findings showed that promoter CpG island methylation changed significantly in pre-invasive lesions, and was similar in IDC and DCIS, suggesting that CpG island methylation of tumor-related genes is an early event in breast cancer progression.

Related: Breast Cancer

Chan WH, Chang KP, Yang SW, et al.
Transcriptional repression of DLEC1 associates with the depth of tumor invasion in oral squamous cell carcinoma.
Oral Oncol. 2010; 46(12):874-9 [PubMed] Related Publications
The objective of this study was to clarify the expression and epigenetic regulation of DLEC1, a candidate tumor suppressor gene (TSG) located at 3p21.3-p22, in oral squamous cell carcinoma (OSCC) and the clinical relevance of its down-expression. Quantitative RT-PCR was performed to exam the expression level of DLEC1 in matched OSCC and normal oral samples from 57 prospectively enrolled patients (with additional matched leukoplakia samples from 9 patients). We defined DLEC1 down-expression as a 2-fold decrease in expression of DLEC1 between normal tissues and tumors, and determined its correlation with clinical characteristics. Methylation-specific PCR (MSP) and bisulfite sequencing were used to evaluate the promoter methylation status of DLEC1 in 19 OSCC, 19 oral leukoplakia (OL), and 17 normal oral tissues. A statistically significant association between DLEC1 down-expression and invasive depth of OSCC was observed (P=0.026). Besides, expression of DLEC1 decreased sequentially from normal tissues to OL and then to OSCC (P<0.05), which was inversely correlated with methylation status of the DLEC1 promoter. Promoter methylation of DLEC1 increased progressively among normal tissues, OL, and OSCC, as revealed by MSP, and confirmed by sequencing. Treatment of OSCC cell lines with 5-aza-2'-deoxycytidine (5-Aza-dC) reversed the methylation and restored DLEC1 expression. Our results demonstrating that down-expression and promoter methylation of DLEC1 increased from normal tissues to premalignancies and then to malignancies. Furthermore, its transcriptional repression is associated with the depth of tumor invasion.

Related: Oral Cancer

Zhang Q, Ying J, Li J, et al.
Aberrant promoter methylation of DLEC1, a critical 3p22 tumor suppressor for renal cell carcinoma, is associated with more advanced tumor stage.
J Urol. 2010; 184(2):731-7 [PubMed] Related Publications
PURPOSE: Identifying tumor suppressor genes silenced by promoter CpG methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic biomarkers for early cancer detection. DLEC1 is located at 3p22.3, a critical tumor suppressor gene locus for renal cell carcinoma. We explored its epigenetic alteration in renal cell carcinoma and possible clinicopathological association.
MATERIALS AND METHODS: We examined DLEC1 expression and methylation by semiquantitative reverse transcriptase and methylation specific polymerase chain reaction in 9 renal cell carcinoma cell lines and 81 primary tumors. We also analyzed the relationship between DLEC1 methylation and clinicopathological features in patients with renal cell carcinoma. We assessed DLEC1 inhibition of renal cell carcinoma cell growth by colony formation assay.
RESULTS: DLEC1 methylation and down-regulation were detected in all renal cell carcinoma cell lines. Treatment with 5-aza-2'-deoxycytidine (Sigma) and/or trichostatin A (Cayman Chemical, Ann Arbor, Michigan) reversed methylation and restored DLEC1 expression, indicating that methylation directly mediates its silencing. Aberrant methylation was further detected in 25 of 81 primary tumors (31%) but only 1 of 53 nonmalignant renal tissues (2%) showed methylation. DLEC1 methylation status was significantly associated with TNM classification and grade in patients with renal cell carcinoma (chi-square test p = 0.01 and 0.04, respectively). DLEC1 ectopic expression in silenced renal cell carcinoma cells resulted in substantial tumor cell clonogenicity inhibition.
CONCLUSIONS: To our knowledge we report for the first time that DLEC1 is often down-regulated by CpG methylation and shows tumor inhibitory function in renal cell carcinoma cells, indicating its role as a tumor suppressor. DLEC1 tumor specific methylation may serve as a biomarker for early detection and prognosis prediction of this tumor.

Related: Kidney Cancer

Zhang Y, Miao Y, Yi J, et al.
Frequent epigenetic inactivation of deleted in lung and esophageal cancer 1 gene by promoter methylation in non-small-cell lung cancer.
Clin Lung Cancer. 2010; 11(4):264-70 [PubMed] Related Publications
BACKGROUND: Deleted in lung and esophageal cancer 1 (DLEC1) gene was a new candidate tumor suppressor gene. We determined the expression level and methylation status of DLEC1 in non-small-cell lung cancer (NSCLC), and the DLEC1 methylation in plasma DNA as a biomarker for NSCLC was further evaluated.
PATIENTS AND METHODS: The study population enrolled 78 paired NSCLC specimens and adjacent normal tissues and 25 benign pulmonary lesions. Meanwhile, corresponding plasma samples were collected. Methylation-specific polymerase chain reaction (PCR) was used to detect the DLEC1 methylation status. DLEC1 gene expression was determined by reverse transcriptase PCR and immunohistochemistry.
RESULTS: Hypermethylation of DLEC1 was found in 41% (32/78) of NSCLC tissues, which was significantly higher than that of adjacent normal tissues (3.8%; 3/78) and benign lesions (0/25; P < .001). Also, DLEC1 methylation was closely correlated with loss of expression, and treatment with 5-aza-2'-deoxycytidine induced DLEC1 restoration in A549 and SPC-A1 cell lines. Furthermore, DLEC1 hypermethylation was associated with advanced stage (P = .011) and lymph node metastasis (P = .019). Methylated DLEC1 was detected in 35.9% (28/78) of plasma samples from NSCLC patients and only 2% (1/50) in cancer-free controls, and the concordance of DLEC1 methylation status in plasmas and corresponding tumor tissues was good.
CONCLUSION: DLEC1 is silenced by promoter methylation in NSCLC specimens and is widely expressed in adjacent normal tissues and benign control samples. The high detection rate of methylated DLEC1 in plasma DNA further indicates its potential diagnostic and prognosis values in NSCLC.

Related: Non-Small Cell Lung Cancer Lung Cancer

Al Sarakbi W, Reefy S, Jiang WG, et al.
Evidence of a tumour suppressor function for DLEC1 in human breast cancer.
Anticancer Res. 2010; 30(4):1079-82 [PubMed] Related Publications
UNLABELLED: DLEC1 (deleted in lung and oesophageal cancer), located on 3p22.3, is a candidate tumour suppressor gene in lung, esophageal, and renal cancer. The aim of this study was determine whether the mRNA expression levels of DLEC1 were consistent with a tumour suppressive function.
MATERIALS AND METHODS: A total of 153 samples were analysed. The levels of transcription of DLEC1 were determined using quantitative PCR and normalised against (CK19). Transcript levels within breast cancer specimens were compared to normal background tissues.
RESULTS: Levels of transcription were lower [corrected] in tumour samples compared to adjacent non cancerous tissue (ANCT) samples but this was not statistically significant (median 0.167 vs. 0.03; p=0.138). DLEC1 expression levels were significantly lower in samples from patients who developed metastasis, local recurrence, or died of breast cancer when compared to those who were disease free for >10 years (p=0.041).
DISCUSSION: These findings are consistent with a possible tumour suppressor function of DLEC1 in breast cancer.

Related: Breast Cancer

Smith IM, Mithani SK, Liu C, et al.
Novel integrative methods for gene discovery associated with head and neck squamous cell carcinoma development.
Arch Otolaryngol Head Neck Surg. 2009; 135(5):487-95 [PubMed] Related Publications
OBJECTIVE: To find head and neck squamous cell carcinoma (HNSCC) specific genetic changes using integrative genetics.
DESIGN: Genetic analysis.
PATIENTS: Three separate cohorts of patients with primary HNSCC were evaluated for expression-microarray of 33 000 genes (8 patients), quantitative real-time polymerase chain reaction (qRT-PCR) (36 patients), and quantitative DNA/qRT-PCR (12 patients). Controls with normal upper-aerodigestive mucosa were evaluated for expression microarray (6 patients) and qRT-PCR (7 patients).
INTERVENTIONS: We utilized (1) prior reports of DNA loss and gain HNSCC accompanied by comparative genomic hybridization high-definition array data of the entire human genome, (2) a genome-wide survey of cancer-specific DNA mutations from the consensus cancer coding sequence (13 023 genes), and (3) our RNA expression microarray data of 33 000 genes to define candidate oncogenes activated by amplification or candidate tumor suppressor genes inactivated by deletion.
MAIN OUTCOME MEASURES: Gene expression in tissue measured by quantitative reverse transcriptase PCR. Gene copy number was measured by quantitative PCR.
RESULTS: We found 20 genes that were in areas of demonstrated amplification or deletion overlapping with the somatic mutants from genome-wide screening of the consensus DNA cancer coding sequence reported by Sjöblom et al. Three were chosen for further study based on expression differences and proof of cancer causation from in silico study: RUNX1T1, RFC4, and DLEC1. From 12 patients with HNSCC, matched tumor DNA/RNA and leukocyte-derived DNA were studied. Six of 12 (50%) of the tumors demonstrated amplification of the RUNX1T1 locus (P = .01), and 4 of those 6 (67%) demonstrated upregulated transcription of this gene (P = .02). Five of 12 (42%) of the tumors demonstrated amplification of the RFC4 locus (P = .03), and 1 of those 5 (20%) demonstrated upregulated messenger RNA (mRNA) transcription of the gene (P = .60). Four of 12 of the tumors (33%) (P = .05) demonstrated deletion in the DLEC locus (consistent with previously published 3p22 loss of 40%), and 3 of those 4 (75%) demonstrated reductions in mRNA expression (P = .06).
CONCLUSION: With the advent of high-throughput techniques to study cancer genetics, novel comparisons of large data sets using integrative methods may elucidate genetic alterations in HNSCC cancer.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology

Ma BB, Sung F, Tao Q, et al.
The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines.
Invest New Drugs. 2010; 28(2):107-14 [PubMed] Related Publications
The activity of the histone deacetylase inhibitor PXD101 was investigated in three hepatocellular carcinoma (HCC) cell lines. PXD101 was found to inhibit cell growth at a dose-dependent manner and induce histone acetylation in PLC/PRF/5, Hep3B and HepG2 cells. In PLC/PRF/5 and Hep3B cells which express hepatitis B-related genes (HBx, HBc and HBc), treatment with PXD101 resulted in apoptosis without a significant effect on viral gene expression. Exposure to PXD101 for up to 48 h had varying effects on the expression of 12 cellular genes with tumor suppressor functions, including p21, SOCS1, CMTM5, RASAL1, DLEC1, SFRP (-1, -2, -4 and -5), ADAMTS (-8 and -9). This study provided the basis for a phase II clinical trial of PXD101 in inoperable hepatitis-B associated HCC.

Related: Apoptosis Liver Cancer

Ying J, Poon FF, Yu J, et al.
DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers.
Br J Cancer. 2009; 100(4):663-9 [PubMed] Free Access to Full Article Related Publications
Promoter CpG methylation of tumour suppressor genes (TSGs) is an epigenetic biomarker for TSG identification and molecular diagnosis. We screened genome wide for novel methylated genes through methylation subtraction of a genetic demethylation model of colon cancer (double knockout of DNMT1 and DNMT3B in HCT116) and identified DLEC1 (Deleted in lung and oesophageal cancer 1), a major 3p22.3 TSG, as one of the methylated targets. We further found that DLEC1 was downregulated or silenced in most colorectal and gastric cell lines due to promoter methylation, whereas broadly expressed in normal tissues including colon and stomach, and unmethylated in expressing cell lines and immortalised normal colon epithelial cells. DLEC1 expression was reactivated through pharmacologic or genetic demethylation, indicating a DNMT1/DNMT3B-mediated methylation silencing. Aberrant methylation was further detected in primary colorectal (10 out of 34, 29%) and gastric tumours (30 out of 89, 34%), but seldom in paired normal colon (0 out of 17) and gastric (1 out of 20, 5%) samples. No correlation between DLEC1 methylation and clinical parameters of gastric cancers was found. Ectopic expression of DLEC1 in silenced HCT116 and MKN45 cells strongly inhibited their clonogenicity. Thus, DLEC1 is a functional tumour suppressor, being frequently silenced by epigenetic mechanism in gastrointestinal tumours.

Related: Chromosome 3 Stomach Cancer Gastric Cancer

Ayadi W, Karray-Hakim H, Khabir A, et al.
Aberrant methylation of p16, DLEC1, BLU and E-cadherin gene promoters in nasopharyngeal carcinoma biopsies from Tunisian patients.
Anticancer Res. 2008 Jul-Aug; 28(4B):2161-7 [PubMed] Related Publications
BACKGROUND: Aberrant methylation of tumor suppressor gene (TSG) promoters has been extensively investigated in nasopharyngeal carcinomas (NPC) from South East Asia but not from North Africa.
PATIENTS AND METHODS: The methylation status of p16, deleted in lung and esophageal cancer (DLEC1), zinc finger, MYND-type containing 10 (BLU) and E-cadherin gene promoters was investigated in 44 Tunisian NPC biopsies and three NPC xenografts, by methylation-specific PCR (MSP) combined with a quantitative assessment of some of the samples.
RESULTS: The frequencies of aberrant promoter methylation were similar to previous figures reported for Asian series: p16 27/44 (65%), DLEC1 38/44 (86.3%), BLU 15/44 (34.1%) and E-cadherin 35/44 (79.5%). Although in other malignancies, aberrant promoter hypermethylation increases with patient age, it was at the same high frequency in the juvenile and adult forms of Tunisian NPCs. However, there was a strong association between aberrant methylation of E-cadherin promoter and lymph node invasion (p < 0.01). In addition, aberrant methylation of the BLU promoter was significantly correlated with an undifferentiated histological type (p = 0.03).
CONCLUSION: Aberrant methylation of tumor suppressor genes occurs with the same high frequency in NPCs from North Africa as in South East Asia, regardless of patient age.

Related: CDKN2A Nasopharyngeal Cancer

Seng TJ, Currey N, Cooper WA, et al.
DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma.
Br J Cancer. 2008; 99(2):375-82 [PubMed] Free Access to Full Article Related Publications
The significance of chromosome 3p gene alterations in lung cancer is poorly understood. This study set out to investigate promoter methylation in the deleted in lung and oesophageal cancer 1 (DLEC1), MLH1 and other 3p genes in 239 non-small cell lung carcinomas (NSCLC). DLEC1 was methylated in 38.7%, MLH1 in 35.7%, RARbeta in 51.7%, RASSF1A in 32.4% and BLU in 35.3% of tumours. Any two of the gene alterations were associated with each other except RARbeta. DLEC1 methylation was an independent marker of poor survival in the whole cohort (P=0.025) and in squamous cell carcinoma (P=0.041). MLH1 methylation was also prognostic, particularly in large cell cancer (P=0.006). Concordant methylation of DLEC1/MLH1 was the strongest independent indicator of poor prognosis in the whole cohort (P=0.009). However, microsatellite instability and loss of MLH1 expression was rare, suggesting that MLH1 promoter methylation does not usually lead to gene silencing in lung cancer. This is the first study describing the prognostic value of DLEC1 and MLH1 methylation in NSCLC. The concordant methylation is possibly a consequence of a long-range epigenetic effect in this region of chromosome 3p, which has recently been described in other cancers.

Related: Non-Small Cell Lung Cancer Chromosome 3 Lung Cancer MLH1 RASSF1 RARB

Qiu GH, Salto-Tellez M, Ross JA, et al.
The tumor suppressor gene DLEC1 is frequently silenced by DNA methylation in hepatocellular carcinoma and induces G1 arrest in cell cycle.
J Hepatol. 2008; 48(3):433-41 [PubMed] Related Publications
BACKGROUND/AIMS: The chromosome locus 3p21.3 is a "hot-spot" for chromosomal aberrations and loss of heterozygosity in cancers. The 35 genes mapped to the AP20 subregion of this locus were screened for their expression to identify candidate tumor suppressor genes. DLEC1 was selected for further characterization in primary hepatocellular carcinomas and cell lines.
METHODS: RT-PCR and methylation-specific PCR were performed to examine the expression and methylation. Stable clones with DLEC1 overexpression were established to analyze cell proliferation and cell cycle.
RESULTS: DLEC1 was silenced and hypermethylated in 9 of 11 cell lines examined. Treatment with 5-aza-2'-deoxycytidine reversed the methylation and restored DLEC1 expression. The correlation between hypermethylation and expression was also demonstrated in 10 pairs of hepatocellular carcinoma and adjacent normal tissues (t-test, p<0.05). Hypermethylation of DLEC1 was detected in 70.6% of tumors, compared to 10.3% in normal tissues (n=68, p<0.001, chi(2)). Of interest, DLEC1 methylation was associated with the AJCC staging of the tumors (p=0.036, chi(2)). DLEC1 over-expression in cell lines decreased colony formation, cell growth and cell size, and induced a G1 arrest in cell cycle.
CONCLUSIONS: Our data indicate that DLEC1 is a candidate tumor suppressor gene that plays an important role in the development and progression of hepatocellular carcinoma.

Related: Liver Cancer

Kang GH, Lee S, Cho NY, et al.
DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis.
Lab Invest. 2008; 88(2):161-70 [PubMed] Related Publications
Transcriptional silencing by CpG island hypermethylation is a potential mechanism for the inactivation of tumor-related genes. Virtually, all types of human cancers show CpG island hypermethylation, and gastric carcinoma (GC) is one of the tumors with a high frequency of aberrant CpG island hypermethylation. In this study, we prescreened DNA methylation of 170 CpG island loci in a training set of 8 paired GC and GC-associated non-neoplastic mucosae (GCN) using MethyLight technology and selected 27 DNA methylation markers showing higher methylation frequency or level in GC than in GCN. These markers were then analyzed in a tester set of 25 paired GC and GCN and 27 chronic gastritis (CG) from non-cancer patients to generate their DNA methylation profiles. We identified 17 novel methylation markers in GC, including SFRP4, SEZ6L, TWIST1, BCL2, KL, TERT, SCGB3A1, IGF2, GRIN2B, SFRP5, DLEC1, HOXA1, CYP1B1, SMAD9, MT1G, NR3C1, and HOXA10. Of the 27 selected CpG island loci, 23 were methylated in GC, GCN, and CG and the remainder four loci (DLEC1, CHFR, CYP1B1, and NR3C1) were only methylated in GC. We found that the number of methylated loci was significantly higher in GC than in GCN or CG and that Helicobacter pylori infection was strongly associated with aberrant CpG island hypermethylation in CG. Hypermethylation was more prevalent in Epstein-Barr virus (EBV)-positive GC than in EBV-negative GC and in diffuse-type GC than in intestinal-type GC. Through our large-scale screening of 170 CpG island loci, we found 17 new DNA methylation markers of GC, which may serve as useful markers that may identify a distinct subset of GC.

Related: Stomach Cancer Gastric Cancer

Kwong J, Chow LS, Wong AY, et al.
Epigenetic inactivation of the deleted in lung and esophageal cancer 1 gene in nasopharyngeal carcinoma.
Genes Chromosomes Cancer. 2007; 46(2):171-80 [PubMed] Related Publications
Deletion of the short arm of chromosome 3 is a common event in nasopharyngeal carcinoma (NPC), suggesting that one or more tumor suppressor genes at 3p are involved in this cancer. DLEC1, Deleted in Lung and Esophageal Cancer 1, located at 3p22.2, was recently identified as a candidate tumor suppressor gene in lung, esophageal, and renal cancers. In this study, we investigated the involvement of DLEC1 in the development of NPC. Down-regulation of DLEC1 and promoter hypermethylation were observed in all NPC cell lines and xenografts but not in normal nasopharyngeal epithelial cells. Promoter hypermethylation of DLEC1 was also detected in 30 of 42 (71%) NPC primary tumors. Treatment of NPC cell lines with demethylating agent or histone deacetylase inhibitor resulted in restoration of DLEC1 expression. Overexpression of DLEC suppressed growth and reduced invasiveness of NPC cells. Furthermore, the tumorigenic potential of DLEC1 expressing NPC cells was highly reduced in nude mice. Taken together, our results strongly suggest that silencing of DLEC1 expression by promoter hypermethylation and histone deacetylation may be important in NPC tumorigenesis.

Related: Nasopharyngeal Cancer

Rauch T, Li H, Wu X, Pfeifer GP
MIRA-assisted microarray analysis, a new technology for the determination of DNA methylation patterns, identifies frequent methylation of homeodomain-containing genes in lung cancer cells.
Cancer Res. 2006; 66(16):7939-47 [PubMed] Related Publications
We present a straightforward and comprehensive approach for DNA methylation analysis in mammalian genomes. The methylated-CpG island recovery assay (MIRA), which is based on the high affinity of the MBD2/MBD3L1 complex for methylated DNA, has been used to detect cell type-dependent differences in DNA methylation on a microarray platform. The procedure has been verified and applied to identify a series of novel candidate lung tumor suppressor genes and potential DNA methylation markers that contain methylated CpG islands. One gene of particular interest was DLEC1, located at a commonly deleted area on chromosome 3p22-p21.3, which was frequently methylated in primary lung cancers and melanomas. Among the identified methylated genes, homeodomain-containing genes were unusually frequent (11 of the top 50 hits) and were targeted on different chromosomes. These genes included LHX2, LHX4, PAX7, HOXB13, LBX1, SIX2, HOXD3, DLX1, HOXD1, ONECUT2, and PAX9. The data show that MIRA-assisted microarray analysis has a low false-positive rate and has the capacity to catalogue methylated CpG islands on a genome-wide basis. The results support the hypothesis that cancer-associated DNA methylation events do not occur randomly throughout the genome but at least some are targeted by specific mechanisms.

Related: Chromosome 3 Lung Cancer

Daigo Y, Nishiwaki T, Kawasoe T, et al.
Molecular cloning of a candidate tumor suppressor gene, DLC1, from chromosome 3p21.3.
Cancer Res. 1999; 59(8):1966-72 [PubMed] Related Publications
The short arm of chromosome 3 is thought to contain multiple tumor suppressor genes, because one copy of this chromosomal arm frequently is missing in carcinomas that have arisen in a variety of tissues. We have isolated a novel gene encoding a 1755-amino acid polypeptide, through large-scale sequencing of genomic DNA at 3p21.3. Mutational analysis of this gene by reverse transcription-PCR revealed the lack of functional transcripts and an increase of nonfunctional RNA transcripts in a significant proportion (33%) of cancer cell lines and primary cancers (4 of 14 esophageal cancer cell lines, 2 of 2 renal cancer cell lines, 11 of 30 primary non-small cell lung cancers, and 3 of 10 primary squamous cell carcinomas of the esophagus). However, no alterations of the gene itself were detected in any of the cancers examined. Introduction of the cDNA significantly suppressed the growth of four different cancer cell lines, two of which produced no normal transcript on their own. No such effect occurred when antisense cDNA, cDNA corresponding to an aberrant transcript, or the vector DNA alone were transfected. These data suggest that aberrant transcription of this gene, designated DLC1 (deleted in lung cancer 1), may be involved in carcinogenesis of the lung, esophagus, and kidney.

Related: Chromosome 3


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Cite this page: Cotterill SJ. DLEC1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/DLEC1.htm Accessed: date

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