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1.
BACKGROUND:
In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP‐negative. The role of this classification in predicting recurrence and disease‐free survival (DFS) in resected stage III CRC was evaluated.METHODS:
Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE‐1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed.RESULTS:
Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K‐means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8%), associated with KRAS mutations; and CIMP‐negative (n = 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP‐negative) and a worse DFS (P = .015). Also in proximal CRC, LINE‐1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P = .049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P = .008 for classification by K‐means clustering analysis; P = .040 for LINE‐1 methylation status).CONCLUSIONS:
DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings. Cancer 2011. © 2010 American Cancer Society. 相似文献2.
Feng Jing Wang Yuping Chen Yong Luo Jie Lu Jun Tang Xuanbing Hu Lihua 《Tumour biology》2010,31(4):321-331
CpG island methylator phenotype (CIMP) involves methylation targeted toward the promoters of multiple genes. We determined a methylation profile of tumor-related genes in serum of sporadic breast cancer (SBC). The multigene methylation was examined by methylation-specific polymerase chain reaction assay in serum of 50 SBCs and 50 paired nontumors, and CIMP+ was defined as having three genes that are concordantly methylated. The methylation frequency of ten genes in serum of 50 SBCs varied from 10% in FHIT to 74% in RASSF1A. The methylation status of RASSF1A, BRCA1, p16, CDH1, ER, RARβ2, APC, and DAPK was significantly correlated with SBC and nontumor serum (P?<?0.05). Methylation of at least one gene was found in 92% SBC; CIMP was more frequent in SBC than nontumor serum (P?<?0.001). There was a significant association between CIMP and methylation of RASSF1A, BRCA1, p16, CDH1, ER, RARβ2, APC, and DAPK (P?<?0.05); the methylation link profile of CDH1, RASSF1A, BRCA1, and RARβ2 as breast cancer marker may contribute high sensitivity (90%) and specificity (88%). ER and RARβ2 methylation was associated with elevated serum CA153 levels in 39 SBC samples with CIMP+ (P?<?0.05). Multivariate analysis showed that living area of patients was found to provide independent prognostic information associated with a relative risk of tumor recurrence of 5.3. Multigene-specific methylation profile in serum was association with the recurrence risk of rural SBC, and positive correlation of CIMP can serve as a promising molecular marker of SBC. 相似文献
3.
Reza R. Serizawa Ulrik Ralfkiær Kenneth Steven Gitte W. Lam Sven Schmiedel Joachim Schüz Alastair B. Hansen Thomas Horn Per Guldberg 《International journal of cancer. Journal international du cancer》2011,129(1):78-87
The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We also analyzed urine samples from 33 patients with noncancerous urinary lesions. A total of 95 oncogenic mutations and 189 hypermethylation events were detected in the 105 tumor biopsies. The total panel of markers provided a sensitivity of 93%, whereas mutation and methylation markers alone provided sensitivities of 72% and 70%, respectively. In urine samples, the sensitivity was 70% for all markers, 50% for mutation markers and 52% for methylation markers. FGFR3 mutations occurred more frequently in tumors with no methylation events than in tumors with one or more methylation events (78% vs. 33%; p < 0.0001). FGFR3 mutation in combination with three methylation markers (APC, RASSF1A and SFRP2) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve noninvasive, DNA‐based detection of bladder cancer. 相似文献
4.
Toyoki Moribe Norio Iizuka Toshiaki Miura Naoki Kimura Shigeru Tamatsukuri Hideo Ishitsuka Yoshihiko Hamamoto Kazuhiko Sakamoto Takao Tamesa Masaaki Oka 《International journal of cancer. Journal international du cancer》2009,125(2):388-397
The current study was conducted to identify robust methylation markers and their combinations that may prove useful for the diagnosis of early hepatocellular carcinoma (HCC). To achieve this, we performed in silico CpG mapping, direct sequencing and pyrosequencing after bisulfite treatment, and quantitative methylation‐specific PCR (MSP) in HCC and non‐HCC liver tissues. In the filtering group (25 HCCs), our direct sequencing analysis showed that, among the 12 methylation genes listed by in silico CpG mapping, 7 genes (RASSF1A, CCND2, SPINT2, RUNX3, GSTP1, APC and CFTR) were aberrantly methylated in stages I and II HCCs. In the validation group (20 pairs of HCCs and the corresponding non‐tumor liver tissues), pyrosequencing analysis confirmed that the 7 genes were aberrantly and strongly methylated in early HCCs, but not in any of the corresponding non‐ tumor liver tissues (p < 0.00001). The results obtained using our novel quantitative MSP assay correlated well with those observed using the pyrosequencing analysis. Notably, in MSP assay, RASSF1A showed the most robust performance for the discrimination of HCC and non‐HCC liver tissues. Furthermore, a combination of RASSF1A, CCND2 and SPINT2 showed 89–95% sensitivity, 91–100% specificity and 89–97% accuracy in discriminating between HCC and non‐HCC tissues, and correctly diagnosed all early HCCs. These results indicate that the combination of these 3 genes may aid in the accurate diagnosis of early HCC. © 2009 UICC 相似文献
5.
Carolina Alvarez Teresa Tapia Valeria Cornejo Wanda Fernandez Alex Muñoz Mauricio Camus Manuel Alvarez Luigi Devoto Dr. Pilar Carvallo 《Molecular carcinogenesis》2013,52(6):475-487
Promoter hypermethylation is gaining strength as one of the main mechanisms through which tumor suppressor genes are silenced during tumor progression. Three tumor suppressor genes are frequently found methylated in their promoter, in concordance with absence of expression, RASSF1A, SLIT2, and WIF1. In addition, a previous array‐CGH analysis from our group showed that these genes are found in deleted genomic regions observed in hereditary breast cancer tumors. In the present work we analyzed the methylation status of these three tumor suppressor gene promoters in 47 hereditary breast cancer tumors. Promoter methylation status analysis of hereditary breast tumors revealed high methylation frequencies for the three genes (67% RASSF1A, 80% SLIT2, and 72% WIF1). Additionally, the presence of methylated PCR products was associated with absence of protein expression for the three genes and statistically significant for RASSF1A and WIF1. Interestingly, methylation of all the three genes was found in 4 out of 6 grade I invasive ductal carcinoma tumors. Association between RASSF1A methylation and DCIS tumors was found. These results suggest that silencing of these tumor suppressor genes is an early event in hereditary breast cancer, and could be a marker for pre‐malignant phenotypes. © 2012 Wiley Periodicals, Inc. 相似文献
6.
LOC283731 promoter hypermethylation prognosticates survival after radiochemotherapy in IDH1 wild‐type glioblastoma patients
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Christian Orlik Rolf Warta Christian Schwager Christine Jungk Céline Dutruel Lea Geiselhart Dieter Weichenhan Manuela Zucknick Ann‐Katrin Nied Sara Friauf Janina Exner David Capper Christian Hartmann Bernd Lahrmann Niels Grabe Jürgen Debus Andreas von Deimling Odilia Popanda Christoph Plass Andreas Unterberg Christel Herold‐Mende 《International journal of cancer. Journal international du cancer》2016,139(2):424-432
MGMT promoter methylation status is currently the only established molecular prognosticator in IDH wild‐type glioblastoma multiforme (GBM). Therefore, we aimed to discover novel therapy‐associated epigenetic biomarkers. After enrichment for hypermethylated fractions using methyl‐CpG‐immunoprecipitation (MCIp), we performed global DNA methylation profiling for 14 long‐term (LTS; >36 months) and 15 short‐term (STS; 6–10 months) surviving GBM patients. Even after exclusion of the G‐CIMP phenotype, we observed marked differences between the LTS and STS methylome. A total of 1,247 probes in 706 genes were hypermethylated in LTS and 463 probes in 305 genes were found to be hypermethylated in STS patients (p values < 0.05, log2 fold change ± 0.5). We identified 13 differentially methylated regions (DMRs) with a minimum of four differentially methylated probes per gene. Indeed, we were able to validate a subset of these DMRs through a second, independent method (MassARRAY) in our LTS/STS training set (ADCY1, GPC3, LOC283731/ISLR2). These DMRs were further assessed for their prognostic capability in an independent validation cohort (n = 62) of non‐G‐CIMP GBMs from the TCGA. Hypermethylation of multiple CpGs mapping to the promoter region of LOC283731 correlated with improved patient outcome (p = 0.03). The prognostic performance of LOC283731 promoter hypermethylation was confirmed in a third independent study cohort (n = 89), and was independent of gender, performance (KPS) and MGMT status (p = 0.0485, HR = 0.63). Intriguingly, the prediction was most pronounced in younger GBM patients (<60 years). In conclusion, we provide compelling evidence that promoter methylation status of this novel gene is a prognostic biomarker in IDH1 wild‐type/non‐G‐CIMP GBMs. 相似文献
7.
Invasive Fusobacterium nucleatum may play a role in the carcinogenesis of proximal colon cancer through the serrated neoplasia pathway
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Xiangsheng Fu Xian Zhou Yan Peng Lei Shi Ting Chen Yaxin Wu 《International journal of cancer. Journal international du cancer》2016,139(6):1318-1326
The prevalence of invasive Fusobacterium nucleatum (Fn) within the serrated neoplasia pathway of the proximal colon has seldom been investigated. We examined the invasive Fn and bacterial biofilms in 35 proximal hyperplastic polyps (HPs), 33 sessile serrated adenomas (SSAs), 48 proximal colorectal cancers (CRCs) and 10 matched metastatic lymph nodes using 16S rRNA fluorescence in situ hybridization (FISH). Samples of normal mucosa, traditional adenomas (TAs), distal HPs, distal CRCs and matched lymph nodes with or without metastases were used as controls. The prevalence of invasive Fn within proximal HPs (65.7%) and SSAs (78.8%) were significantly higher than that of proximal TAs (28.9%) and distal TAs (24.4%; p < 0.05). Invasive Fn was detected in markedly more proximal CRCs (89.6%) than in distal CRCs (42.2%; p < 0.05). Moreover, invasive Fn was detected in a significantly higher proportion of matched metastatic lymph nodes (100%) than that within nonmetastatic lymph nodes (40.0%; p < 0.001). Bacterial biofilms were found on 52.1% of proximal CRCs, 55.6% of distal CRCs and 48.5% of SSAs. Biofilms were positive for Fn in 47.9% of proximal CRCs, 48.9% of distal CRCs and 27.3% of SSAs. However, the presence of Fn in biofilms was not related to invasive Fn within colorectal tissues (p = 0.415). Invasive Fn may play a role in the carcinogenesis of proximal colon developing via the serrated neoplasia pathway, but might have a less important role in the TA‐carcinoma sequence. Bacterial biofilms may not contribute to the invasion of Fn into tumor tissues. 相似文献
8.
Katie T. Huang Alexander Dobrovic Max Yan Rooshdiya Z. Karim C. Soon Lee Sunil R. Lakhani Stephen B. Fox 《Breast cancer research and treatment》2010,124(2):555-565
Phyllodes tumours and cellular fibroadenomas are both fibroepithelial tumours of the breast. Phyllodes tumours, unlike fibroadenomas,
have the ability to recur and metastasise. Although these lesions can be distinguished by their stromal cellularity, mitotic
index, presence or absence of stromal overgrowth and cellular atypia, there is overlap and not infrequently a definitive diagnosis
cannot be made, particularly on biopsy. We sought to evaluate whether DNA promoter methylation profiling using selected genes
known to be methylated in cancer would allow us to learn more about the biology of these tumours, and whether it could identify
methylation markers that could differentiate phyllodes tumours from fibroadenomas and/or distinguish phyllodes tumours of
different grades. Methylation-sensitive high resolution melting (MS-HRM) was used to screen promoter DNA methylation changes
in 86 phyllodes tumours (15 benign, 28 borderline, 43 malignant) and 26 fibroadenomas. A panel of 11 genes (RASSF1A, TWIST1, APC, WIF1, MGMT, MAL, RARβ, CDKN2A, CDH1,
TP73 and MLH1) was tested. Methylation status was correlated with histology and with clinicopathological parameters. Five of the gene promoters
showed some methylation in a proportion of phyllodes tumours; RASSF1A, 45.3%; TWIST1, 10.7%; APC, 4.1%; WIF1, 2.9% and MGMT, 1.3%. Only two genes showed any methylation in fibroadenomas usually at background levels; RASSF1A, 53.8% and MGMT, 8.3%. No CDKN2A methylation was observed in either tumour type, contrary to previous reports. Overall, the methylation patterns differed
little from that which might be seen in normal cells. However, significant levels of methylation of RASSF1A (24.4%) and TWIST1 (7.1%) was observed in some phyllodes tumours. Elevated RASSF1A and/or TWIST1 methylation was significantly associated with phyllodes tumours compared with fibroadenomas (P = 0.02), TWIST1 methylation correlated with increasing malignancy in phyllodes tumours (P < 0.001). In conclusion, assessment of methylation of RASSF1A and TWIST1 may aid in the diagnosis of phyllodes tumours. The absence of frequent methylation in fibroadenomas supports a non-neoplastic
origin. 相似文献
9.
Antoinette S. Perry Gillian O'Hurley Omer A. Raheem Kevin Brennan Simon Wong Anthony O'Grady Anne‐Marie Kennedy Laure Marignol Therese M. Murphy Linda Sullivan Ciara Barrett Barbara Loftus John Thornhill Stephen M. Hewitt Mark Lawler Elaine Kay Thomas Lynch Donal Hollywood 《International journal of cancer. Journal international du cancer》2013,132(8):1771-1780
10.
Toshiyuki Okada Munetaka Nakamura Jun Nishikawa Kouhei Sakai Yibo Zhang Mari Saito Akihiro Morishige Atsunori Oga Kosuke Sasaki Yutaka Suehiro Yuji Hinoda Isao Sakaida 《Cancer science》2013,104(10):1309-1314
We studied the comprehensive DNA methylation status in the naturally derived gastric adenocarcinoma cell line SNU‐719, which was infected with the Epstein–Barr virus (EBV) by methylated CpG island recovery on chip assay. To identify genes specifically methylated in EBV‐associated gastric carcinomas (EBVaGC), we focused on seven genes, TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1, based on the results of methylated CpG island recovery on chip assay. We confirmed DNA methylation of the genes by methylation‐specific PCR and bisulfite sequencing in SNU‐719. The expression of the genes, except for BCL7A, was upregulated by a combination of 5‐Aza‐2′‐deoxycytidine and trichostatin A treatment in SNU‐719. After the treatment, unmethylated DNA became detectable in all seven genes by methylation‐specific PCR. We verified DNA methylation of the genes in 75 primary gastric cancer tissues from 25 patients with EBVaGC and 50 EBV‐negative patients who were controls. The methylation frequencies of TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1 were significantly higher in EBVaGC than in EBV‐negative gastric carcinoma. We identified seven genes with promoter regions that were specifically methylated in EBVaGC. Inactivation of these genes may suppress their function as tumor suppressor genes or tumor‐associated antigens and help to develop and maintain EBVaGC. 相似文献
11.
12.
Lars Jansen Herbert Diebolder Matthias Dürst Ingo B. Runnebaum 《International journal of cancer. Journal international du cancer》2016,138(1):217-228
Treatment of epithelial ovarian cancer consists of surgery plus platinum‐taxane based chemotherapy. Neither prognostic nor predictive serum or tissue markers except BRCA1/2 mutations are available thus precluding individualized treatment. Aim of this study is the identification and validation of DNA‐methylation markers with prognostic value. Genome‐wide array analyses were used to determine methylation patterns in groups of serous EOC with different outcome (PFS < vs. > 3 years, each n = 6) but comparable clinical parameters. Two hundred and twenty differentially methylated regions in tumor tissue of patients with short vs. long PFS (106 hypo‐ and 114 hypermethylated regions) were identified. Thirty‐five of 37 selected CpG islands were validated by MSP using the same samples as for microarray analyses. Six of these regions were analyzed by targeted next‐generation bisulfite‐sequencing confirming array and MSP results. Validation experiments with an enlarged patient group of Type II EOC samples (PFS <3 years n = 30; >3 years n = 18) revealed the CpG island of RUNX3 as significantly more often methylated in patients with short PFS (10/30 vs. 0/18; p < 0.01). Marker combinations with significantly different methylation frequencies in patient groups reached an increased sensitivity with equal specificity (RUNX3+CAMK2N1; sens 40%; spec 100%; p < 0.01). RUNX3/CAMK2N1 methylation‐positive patients of the array‐independent subset (n = 36) showed a significantly lower PFS (p < 0.01) but no other difference in clinical parameters compared to methylation‐negative patients. Genome‐wide methylation analyses reliably identified markers of potentially prognostic value. Hypermethylation of RUNX3/CAMK2N1 is associated with poor clinical outcome in Type II EOC, also after macroscopic complete resection. 相似文献
13.
Masashi Kusakabe Tomoko Kutomi Kousuke Watanabe Noriko Emoto Naomi Aki Hidenori Kage Emi Hamano Hiroshi Kitagawa Takahide Nagase Atsushi Sano Yukihiro Yoshida Takeshi Fukami Tomohiro Murakawa Jun Nakajima Shinichi Takamoto Satoshi Ota Masashi Fukayama Yutaka Yatomi Nobuya Ohishi Daiya Takai 《International journal of cancer. Journal international du cancer》2010,126(8):1895-1902
Epigenetic changes can lead to abnormal expression of genes in cancer, and several genes have been reported to have aberrant promoter DNA methylation in non‐small‐cell lung cancer (NSCLC). We identified aberrantly methylated genes in NSCLC by combination of in silico and experimental approaches. We first applied bioinformatics, and from microarray datasets, we selected genes with low expression and having functions related to cancer. Next, combined bisulfite restriction analysis was carried out in 10 pooled resected lung cancer tissues to screen for genes that were aberrantly methylated, and the methylation ratio (the fraction of methylated DNA in extracted DNA from a cancer tissue sample) was quantified using quantitative analysis of methylated alleles. We identified 8 methylated genes (ARPC1B, DNAH9, FLRT2, G0S2, IRS2, PKP1, SPOCK1 and UCHL1) previously unreported in NSCLC. Analyses of methylation profiles of 101 resected lung cancer tissue samples revealed quantitatively low methylation in whole, methylation ratios were almost less than 30% even in the methylated samples, and no significant correlation to prognosis after 2 years of follow‐up using hierarchical clustering. DNA methylation of G0S2 gene was significantly more frequent in squamous lung cancer (n = 18, mean of methylation ratios: 15%) compared with nonsquamous lung cancer (n = 83, mean of methylation ratios: 2.6%) (Mann‐Whitney U test, p < 0.001). DNA methylation of G0S2 can be an important biomarker for squamous lung cancer. 相似文献
14.
Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway
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Eiji Sakai Masaki Fukuyo Ken Ohata Keisuke Matsusaka Noriteru Doi Yasunobu Mano Kiyoko Takane Hiroyuki Abe Koichi Yagi Nobuyuki Matsuhashi Junichi Fukushima Masashi Fukayama Kiwamu Akagi Hiroyuki Aburatani Atsushi Nakajima Atsushi Kaneda 《International journal of cancer. Journal international du cancer》2016,138(7):1634-1644
To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway. 相似文献
15.
Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway
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Kei Mitsuhashi Hiroyoshi Kurihara Hisayoshi Igarashi Taiga Takahashi Mami Tachibana Hiroaki Takahashi Shinji Yoshii Toshinao Takenouchi Tadashi Hasegawa Kenji Okita Koichi Hirata Reo Maruyama Hiromu Suzuki Kohzoh Imai Yasuhisa Shinomura 《International journal of cancer. Journal international du cancer》2015,137(6):1258-1268
Human gut microbiota is being increasingly recognized as a player in colorectal cancers (CRCs). Evidence suggests that Fusobacterium nucleatum (F. nucleatum) may contribute to disease progression and is associated with CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in CRCs; however, to date, there are no reports about the relationship between F. nucleatum and molecular features in the early stage of colorectal tumorigenesis. Therefore, we investigated the presence of F. nucleatum in premalignant colorectal lesions. In total, 465 premalignant lesions (343 serrated lesions and 122 non‐serrated adenomas) and 511 CRCs were studied. We determined the presence of F. nucleatum and analyzed its association with molecular features including CIMP, MSI and microRNA‐31 status. F. nucleatum was detected in 24% of hyperplastic polyps, 35% of sessile serrated adenomas (SSAs), 30% of traditional serrated adenomas (TSAs) and 33% of non‐serrated adenomas. F. nucleatum was more frequently detected in CIMP‐high premalignant lesions than in CIMP‐low/zero lesions (p = 0.0023). In SSAs, F. nucleatum positivity increased gradually from sigmoid colon to cecum (p = 0.042). F. nucleatum positivity was significantly higher in CRCs (56%) than in premalignant lesions of any histological type (p < 0.0001). In conclusion, F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP‐high lesions. Moreover, F. nucleatum positivity increased according to histological grade, suggesting that it may contribute to the progression of colorectal neoplasia. Our data also indicate that F. nucleatum positivity in SSAs may support the “colorectal continuum” concept. 相似文献
16.
Tamotsu Sugai Wataru Habano Masaki Endoh Yasuhiro Konishi Risaburo Akasaka Minoru Toyota Hiroo Yamano Keisuke Koeda Go Wakabayashi Kazuyuki Suzuki 《International journal of cancer. Journal international du cancer》2010,127(11):2500-2509
Identification of the molecular characteristics of intramucosal (IMCs) and submucosal cancers (SMCs) is essential to our understanding of early gastric carcinogenesis. However, little is known regarding the differences between the 2 lesions. One hundred and forty‐eight patients with primary early gastric cancer [IMC, 106; SMC, 42] were characterized for expression of cell cycle‐related proteins and loss of heterozygosity (LOH). We also examined microsatellite instability (MSI) and methylation status. For LOH and methylation studies, we used a panel of 17 microsatellite markers (3p, 4p, 5q, 9p. 13q, 17p, 18q and 22q) and promoter regions of 9 genes (MLH‐1, RUNX3, p16, HPP1, RASSF2A, SFRP1, DKK‐1, ZFP64 and SALL4) that are frequently altered or methylated in gastric cancers. Overexpression of p53 and cyclin D1 was observed in SMC. In addition, low expression of p27 was more frequent in SMC than in IMC. Frequencies of 4p, 9p, 13q and 22q were significantly higher in SMC than in IMC. The SALL4 gene was frequently methylated in SMC compared with IMC. However, other gene methylations were common in both IMC and SMC. The frequency of LOH‐high status/methylation‐low status was significantly higher in SMC than in IMC. However, LOH‐low status/methylation‐high status in SMC was more frequently found in IMC. Our data confirm that methylation of cancer‐related genes plays a major role in the development of IMCs. Importantly, the results also show that gastric submucosal progression is characterized by the accumulation of specific genetic alterations. In addition, changes of cell cycle‐related proteins are associated with cancer progression. 相似文献
17.
Anastasia A. Ponomaryova Elena Yu. Rykova Nadezda V. Cherdyntseva Tatiana E. Skvortsova Alexey Yu. Dobrodeev Alexander A. Zav’yalov Leonid O. Bryzgalov Sergey A. Tuzikov Valentin V. Vlassov Pavel P. Laktionov 《Lung cancer (Amsterdam, Netherlands)》2013
To date, aberrant DNA methylation has been shown to be one of the most common and early causes of malignant cell transformation and tumors of different localizations, including lung cancer. Cancer cell-specific methylated DNA has been found in the blood of cancer patients, indicating that cell-free DNA circulating in the blood (cirDNA) is a convenient tumor-associated DNA marker that can be used as a minimally invasive diagnostic test. In the current study, we investigated the methylation status in blood samples of 32 healthy donors and 60 lung cancer patients before and after treatment with neoadjuvant chemotherapy followed by total tumor resection. Using quantitative methylation-specific PCR, we found that the index of methylation (IM), calculated as IM = 100 × [copy number of methylated/(copy number of methylated + unmethylated gene)], for the RASSF1A and RARB2 genes in the cirDNA isolated from blood plasma and cell-surface-bound cirDNA was elevated 2- to 3-fold in lung cancer patients compared with healthy donors. Random forest classification tree model based on these variables combined (RARB2 and RASSF1A IM in both plasma and cell-surface-bound cirDNA) lead to NSCLC patients’ and healthy subjects’ differentiation with 87% sensitivity and 75% specificity. An association of increased IM values with an advanced stage of non-small-cell lung cancer was found for RARB2 but not for RASSF1A. Chemotherapy and total tumor resection resulted in a significant decrease in the IM for RARB2 and RASSF1A, in both cirDNA fractions, comparable to the IM level of healthy subjects. Importantly, a rise in the IM for RARB2 was detected in patients within the follow-up period, which manifested in disease relapse at 9 months, confirmed with instrumental and pathologic methods. Our data indicate that quantitative analysis of the methylation status of the RARB2 and RASSF1A tumor suppressor genes in both cirDNA fractions is a useful tool for lung cancer diagnostics, evaluation of cancer treatment efficiency and post-treatment monitoring. 相似文献
18.
Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer
Aditi Hazra Charles S. Fuchs Takako Kawasaki Gregory J. Kirkner David J. Hunter Shuji Ogino 《Cancer causes & control : CCC》2010,21(3):331-345
Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence
global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between
single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer.
Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype
(CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide
DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of
the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (≥6/8 methylated
promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32–43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02–14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there
were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data
provide suggestive evidence for the association of MTHFR
429 Ala/Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer. 相似文献
19.
Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma
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Yuichi Saito Genta Nagae Noriko Motoi Eisaku Miyauchi Hironori Ninomiya Hirofumi Uehara Mingyon Mun Sakae Okumura Fumiyoshi Ohyanagi Makoto Nishio Yukitoshi Satoh Hiroyuki Aburatani Yuichi Ishikawa 《Cancer science》2016,107(3):320-325
Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome‐wide methylation profile of SCLC. We investigated the genome‐wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non‐negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non‐CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis‐related chemotherapeutic agents for treatment of the aggressive tumor. 相似文献
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Timo Gaiser Sandra Meinhardt Daniela Hirsch Jonathan Keith Killian Jochen Gaedcke Peter Jo Immaculada Ponsa Rosa Miró Josef Rüschoff Gerhard Seitz Yue Hu Jordi Camps Thomas Ried 《International journal of cancer. Journal international du cancer》2013,132(8):1800-1810
Colorectal cancer (CRC) mostly develops from a variety of polyps following mainly three different molecular pathways: chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylation (CIMP). Polyps are classified histologically as conventional adenomas, hyperplastic polyps, sessile serrated adenomas/polyps (SSA/P) and traditional serrated adenomas (TSA). However, the association of these polyps with the different types of CRCs and the underlying genetic and epigenetic aberrations has yet to be resolved. In order to address this question we analyzed 140 tumors and 20 matched mucosae by array comparative genomic hybridization, by sequence analysis of the oncogenes BRAF, KRAS, PI3K3CA and by methylation arrays. MSI was tested indirectly by immunohistochemistry (IHC) and a loss of MLH1, MSH2, MSH6 or PMS2 was assigned as high microsatellite instability (MSI‐H), while low microsatellite instability (MSI‐L) was defined as MGMT IHC negativity only. CIN was detected in 78% of all MSI‐H CRCs, most commonly as a gain of chromosome 8. Methylation data analyses allowed classification of samples into four groups and detected similar methylation profiles in SSA/P and MSI‐H CRC. TSA also revealed aberrant methylation pattern, but clustered more heterogeneously and closer to microsatellite stable (MSS) CRCs. SSA/P, TSA and MSI‐H CRCs had the highest degree of promotor methylation (CIMP pathway). Chromosomal instability, in contrast to the established doctrine, is a common phenomenon in MSI CRCs, yet to a lower extent and at later stages than in MSS CRCs. Methylation analyses suggest that SSA/P are precursors for MSI‐H CRCs and follow the CIMP pathway. 相似文献