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PubMed2005

Subunit assembly modulates the activities of the Type III restriction-modification enzyme PstII in vitro.

We demonstrate that, like other Type III restriction endonuclease, PstII does not turnover such that a DNA substrate is only fully cleaved at a Res2Mod2-to-site ratio of approximately 1:1. However, unlike other Type III enzymes, the cleavage rate profiles varied with protein concentration: using 5 nM DNA and 25 nM PstII, approximately half of the DNA was cut at a fast rate while the remainder was cut 24 times more slowly; in comparison, with 100 nM PstII cleavage occurs at a single fast rate. The inclusion of the methyl donor S-adenosyl methionine does not alter the rates with 100 nM PstII but with 25 nM PstII the reaction stopped after completion of the initial fast cleavage phase owing to methylation. Concentration-dependent rates were also observed in methylation assays: at 100 nM PstII, a single slow rate was measured while at lower PstII concentrations both fast and slow rates were measured. We propose a model in which the intact Res2Mod2 complex favoured at high PstII concentrations is a fast endonuclease/slow methyltransferase while the various subassemblies which coexist at lower concentrations are fast methyltransferases. A potential role for disassembly in control of restriction activity in vivo is discussed.

Bacterial Proteins↗

PubMed2003

Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis.

To date, several reports on methylation of various genes in gastric cancer (GC) have been published. However, most of these studies focused on cancer tissues or a single gene only and gave no information about the methylation status of specific genes in the premalignant stages or about the concurrent methylation of other genes in specific lesions. We attempted to investigate methylation of multiple genes in a large sample collection of GC (n = 80), gastric adenoma (GA) (n = 79), intestinal metaplasia (IM) (n = 57), and chronic gastritis (CG) (n = 74). We determined the methylation frequency of 12 genes, including APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p16, p14, RASSF1A, THBS1, and TIMP3 by methylation-specific PCR. Five different classes of methylation behaviors were found: (1) genes methylated in GC only (GSTP1 and RASSF1A); (2) genes showing low methylation frequency (<12%) in CG, IM, and GA, but significantly higher methylation frequency in GC (COX-2, hMLH1, and p16); (3) a gene with low and similar methylation frequency (8.8-21.3%) in four-step lesions (MGMT); (4) genes with high and similar methylation frequency (53-85%) in four-step lesions (APC and E-cadherin); and (5) genes showing an increasing tendency with or without fluctuation of the methylation frequency along the progression (DAP-kinase, p14, THBS1, and TIMP3). The average number of methylated genes was 2.7, 3.6, 3.4, and 5.2 per 12 tested genes in CG, IM, GA, and GC, respectively. Our results suggest that tumor suppressor genes show a gene type-specific methylation profile and that aberrant CpG island methylation tends to accumulate along the pathway of multistep carcinogenesis.

Adolescent↗

PubMed2025

Long-read sequencing of single cell-derived melanoma subclones reveals divergent and parallel genomic and epigenomic evolutionary trajectories.

Tumor evolution is driven by various mutational processes, ranging from single-nucleotide variants (SNVs) to large structural variants (SVs) to dynamic shifts in DNA methylation. Current short-read sequencing methods struggle to accurately capture the full spectrum of these genomic and epigenomic alterations due to inherent technical limitations. To overcome that, here we introduce an approach for long-read sequencing of single-cell derived subclones, and use it to profile 23 subclones of a mouse melanoma cell line, characterized with distinct growth phenotypes and treatment responses. We develop a computational framework for harmonization and joint analysis of different variant types in the evolutionary context. Uniquely, our framework enables detection of recurrent amplifications of putative driver genes, generated by independent SVs across different lineages, suggesting parallel evolution. In addition, our approach revealed gradual and lineage-specific methylation changes associated with aggressive clonal phenotypes. We also show our set of phylogeny-constrained variant calls along with openly released sequencing data can be a valuable resource for the development of new computational methods.

Journal Article↗

PubMed2006

Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas.

AIM: To study the role of CDH1/E-cadherin (E-cad) gene alteration profiles including mutation, loss of heterozygosity (LOH), promoter polymorphism and hypermethylation in mechanisms of CDH1 inactivation in gastric carcinoma (GC). METHODS: Specimens were collected surgically from 70 patients with GC. Allelotyping PCR and detection of LOH, denaturing high pressure liquid chromatography and DNA sequencing, restriction fragment length polymorphism analysis, methylation specific PCR, and immunohistochemical staining were used. RESULTS: Promoter polymorphism was not a major mechanism of E-cad inactivation. Only one truncating mutation was found in a diffuse type tumor (3%). Both LOH and promoter hypermethylation were major mechanisms of E-cad inactivation, but interestingly, there was a negative association between the fraction of allelic loss (LOH) in tumors and hypermethylation of CDH1. Therefore LOH and hypermethylation were two different tumorigenic pathways involved in GC. CONCLUSION: Given the findings that somatic mutation was extremely low and the relationship between LOH and hypermethylation was inverse, any two combinations of these three factors cannot fulfill the classical two-hit hypothesis of CDH1 inactivation. Thus, other mechanisms operating at the transcriptional level or at the post-translational level might be required to induce E-cadherin inactivation.

Adult↗

PubMed2001

Methylation profiling of human cancers in blood: molecular monitoring and prognostication (review).

Cancer is a polygenetic and polyepigenetic disease. Circulating tumor cells in peripheral blood have been demonstrated to reflect the biological characteristics of tumors including the potential of metastasis development and tumor recurrence. Aberrant promoter methylation has emergingly become a fundamental molecular abnormality leading to transcriptional silencing of tumor suppressor genes, DNA repair genes and metastasis inhibitor genes, and is linked to the predisposition of genetic alterations of other cancer-associated genes. This epigenetic inheritance has significant biological implications for cancer progression and metastasis formation. Of significance, DNA hypermethylation of multiple genes successfully detected in circulating tumor cells from cancer patients may prove valuable for disease monitoring. A number of epigenetic markers may feasibly enable the detection of circulating tumor cells from patients with different cancer types. The prognostic and therapeutic implications of aberrant DNA methylation could eventually bring forth improved outcome of cancer patients. A growing body of evidence and future advances in understanding cancer epigenetics may fuel us to monitor and treat cancers in alternative ways.

DNA Methylation↗

PubMed2025

The chromosome-level genome of Stylosanthes guianensis provides insights into genome evolution and environmental adaptation.

Stylosanthes guianensis is a leguminous forage crop of significant economic importance, primarily distributed in tropical and subtropical regions. It exhibits strong adaptability to various stresses, yet the genetic basis underlying this trait remains unclear. In this study, we constructed the first chromosome-scale reference genome of S. guianensis using a combination of Nanopore and Hi-C sequencing technologies. The assembled genome size is 1254 Mb, with 10 pseudochromosomes. Using Nanopore full-length transcriptome data, we generated high-quality transcript-level gene annotations, identifying 36 585 gene models and 110 601 transcripts. The repetitive sequences in S. guianensis account for 79.16% of the genome, with the extensive expansion of Gypsy elements in long terminal repeats contributing to its genome size enlargement. Comparative genomic and transcriptomic analyses revealed that flavonoid metabolism plays a pivotal role in stress adaptation, providing new insights into the genetic basis of stress tolerance. Additionally, we generated whole-genome methylation profiles under cold treatment and control conditions, offering valuable data for future epigenomic research. These findings provide essential molecular resources for understanding stress resilience in S. guianensis and advancing its molecular breeding.

Genome, Plant↗

PubMed2002

Evaluation of a potential epigenetic biomarker by quantitative methyl-single nucleotide polymorphism analysis.

Tumorigenesis is characterized by alterations of methylation profiles including loss and gain of 5-methylcytosine. Recently, we identified a single CpG, which seemed to be consistently hypomethylated in pilocytic astrocytomas but not in other gliomas. To evaluate its applicability as a biomarker, we examined its methylation status in a large panel of gliomas (n = 97). Methylation-dependent DNA sequence variation may be considered a kind of single nucleotide polymorphism (methylSNP). MethylSNPs can be easily converted into common SNPs of the C/T type by sodium bisulfite treatment of the DNA and afterwards subjected to conventional SNP typing. We adapted SnaPshot trade mark and Pyrosequencing trade mark to determine the methylation of our test CpG in a quantitative manner. The adapted methods, called SNaPmeth and PyroMeth, respectively, gave nearly identical results, however data obtained with PyroMeth showed less scattering. Furthermore, the integrated software for allele frequency determination from Pyrosequencing could be used directly for data analysis while SnaPmeth data had to be exported and processed manually. Although data did not confirm our previous result of a preferential hypomethylation of the tested CpG in pilocytic astrocytomas, we consider quantitative methylSNP analysis by SNaPmeth or PyroMeth a favorable alternative to existing high-throughput methylation assays. It combines single CpG analysis with accurate quantitation and is amenable to high throughput.

Adolescent↗

PubMed1984

Effect of alkylation with N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea on the secondary structure of DNA.

We have earlier reported that alkylation of DNA by the chemical carcinogen dimethyl sulphate, which mainly alkylates N-7 of guanine and N-3 of adenine, causes the formation of partially denatured regions in double-stranded DNA (Rizvi RY, Alvi NK & Hadi SM, Biosci. Rep. 2, 315-322, 1982). It is known that the major site of alkylation in DNA by N-ethyl-N-nitrosourea (EtNu) are the phosphate groups. N-methyl-N-nitrosourea (MeNu), on the other hand, causes the alkylation of mainly guanine residues. We have therefore studied the effect of these two alkylating carcinogens on the secondary structure of DNA. DNA alkylated with increasing concentrations of EtNu and MeNu was subjected to alkaline and S1 nuclease hydrolysis. Thermal melting profiles of alkylated DNA were also determined using S1 nuclease. The results indicated that alkylation by the two alkylating agents had a differential effect on the secondary structure of DNA. EtNu-alkylated DNA was found to be more thermostable than native DNA at neutral pH. It was however more alkali-labile than MeNu-alkylated DNA. The greater stability of EtNu-alkylated DNA was considered to be due to abolition of negative charges on phosphate alkylation.

Alkylation↗

PubMed2026

Integrated pan-cancer profiling highlights OSR2 as a prognostic indicator and immune-associated biomarker.

BACKGROUND: Odd-skipped-related 2 (OSR2), encoded by the OSR2 gene, has been reported to function as a checkpoint associated with CD8⁺ T-cell exhaustion in the tumor microenvironment of solid malignancies, suggesting its potential as a therapeutic target to improve immunotherapeutic responses. Nevertheless, the molecular and clinical significance of OSR2 across diverse cancer types has not yet been systematically investigated, and its pan-cancer expression profile, prognostic implications, and associations with tumor immunity remain to be fully elucidated. METHODS: In this study, we integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) portal, and the Human Protein Atlas to construct a systematic pan-cancer profile of OSR2. The prognostic value of OSR2 was comprehensively assessed using univariate Cox regression, survival analysis, and receiver operating characteristic (ROC) curve analysis. In addition, we performed an in-depth analysis of the relationships between OSR2 and multiple molecular and immunological features, including copy number variation (CNV), DNA methylation, tumor mutational burden (TMB), microsatellite instability (MSI), immune-related gene expression, immune cell infiltration, and drug sensitivity, with the aim of exploring its potential immunological associations with the tumor microenvironment. RESULTS: OSR2 expression was significantly upregulated or downregulated in the majority of tumor tissues relative to normal counterparts and exhibited distinct cancer-type-specific patterns across clinical stages. CNV alterations and aberrant DNA methylation were closely associated with abnormal OSR2 mRNA expression in multiple cancers. Prognostic analyses indicated that OSR2 expression was significantly associated with overall survival, disease-specific survival, disease-free interval, and progression-free interval across multiple cancer types, showing either risk-associated or protective associations in a tumor-context-dependent manner. Furthermore, OSR2 expression showed strong associations with immune cell infiltration, particularly T-cell subsets, and was significantly correlated with the expression of multiple immune checkpoint-related genes across diverse malignancies. OSR2 expression was also closely associated with TMB, MSI, and sensitivity to multiple anticancer agents. CONCLUSION: Taken together, these findings suggest that OSR2 is associated with prognosis and immune-related features across multiple cancer types. OSR2 may be linked to features of the tumor immune microenvironment through its relationships with immune cell infiltration, immune checkpoint gene expression, and genomic instability, and thus may serve as a candidate biomarker for further investigation in cancer immunotherapy.

CD8⁺ T-cell↗

PubMed1999

Genotoxicity and embryotoxicity of urban air particulate matter collected during winter and summer period in two different districts of the Czech Republic.

This study is the in vitro part of a long-term program to investigate the impact of air pollution on the health of a population in a polluted region of Northern Bohemia. In order to assess the possible health risks associated with a complex mixture of hundreds of organic compounds adsorbed to air particles, we used a biomarker-directed fractionation procedure to evaluate biological activities of different chemical compound classes. The extractable organic compounds from the air particles collected in both the polluted and the control districts during the summers and winters of 1993-1994 were investigated. The principal aim of this study was to compare the DNA binding activities of those compound classes using an in vitro acellular assay coupled with 32P-postlabeling and an embryotoxicity assay using Chick Embryotoxicity Screening Test (CHEST). In both assays, the highest activity was due to the neutral fractions from which the aromatic subfractions containing mainly polycyclic aromatic hydrocarbons (PAHs) and their methyl-derivates were the most active for both localities and seasons. A good correlation between the levels of DNA adduct formation using S9 metabolic activation and the ED50 for all different complex mixtures of organic compounds was observed (r=0.773, p<0.001). DNA adduct maps and high performance liquid chromatography (HPLC) profiles were similar for samples from both districts and seasons. The major DNA adducts resulting from the crude extracts were identical to those derived from aromatic fractions. The DNA adducts tentatively identified constituted about 50% of the total adducts formed by the crude extracts following S9-metabolic activation. Our results confirmed the similarities of the major ubiquitous emission sources of organic compounds in both districts. This is the first report in which the biological activities of complex mixtures in short-term assays with remarkably different endpoints such as DNA adduct formation and embryotoxicity have been compared.

Air Pollutants↗

PubMed2006

Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers.

Morphologically, early colorectal tumors are divided into two groups, protruded-type tumors and flat-type tumors. Although some studies have shown genetic alterations in protruded-type tumors, little is known about genetic and epigenetic alterations in flat-type tumors, as well as pT1 (early invasive) colorectal cancers (CRCs). In the current study, we compared the frequencies of genetic and epigenetic alterations of the RAS-RAF and Wnt signaling pathways in flat-type and protruded-type tumors. In addition, we investigated the relationship between those alterations and invasive potential of pT1 CRCs. Methylations of RASSF2, O-6-methylguanine-DNA methyltransferase (MGMT), Wnt inhibitory factor-1 (WIF-1), EPHB2, CDKN2A and MLH1 were detected in 44.3, 30.3, 81.4, 7.5, 43.6 and 13.4% of the 307 early colorectal tumors, respectively. Mutations of KRAS, BRAF, catalytic subunit alpha of phosphatidylinositol 3'-kinase (PIK3CA) and beta-catenin were detected in 25.4, 4.6, 1.6 and 9.4% of those tumors, respectively. Methylations of MGMT, WIF-1 and CDKN2A were detected in significantly higher percentages of protruded-type tumors than in flat-type tumors. Mutation of at least one gene was detected in a significantly higher percentage of flat-type tumors than in protruded-type tumors. RASSF2 methylation was correlated significantly with KRAS, BRAF or PIK3CA mutation. Multiple logistic analysis showed that lymphatic invasion and RASSF2 methylation with KRAS, BRAF or PIK3CA mutation were independent risk factors for venous invasion in pT1 CRCs. In conclusion, since genetic alterations of these pathways have frequently occurred in flat-type tumors, flat-type tumors seem to have a distinct genetic profile different from that of protruded-type tumors. RASSF2 methylation with oncogenic activation is a promising biomarker for predicting invasive potential of pT1 CRCs.

Aged↗

PubMed2006

Extent and pattern of DNA methylation alteration in rice lines derived from introgressive hybridization of rice and Zizania latifolia Griseb.

We have reported previously that introgression by Zizania latifolia resulted in extensive DNA methylation changes in the recipient rice genome, as detected by a set of pre-selected DNA segments. In this study, using the methylation-sensitive amplified polymorphism (MSAP) method, we globally assessed the extent and pattern of cytosine methylation alterations in three typical introgression lines relative to their rice parent at approximately 2,700 unbiased genomic loci each representing a recognition site cleaved by one or both of the isoschizomers, HpaII/MspI. Based on differential digestion by the isoschizomers, it is estimated that 15.9% of CCGG sites are either fully methylated at the internal Cs and/or hemi-methylated at the external Cs in the rice parental cultivar Matsumae. In comparison, a statistically significant increase in the overall level of both methylation types was detected in all three studied introgression lines (19.2, 18.6, 19.6%, respectively). Based on comparisons of MSAP profiles between the isoschizomers within the rice parent and between parent and the introgression lines, four major groups of MSAP banding patterns are recognized, which can be further divided into various subgroups as a result of inheritance of, or variation in, parental methylation patterns. The altered methylation patterns include hyper- and hypomethylation changes, as well as inter-conversion of hemi- to full-methylation, or vice versa, at the relevant CCGG site(s). Most alterations revealed by MSAP in low-copy loci can be validated by DNA gel blot analysis. The changed methylation patterns are uniform among randomly selected individuals for a given introgression line within or among selfed generations. Sequencing on 31 isolated fragments that showed different changing patterns in the introgression line(s) allowed their mapping onto variable regions on one or more of the 12 rice chromosomes. These segments include protein-coding genes, transposon/retrotransposons and sequences with no homology. Possible causes for the introgression-induced methylation changes and their implications for genome evolution and crop breeding are discussed.

Cytosine↗

PubMed1998

Cytotoxics derived from distamycin A and congeners.

Distamycin A is an antibiotic, characterised by an oligopeptidic pyrrolocarbamoyl frame ending with an amidino moiety, which binds reversibly to DNA minor groove with high selectivity for TA-rich sequences and shows antiviral and antiprotozoal activity. Distamycin was used as DNA sequence selective vector of alkylating functions, leading to a substantial increase of cytotoxicity in comparison to that, very weak, of distamycin itself. The benzoyl nitrogen mustard derivative of desformyldistamycin, tallimustine, was selected as a candidate antineoplastic drug in view of its strong activity against a series of experimental tumors. Tallimustine, like distamycin, shows DNA selective binding to TA-rich sequences but its cytotoxicity is not associated with DNA strand breaks and interstrand crosslinking, at variance with classical phenyl nitrogen mustards. Tallimustine represents an important model for the design of new minor groove alkylating agents derived from distamycin and analogues, including the so-called lexitropsins, sequence-reading oligopeptides in which one or more N-methyl-pyrrole units of distamycin are replaced by imidazole or other rings. The structural features of the alkylating moieties and binding frames, the antitumor activities and the mechanism of action of most representative cytotoxics derived from distamycin and congeners are discussed. Some of these, recently reported, show an activity profile apparently superior to tallimustine. Finally, a concise survey of representative hybrid compounds in which known non-alkylating cytotoxic agents or their active moieties have been tethered to distamycin and congeners is presented and briefly discussed. These compounds witness the attention paid to this approach on the basis of the interest for the DNA binding features of distamycin A.

Alkylating Agents↗

PubMed2006

Characterization of four RecQ homologues from rice (Oryza sativa L. cv. Nipponbare).

The RecQ family of DNA helicases is conserved throughout the biological kingdoms. In this report, we have characterized four RecQ homologues clearly expressed in rice. OsRecQ1, OsRecQ886, and OsRecQsim expressions were strongly detected in meristematic tissues. Transcription of the OsRecQ homologues was differentially induced by several types of DNA-damaging agents. The expression of four OsRecQ homologues was induced by MMS and bleomycin. OsRecQ1 and OsRecQ886 were induced by H(2)O(2), and MitomycinC strongly induced the expression of OsRecQ1. Transient expression of OsRecQ/GFP fusion proteins demonstrated that OsRecQ2 and OsRecQ886 are found in nuclei, whereas OsRecQ1 and OsRecQsim are found in plastids. Neither OsRecQ1 nor OsRecQsim are induced by light. These results indicate that four of the RecQ homologues have different and specific functions in DNA repair pathways, and that OsRecQ1 and OsRecQsim may not involve in plastid differentiation but different aspects of a plastid-specific DNA repair system.

Adenosine Triphosphatases↗

PubMed1998

Recognition of specific sequences in DNA by a topoisomerase I inhibitor derived from the antitumor drug rebeccamycin.

We investigated the interaction with DNA of two synthetic derivatives of the antitumor antibiotic rebeccamycin: R-3, which is a potent topoisomerase I inhibitor and contains a methoxyglucose moiety appended to the indolocarbazole chromophore, and its aglycone, R-4. Spectroscopic measurements indicate that R-3 intercalates into DNA and that its carbohydrate domain contributes significantly to reinforce the affinity for DNA. Two complementary ligation assays concur that R-3, but not its aglycone counterpart, exerts a significant effect on the curvature and/or the flexibility of DNA. The sugar moiety may be responsible for preferential binding of R-3 to circular (or bent) DNA molecules as opposed to linear DNA fragments. The sequence selectivity of binding to DNA has been studied thoroughly by footprinting with DNase I and two other nucleases. The glycosylated compound is highly selective for nucleotide sequences containing GpT (ApC) and TpG (CpA) steps. The derivative lacking the sugar moiety on the indolocarbazole chromophore binds at essentially identical sites but with considerably lower affinity, so it seems that the chromophore rather than the carbohydrate is responsible for the preferential binding to sequences surrounding GpT and TpG steps. The influence of the exocyclic substituents present on the bases at the recognition sites (i.e., the 2-amino group of guanine and the 5-methyl group of thymine) was evaluated using two series of modified DNA molecules prepared by polymerase chain reaction containing inosine and/or 2,6-diaminopurine and uridine and/or 5-methylcytosine residues. The introduction of the amino group onto purine residues or the addition of a methyl group to pyrimidine residues suffices to create new drug binding sites. Therefore, unlike most DNA-binding small molecules, the rebeccamycin analogue seems to be highly sensitive to any modification of the exocyclic substituents on the bases in both the major and minor grooves of the double helix. The footprinting profiles with the different DNA fragments bear a remarkable resemblance to those determined for nogalamycin and bisnaphthalimide compounds known to recognize their preferred GpT and TpG sites via intercalation from the major groove. The unique DNA binding characteristics of the rebeccamycin analogue correlate well with its inhibitory effects on topoisomerase I.

Aminoglycosides↗

PubMed2006

The intraductal approach to breast cancer biomarker discovery.

Established methods of breast cancer detection have well-described limitations, and new diagnostic techniques are evolving continually to improve diagnostic accuracy. The intraductal approach encompasses the modalities of nipple aspiration, ductal lavage, and duct endoscopy, and is a means of directly accessing the microenvironment of the breast and either sampling or visualizing this intraductal milieu. The aim of sampling this mammary microenvironment is to obtain samples from the physical surroundings of cells that are undergoing malignant transformation, thereby providing a new method of detection before the development of a clinically or radiologically discernible mass. A literature review was conducted to investigate the evolution of the intraductal approach and its particular application in the field of biomarker discovery, primarily using the intraductal technique of nipple aspiration, in combination with emerging protein profiling techniques.

Angiogenesis Inducing Agents↗

PubMed2003

Role of SeqA and Dam in Escherichia coli gene expression: a global/microarray analysis.

High-density oligonucleotide arrays were used to monitor global transcription patterns in Escherichia coli with various levels of Dam and SeqA proteins. Cells lacking Dam methyltransferase showed a modest increase in transcription of the genes belonging to the SOS regulon. Bacteria devoid of the SeqA protein, which preferentially binds hemimethylated DNA, were found to have a transcriptional profile almost identical to WT bacteria overexpressing Dam methyltransferase. The latter two strains differed from WT in two ways. First, the origin proximal genes were transcribed with increased frequency due to increased gene dosage. Second, chromosomal domains of high transcriptional activity alternate with regions of low activity, and our results indicate that the activity in each domain is modulated in the same way by SeqA deficiency or Dam overproduction. We suggest that the methylation status of the cell is an important factor in forming and/or maintaining chromosome structure.

Bacterial Outer Membrane Proteins↗

PubMed2006

CpG island methylator phenotype redefines the prognostic effect of t(12;21) in childhood acute lymphoblastic leukemia.

PURPOSE: To examine cancer genes undergoing epigenetic inactivation in a set of ETV6/RUNX1-positive acute lymphoblastic leukemias in order to define the CpG island methylator phenotype (CIMP) in the disease and evaluate its relationship with clinical features and outcome. EXPERIMENTAL DESIGN: Methylation-specific PCR was used to analyze the methylation status of 38 genes involved in cell immortalization and transformation in 54 ETV6/RUNX1-positive samples in comparison with 190 ETV6/RUNX1-negative samples. RESULTS: ETV6/RUNX1-positive samples had at least one gene methylated in 89% of the cases. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP- group (0-2 methylated genes) and 34 (67%) in the CIMP+ group (>2 methylated genes). Remission rate did not differ significantly among either group of patients. Estimated disease-free survival and overall survival at 9 years were 92% and 100% for the CIMP- group and 33% and 73% for the CIMP+ group (P = 0.002 and P = 0.04, respectively). Multivariate analysis showed that methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.01) and overall survival (P = 0.05). A group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive subset of samples. CONCLUSION: Our results suggest that methylation profile may be a potential new biomarker of risk prediction in ETV6/RUNX1-positive acute lymphoblastic leukemias.

Adolescent↗