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At least 127 records · Page 7Linked to original sources
PubMed2006

RIZ1 is epigenetically inactivated by promoter hypermethylation in thyroid carcinoma.

BACKGROUND: Allelotype studies have suggested that chromosome 1p is frequently lost in thyroid cancers, thus suggesting that there is an important tumor suppressor at this location. RIZ1 (PRDM2), located on 1p36, is a recently described tumor suppressor gene and is a member of the protein methyltransferase superfamily. RIZ1 expression is lost in a variety of tumors, primarily by means of epigenetic mechanisms that involve promoter hypermethylation. METHODS: RIZ1 expression was examined in a panel of thyroid tumor cell lines and primary thyroid tissues (14 normal, 19 benign, and 31 cancerous) by using real-time polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using bisulfite sequencing and methylation-specific PCR. RESULTS: The authors demonstrated that RIZ1 expression is lost in thyroid tumor cell lines and is also significantly reduced in thyroid carcinomas, when compared with normal thyroid tissues (P < .0001) and benign tumors (P = .0003). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. One hundred percent of carcinomas were methylated, compared with 33% of normal thyroid tissues (P = .001). RIZ1 mRNA expression was significantly higher (P = .02) in unmethylated (1.22 +/- 1.2, mean +/- standard deviation [SD]), compared with methylated tissues (0.37 +/- 0.42, mean +/- SD). Last, treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline. CONCLUSIONS: The current study suggested an important role for RIZ1 expression in thyroid tumorigenesis and identified a potential novel therapeutic target for tumors unresponsive to other therapies.

Antimetabolites, Antineoplastic↗
PubMed2002

Analysis of 11q21-24 loss of heterozygosity candidate target genes in breast cancer: indications of TSLC1 promoter hypermethylation.

Loss of heterozygosity (LOH) at the distal half of chromosome arm 11q is frequent in a variety of human tumors, including breast cancer, and is often associated with poor prognosis. In an ongoing attempt to locate and characterize the main target genes within this chromosome region, we first looked for aberrations in known genes either suggested to be involved in tumorigenesis or shown to suppress tumor formation. We examined 31 primary breast tumors showing LOH in 11q21-24 for mutations in the MRE11A, CHK1, PPP2R1B, and TSLC1 genes. The absence of intragenic alterations related to cancer led us next to evaluate possible gene silencing resulting from promoter region CpG hypermethylation, using the bisulfite sequencing technique. In addition to the four genes mentioned above, we also analyzed the ATM gene, which had been investigated for certain germline mutations in an earlier study. Only the TSLC1 promoter region exhibited aberrant methylation patterns, and altogether 33% (10/30) of the successfully analyzed tumors showed evidence of elevated levels of TSLC1 CpG methylation. Ten percent (3/30) of the tumors showed significantly increased methylation. Thus, as has been shown in lung and some other forms of cancer, hypermethylation of the TSLC1 promoter region is also frequently a second hit along with LOH in breast cancer.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2003

Mutations and aberrant DNA methylation of the PROX1 gene in hematologic malignancies.

The homeobox gene PROX1 is related to the Drosophila prospero gene, which is expressed in the developing central nervous system and lens-secreting cone cells. We found that the PROX1 gene had missense and nonsense mutations in 4 of 29 hematologic cell lines analyzed. Decreased mRNA expression was also observed in half of these cell lines by RT-PCR. The restoration of PROX1 gene expression after treatment with the demethylating agent 5-aza-2'-deoxycytidine, as well as bisulfite sequencing analysis, indicated that gene silencing is caused by DNA hypermethylation at intron 1. Such hypermethylation was also seen in primary lymphomas (56.3%, 18/32) in a tumor-specific manner. These findings indicate that the profile of the PROX1 gene corresponds to that of a candidate tumor-suppressor gene.

Azacitidine↗
PubMed2006

Detailed methylation analysis of CpG islands on human chromosome region 9p21.

Deletion of 9p21 is the most commonly reported chromosomal abnormality in pediatric acute lymphoblastic leukemia, and published data suggest that the maternal chromosome is preferentially deleted. Preferential maternal deletion of 9p21 and reports of a differentially methylated region (DMR) and of parental effects in mice with lymphoma suggest there may be an unrecognized imprinted locus in this region. To screen for DMRs, we used the mcrBC/HpaII screening method and peripheral-blood DNA. Of 36 CpG islands within an 8.5-Mb region of 9p21, seven were identified as putative DMRs and were further analyzed by bisulfite sequencing. Neither any of the CpG islands nor a previously published putative DMR nearby showed evidence of differential parental methylation; however, the published DMR did demonstrate sequence-dependent differential methylation. Our data, which showed heterogeneous and low-level methylation of CpG islands, have obvious implications for methylation studies.

Adult↗
PubMed2006

Microarray-based survey of CpG islands identifies concurrent hyper- and hypomethylation patterns in tissues derived from patients with breast cancer.

Maintenance of CpG island methylation in the genome is crucial for cellular homeostasis and this balance is disrupted in cancer. Our rationale was to compare the methylation of CpG islands in tissues (tumor, healthy breast and blood) from patients with breast cancer. We studied 72 genes in 103 samples using microarray hybridization and bisulfite sequencing. We observed tumor specific hyper- or hypomethylation of five genes; COL9A1, MT1A, MT1J, HOXA5 and FLJ45983. A general drop of methylation in COL9A1 was apparent in tumors, when compared with blood and healthy breast tissue. Furthermore, one tumor displayed a complete loss of methylation of all five genes, suggesting overall impairment of methylation. The downstream, evolutionary conserved island of HOXA5 showed hypomethylation in 18 tumors and complete methylation in others. This CpG island also displayed a semimethylated state in the majority of normal breast samples, when compared to complete methylation in blood. Distinct methylation patterns were further seen in MT1J and MT1A, belonging to the metallothionein gene family. The CpG islands of these genes are spaced by 2 kb, which shows selective methylation of two structurally and functionally related genes. The promoters of FLJ45983 and MT1A were methylated above 25% in 18 primary and metastatic tumors. Concurrently, there was also >10% methylation of healthy breast tissue in 11 and 5 samples, respectively. This suggests that the methylation process for the latter two genes takes place already in normal breast cells. Our results also point to a considerable heterogeneity of epigenetic disturbance in breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Breast Neoplasms↗
PubMed2005

Widespread disruption of genomic imprinting in adult interspecies mouse (Mus) hybrids.

Mammalian interspecies hybrids exhibit parent-of-origin effects in that offspring of reciprocal matings, even though genetically identical, frequently exhibit opposite phenotypes, especially in growth. This was also observed in hybridization with the genus Mus. These parent-of-origin effects suggested that imbalance in the expression of imprinted genes, which are expressed differentially, depending on their transmission through the maternal or paternal germline, and/or differential loss-of-imprinting (LOI) could underlie these opposite growth phenotypes in reciprocal mammalian hybrids. Here we report that tissue-specific LOI occurs in adult Mus hybrids. Contrary to expectations, LOI patterns were not consistent with a direct influence of altered expression levels of imprinted genes on growth. Bisulfite sequencing revealed that reactivation of maternal alleles of Peg3 and Snrpn in specific tissues was accompanied by partial demethylation at their potential imprinting control regions. We propose that abnormal reprogramming after fertilization and during preimplantation development is in part responsible for hybrid dysgenesis, for which a strong epigenetic basis has been demonstrated.

Animals↗
PubMed2003

Hypermethylation, but not LOH, is associated with the low expression of MT1G and CRABP1 in papillary thyroid carcinoma.

We previously obtained gene expression profiles of 8 matched papillary thyroid carcinoma (PTC) and normal tissues using DNA microarrays. To identify novel tumor suppressor genes involved in thyroid carcinogenesis, we here analyze genes showing lower expression in PTC tumors than in normal thyroid tissues. A search for loss of heterozygosity (LOH) in 49 regions that harbor consistently down-regulated genes revealed LOH in only 4 regions and in just a very small number of tumors. To determine whether the underexpression might be due to promoter methylation, we used combined bisulfite restriction analysis and bisulfite sequencing to study 7 underexpressed genes. Loss of expression of MT1G and CRABP1 is accompanied by hypermethylation in the 5' regions of these genes, but methylation was not seen in other genes tested. Combined treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza-dC) and the histone deacetylase inhibitor trichostatin A (TSA) resulted in demethylation and re-expression of the MT1G gene in the cell line K2. Treatment with 5-Aza-dC alone restored CRABP1 expression in a colorectal cancer cell line, SW48. In conclusion, LOH is a remarkably rare mechanism of loss of gene function in PTC. In contrast, hypermethylation of promoter CpG islands seems to occur at higher frequency. MT1G and CRABP1 are novel genes that are likely involved in the pathogenesis of sporadic PTC.

Adenocarcinoma, Papillary↗
PubMed2003

Promoter methylation of the TSLC1 gene in advanced lung tumors and various cancer cell lines.

We previously identified TSLC1, a tumor suppressor gene in human nonsmall cell lung cancer (NSCLC). TSLC1 belongs to immunoglobulin superfamily molecules and is involved in cell adhesion. Loss of TSLC1 expression was strongly correlated with the promoter hypermethylation in several NSCLC cell lines. Here, we examined the methylation status of the TSLC1 gene promoter in 48 primary NSCLC tumors by bisulfite SSCP in combination with bisulfite sequencing. Six CpG sites around the promoter regions were significantly methylated in 21 of 48 primary NSCLC tumors (44%). Promoter methylation was more likely to be observed in relatively advanced tumors with TNM classification of pT2, pT3 or pT4 (19 of 33, 58%) than in those with pT1 (2 of 15, 13%), suggesting that alteration of TSLC1 would be involved in the progression of human NSCLC. Loss of TSLC1 expression was also observed in 20 of 46 (43%) human cancer cell lines, including those from esophageal (3 of 3), gastric (8 of 9), ovarian (2 of 5), endometrial (2 of 2), breast (1 of 3), colorectal (2 of 8) and small cell lung cancers (2 of 10). Combined analysis of promoter methylation and the allelic state in these cell lines indicated that the TSLC1 gene was often silenced not only by mono-allelic methylation associated with loss of the other allele but also through bi-allelic methylation. These results suggest that alteration of TSLC1 would be involved in advanced NSCLC as well as in many other human cancers.

Adenocarcinoma↗
PubMed2004

Analysis of HIC-1 methylation and transcription in human ependymomas.

Ependymomas are among the most common brain tumors in children. They develop from ependymal cells lining the ventricular system of the CNS. Previous studies have demonstrated a significant rate of allelic loss at chromosome 17p13.3. The HIC-1 putative tumor-suppressor gene, which exhibits hypermethylation and loss of expression in various tumor entities including medulloblastomas and gliomas, maps to the affected region. In the present study, we analyzed HIC-1 in ependymomas. Therefore, we applied methylation-specific PCR of the 5'-untranslated region as well as of a central region of HIC-1 and bisulfite sequencing to determine the methylation status in 52 ependymomas of different histologic subtypes, grades and locations. In addition, we used a competitive RT-PCR approach for sensitive assessment of HIC-1 transcripts. Hypermethylation of at least one of the 2 analyzed regions was found in 43/52 (83%) cases. There was a significant correlation between hypermethylation of HIC-1 and nonspinal localization (p = 0.019) as well as age. Of 27 ependymomas, 22 (81%) showed absent or low expression of HIC-1. The elevated methylation of HIC-1 in nonspinal ependymomas supports the hypothesis that spinal and nonspinal ependymomas represent genetically distinct entities.

Adolescent↗
PubMed2004

Identification of differentially methylated CpG islands in prostate cancer.

Epigenetic change such as DNA methylation is one important mechanism for regulating gene expression as genetic change, such as mutation or loss of heterozygosity. Methylation of cancer-related genes has been shown to play an important role in carcinogenesis and tumor progression. Using methylated CpG island amplification (MCA)/representational difference analysis (RDA), we identified four CpG islands in neurotrophin tyrosine kinase receptor type 2 (NTRK2), Protocadherine Flamingo1 and MFPC (Methylated Fragments in Prostate Cancer) 7 and 8. Bisulfite sequencing revealed that 2 regions of NTRK2 as well as MFPC7 and MFPC8 were aberrantly methylated in prostate cancer cell lines, and COBRA showed that 48 (76.24%), 37 (58.7%) and 14 (22.2%) of 63 prostate cancer tissues were methylated, respectively, for these sites. On the other hand, none of 13 benign prostate samples were methylated, except for 1 (7.7%) with NTRK2. For NTRK2, mRNA expression was negative in prostate cancer cell lines (LNCaP and DU145) but was recovered on a methyltransferase inhibitor (5-Aza-CdR) treatment. The role of NTRK2 within NTRK remains unclear. Our results suggest that these 3 hypermethylated DNA fragments also may be markers of prostate cancer detection.

Animals↗
PubMed2004

High-density methylation of p14ARF and p16INK4A in Epstein-Barr virus-associated gastric carcinoma.

Promoter hypermethylation of various tumor-related genes is extremely frequent in gastric carcinoma (GC) associated with Epstein-Barr virus (EBV). To investigate the significance of the promoter methylation in this type of GC, we examined the methylation densities of the promoter regions of p14ARF and p16INK4A in EBV-associated (n=7) and EBV-negative (n=14) GC. Bisulfite sequencing demonstrated a high frequency of concurrent methylation of p14ARF and p16INK4A promoter regions in EBVaGC. Methylation was observed in all 29 CpG sites of p14ARF and all 16 sites of p16INK4A with equally high densities. In EBV-negative GC, the methylation profiles differed between the 2 genes. Promoter methylation was sporadic and variable in p14ARF, and only the last position of CpG in p14ARF was methylated at high frequency. High-density methylation in p16INK4A was observed in a subset of GC, but the first position of CpG was never methylated in EBV-negative GC. These findings suggest the presence of mechanisms of de novo and maintenance methylation specific to EBVaGC that might be associated with EBV infection.

Adult↗
PubMed2004

Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma.

Suppressor of cytokine signaling (SOCS)-1 inhibits signaling of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway by several cytokines and has tumor suppressor activity. Methylation of the SOCS-1 CpG island has been shown to inactivate the SOCS-1 gene in certain human cancers. In our study, we investigated methylation status of the SOCS-1 gene by methylation-specific PCR in 75 gastric carcinoma (GC) tissues, 25 corresponding nonneoplastic mucosae and 10 normal gastric mucosae from healthy young individuals. We also performed bisulfite sequencing of DNAs from 2 GC tissues. In addition, SOCS-1 mRNA levels were examined in 50 GCs by quantitative RT-PCR. Hypermethylation of the SOCS-1 gene was detected in 33 (44%) of 75 GC tissues and in 3 (12%) of 25 corresponding nonneoplastic mucosae; the incidence was significantly different (p = 0.004). None of the 10 normal gastric tissues from healthy individuals showed hypermethylation. Methylation of the SOCS-1 gene was associated with lymph node metastasis, advanced tumor stage and reduced expression of SOCS-1 in GC tissues (p = 0.009, 0.034 and 0.002, respectively). Reduced expression of SOCS-1 in GC tissues was associated with lymph node metastasis and advanced tumor stage (p = 0.013 and 0.002, respectively). Our results suggest that transcriptional inactivation of the SOCS-1 gene by hypermethylation may be involved in development, progression and metastasis of GC.

Carcinoma↗
PubMed2005

Aberrant promoter methylation of human DAB2 interactive protein (hDAB2IP) gene in lung cancers.

The human DOC-2/DAB2 interactive protein gene (hDAB2IP) is a novel member of the Ras GTPase-activating gene family that is known to act as a tumor suppressor gene and is inactivated by methylation in prostate and breast cancers. We established previously a methylation-specific PCR (MSP) for the promoter region (m2a and m2b regions) of hDAB2IP and examined hDAB2IP methylation status in breast cancers. We analyzed the methylation and expression status of hDAB2IP in lung cancers. The methylation status of hDAB2IP was examined in lung cancer cell lines using bisulfite sequencing and MSP. Expression was examined using conventional and real-time RT-PCR, and methylation was found to be inversely correlated with expression, confirming that the MSP can also be used to examine hDAB2IP methylation status in lung cancers. Aberrant methylation was detected at the m2a region in 19 of 47 lung cancer cell lines (40%) and 26 of 70 primary tumors (37%) and at the m2b in 16 lines (34%) and 25 of 70 tumors (36%). Gene expression was restored in methylated cell lines supplemented with 5-aza-2'-deoxycytidine, confirming that methylation was responsible for downregulation. We also examined the relationship between hDAB2IP methylation and clinico-pathological features of the lung cancers and found that hDAB2IP methylation was associated with advanced disease stage. Our results demonstrate that hDAB2IP methylation is frequently present in lung cancers and plays a key role in hDAB2IP silencing. hDAB2IP methylation could be used as a biomarker for disease stage, reflecting the degree of clinico-pathological malignancy of lung cancer.

Aged↗
PubMed2005

Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma.

Tazarotene-induced gene 1 (TIG1) and Tazarotene-induced gene 3 (TIG3) are retinoid acid (RA) target genes as well as candidate tumor suppressor genes in human cancers. In our study, we have investigated the expression of TIG1 and TIG3 in nasopharyngeal carcinoma (NPC). Loss of TIG1 expression was found in 80% of NPC cell lines and 33% of xenografts, whereas TIG3 was expressed in all NPC samples and immortalized nasopharyngeal epithelial cells. In order to elucidate the epigenetic silencing of TIG1 in NPC, the methylation status of TIG1 promoter was examined by genomic bisulfite sequencing and methylation-specific PCR (MSP). We have detected dense methylation of TIG1 5'CpG island in the 5 TIG1-negative NPC cell lines and xenograft (C666-1, CNE1, CNE2, HONE1 and X666). Partial methylation was observed in 1 NPC cell line HK1 showing dramatic decreased in TIG1 expression. Promoter methylation was absent in 2 TIG1-expressed NPC xenografts and the normal epithelial cells. Restoration of TIG1 expression and unmethylated alleles were observed in NPC cell lines after 5-aza-2'-deoxycytidine treatment. Moreover, the methylated TIG1 sequence was detected in 39 of 43 (90.7%) primary NPC tumors by MSP. In conclusion, our results showed that TIG1 expression is lost in the majority of NPC cell lines and xenografts, while promoter hypermethylation is the major mechanism for TIG1 silencing. Furthermore, the frequent epigenetic inactivation of TIG1 in primary NPC tumors implied that it may play an important role in NPC tumorigenesis.

Animals↗
PubMed2005

Multiple mechanisms downregulate CDKN1C in human bladder cancer.

Expression of the imprinted CDKN1C gene at chromosome 11p15.5 encoding the cell cycle inhibitor p57(KIP2) is disturbed in Beckwith-Wiedemann syndrome and in several human cancers by different mechanisms. Many advanced urothelial cancers (TCC) display downregulation of CDKN1C expression. The responsible mechanisms were investigated in TCC cell lines, with cultured normal urothelial cells (UEC) as controls. CDKN1C mRNA expression was diminished in 12/15 TCC lines and p57(KIP2) protein was decreased accordingly. Because CDKN1C is expressed from the maternal allele only, LOH at 11p15.5 represents one mechanism of downregulation. In 3 cell lines, several polymorphic markers flanking CDKN1C were homozygous compatible with this mechanism. Hypermethylation of the CDKN1C promoter, a reported cause of downregulation in other cancers, was detected by bisulfite sequencing in several cell lines and appeared associated with downregulation in at least one cell line. The methylation inhibitor 5-aza-2'deoxycytidine induced CDKN1C expression in this cell line and others. A third reported mechanism involves a switch of both alleles toward a paternal imprinting pattern, indicated by hypomethylation of a differentially methylated region (DMR) in the imprinting center (IC2). This hypomethylation was detected in most TCC lines, and was associated with re-expression of the non-coding LIT1 RNA and with downregulation of CDKN1C in several. Thus, CDKN1C downregulation in TCC seems to occur by several different mechanisms. This finding and the ability of p57(KIP2) to induce senescence in urothelial cells make CDKN1C a good candidate for a tumor suppressor at 11p in TCC.

Carcinoma, Transitional Cell↗
PubMed2006

DNA mismatch repair as an effector for promoting phorbol ester-induced apoptotic DNA damage and cell killing: implications in tumor promotion.

Phorbol ester was known to activate protein kinase C (PKC) and exert numerous cellular effects, including proliferation, apoptosis, and oncogenic transformation. How phorbol ester stimulates both apoptosis and tumor promotion is not clear. Here DNA mismatch repair (MMR)-proficient human colon cancer cells (DLD-1+Ch2; hMSH6+) treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) undergo rapid cell death, which is significantly abolished by staurosporine (PKC inhibitor) or antioxidant, compared with the paired MMR-deficient (DLD-1; hMSH6-) cells. Induction of reactive oxygen species (ROS) by TPA is shown to be one of downstream effectors required, but not sufficient, for cell killing as it is also observed in DLD-1 cells. Strikingly, DLD-1+Ch2 cells selected for resistance to TPA are found to lose the expression of hMSH6. Treatment of TPA-resistant DLD-1+Ch2 cells with 5-aza-2'-deoxycytidine, not only restores hMSH6 expression but also resensitizes TPA-resistant cells to TPA, suggesting that expression of hMSH6 is transcriptionally silenced by cytosine methylation confirmed directly by bisulfite sequencing. Knockdown hMSH6 or hPMS2 with siRNA in DLD-1+Ch2 cells resulted in more resistant to TPA-induced cell killing, further suggesting that MMR proteins involve in TPA or ROS-induced cell killing. Results suggest that deficiency in MMR could promote tumorigenesis by inhibiting apoptotic responses to ROS-mediated DNA damages as ROS are continuously produced as a byproduct of normal metabolism.

Apoptosis↗
PubMed2006

Hypermethylation of the GATA gene family in esophageal cancer.

The GATA family of transcription factors promotes the normal development of the gastrointestinal tract during embryogenesis and determines tissue differentiation in adult gut epithelium. Loss of GATA-4 and GATA-5 has been reported in human gastric and colon cancer. We examined GATA-4,-5 and -6 gene expression in established esophageal squamous cancer cell lines and the relationship to DNA methylation in the promoter region of these genes. GATA-4 and GATA-5 expression was absent in most esophageal cancer cell lines, but was restored upon treatment with the demethylating agent 5-aza-2'-deoxycytidine. For each of the cell lines without detectable GATA gene expression, aberrant methylation of the promoter region CpG-island was detected by methylation specific PCR. We confirmed these results with genomic bisulfite sequencing. GATA-6 expression was found in each of the cell lines. GATA-4/-5 promoter methylation was not detected in normal esophageal mucosa, but GATA-4 methylation was present in 27 of 44 (61%) squamous carcinomas and 31 of 44 (71%) adenocarcinoma of the esophagus, while GATA-5 methylation was present in 14 of 44 (32%) squamous carcinomas and 24 of 44 (55%) adenocarcinoma of the esophagus. Our studies demonstrate frequent silencing of GATA-4 and GATA-5, but not GATA-6, in human esophageal neoplasia associated with gene promoter hypermethylation.

DNA Methylation↗
PubMed2007

p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma.

To clarify the significance of p73 in Epstein-Barr virus (EBV)-associated gastric carcinoma (GC), the immunohistochemical expression and CpG-island methylation of p73 were evaluated in cancer tissues and adjacent nonneoplastic tissues of GC with and without EBV infection. Loss of p73 expression by immunohistochemistry was specific to EBV-associated GC (11/13) compared to EBV-negative GC (3/38), which was independent of abnormal p53 expression. With methylation-specific polymerase chain reaction (MSP), the aberrant methylation of p73 exon 1 was similarly specific to EBV-associated GC (12/13), and also rare in EBV-negative GC (2/38). Bisulfite sequencing for p73 exon 1 and its 5' region confirmed the MSP results, showing uniform and high-density methylation in EBV-associated GC. Comparative MSP analysis of p14, p16 and p73 methylation, using 20 cases each of formalin-fixed and paraffin-embedded tissues of early GC with and without EBV infection, confirmed 2 types of methylation: global methylation with increased rates (p14 and p16) and specific methylation of p73 in EBV-associated GC. In nonneoplastic mucosa, p14, p16 and p73 methylation occurred in both EBV-associated (8/33, 6/34 and 3/38, respectively) and EBV-negative GC (6/23, 4/35, and 1/35). p73 methylation was observed in the mucosa without H. pylori infection in all 4 samples. Loss of p73 expression through aberrant methylation of the p73 promoter occurs specifically in EBV-associated GC, together with the global methylation of p14 and p16. A specific type of gastritis, prone to a higher grade of atrophy and p73 methylation, may facilitate the development of EBV-associated GC.

Base Sequence↗