|
1
|
Harada H, Nie Y, Araki I, Soeno T, Chuman M, Washio M, Sakuraya M, Ushiku H, Niihara M, Hosoda K, Kumamoto Y, Naitoh T, Sangai T, Hiki N, Yamashita K. Haploinsufficiency by minute MutL homolog 1 promoter DNA methylation may represent unique phenotypes of microsatellite instability-gastric carcinogenesis. PLoS One 2021; 16:e0260303. [PMID: 34936649 PMCID: PMC8694418 DOI: 10.1371/journal.pone.0260303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 11/06/2021] [Indexed: 11/19/2022] Open
Abstract
Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.
Collapse
Affiliation(s)
- Hiroki Harada
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yusuke Nie
- Department of General, Pediatric and Hepatobiliary-Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ippeita Araki
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takafumi Soeno
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Motohiro Chuman
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Marie Washio
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Mikiko Sakuraya
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Hideki Ushiku
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Masahiro Niihara
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kei Hosoda
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yusuke Kumamoto
- Department of General, Pediatric and Hepatobiliary-Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takeshi Naitoh
- Department of Lower Gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takafumi Sangai
- Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Naoki Hiki
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Keishi Yamashita
- Department of Upper-gastrointestinal Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
- Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
- * E-mail:
| |
Collapse
|
|
2
|
Guan Z, Zhang J, Song S, Dai D. Promoter methylation and expression of TIMP3 gene in gastric cancer. Diagn Pathol 2013; 8:110. [PMID: 23819566 PMCID: PMC3737241 DOI: 10.1186/1746-1596-8-110] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 06/29/2013] [Indexed: 01/06/2023] Open
Abstract
Background Gastric carcinoma development is a multi-stage process that involves more than one gene. Aberrant changes in DNA methylation are considered as the third mechanism that leads to anti-oncogene inactivation, which plays an essential role in tumor development. In this study, we assessed the relationship among the aberrant methylation of the promoter CpG islands of tissue inhibitor of metalloproteinase 3 (TIMP3) gene, its protein expression, and the clinicopathological features of gastric adenocarcinoma. Methods The methylation status of the promoter CpG islands and the protein expression of TIMP3 gene in tumors and adjacent normal mucosal tissues of 78 patients with gastric adenocarcinoma were detected by methylation-specific PCR (MSP) and immunohistochemistry. Results The CpG island methylation of TIMP3 was detected in tumor tissues, cancer-adjacent tissues, and lymph nodes with metastasis. In increasing order, the hypermethylation frequency of these tissues were 35.9% (28 of 78 non-neoplastic tissues), 85% (17 of 20 early-stage cases), 89.7% (52 of 58 progressive-stage cases), and 100% (78 of 78 metastatic lymph node). A marked difference was found between tumors and non-neoplastic tissues (P < 0.05), but no difference existed among the subgroups of tumors (P > 0.05). Immunohistochemistry analysis confirmed TIMP3 down-regulation in tumor tissues. The rate of TIMP3 gene expression was 100% in non-neoplastic tissues but apparently decreased to various extents at different stages, i.e., decreased to 30% (6/20) at the early stage, to 3.4% (2/58) at the progressive stage, and to 0% (0/78) in metastatic lymph nodes. Among the 70 tumor tissues with negative TIMP3 expression, 64 (91.4%) were hypermethylated and 6 were unmethylated (8.6%), indicating a significant association between hypermethylation and reduced or negative TIMP3 expression (P < 0.01). Conclusion The hypermethylation of the promoter region in CpG islands is the main mechanism of TIMP3 gene expression and may provide evidence for the molecular diagnosis and stage evaluation of gastric cancer. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1756134016954958
Collapse
Affiliation(s)
- ZhiYu Guan
- Department of Cardiovascular and Thoracic Surgery, TianJin Medical University General Hospital, 154 AnShan Road, HePing Section, TianJin 300052, China.
| | | | | | | |
Collapse
|
|
3
|
Wang X, Fan J, Liu D, Fu S, Ingvarsson S, Chen H. Spreading of Alu methylation to the promoter of the MLH1 gene in gastrointestinal cancer. PLoS One 2011; 6:e25913. [PMID: 22022465 PMCID: PMC3192117 DOI: 10.1371/journal.pone.0025913] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 09/13/2011] [Indexed: 11/26/2022] Open
Abstract
The highly repetitive Alu retroelements are regarded as methylation centres in the genome. Methylation in the gene promoters could be spreading from them. Promoter methylation of MLH1 is frequently detected in cancers, but the underlying mechanism is unclear. The aim of this study is to understand whether the methylation in the Alu elements is associated with promoter methylation in the MLH1 gene. Bisulfite genomic sequencing was used to analyse the CpG sites of the 5′ end (promoter, exon 1 and Alu-containing intron 1) of the MLH1 gene in colorectal cancer cells and tissues, and gastric cancer tissues. Hypomethylation in the Alu elements and hypermethylation in the promoters and the regions between the promoters and the Alu elements were detected in two cancer cell lines and seven cancer tissues. However, demethylation or hypomethylation of the MLH1 promoter and regions between promoter and the Alu elements, and hypermethylation in the Alu elements, were identified in the normal tissues. MLH1 promoter methylation may spread from Alu elements that are located in intron 1 of the MLH1 gene. The trans-acting elements binding to the mutation sites could play a role in the methylation spreading.
Collapse
Affiliation(s)
- Xiyin Wang
- Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Fan
- Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Dong Liu
- Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Siqing Fu
- Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sigurdur Ingvarsson
- Institute for Experimental Pathology and Faculty of Medicine, University of Iceland, Keldur, Reykjavik, Iceland
| | - Huiping Chen
- Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- * E-mail:
| |
Collapse
|
|
4
|
Abstract
BACKGROUND Approximately 2% to 5% of endometrial cancers may be due to an inherited susceptibility. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, an autosomal-dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the DNA mismatch repair genes, accounts for the majority of inherited cases. Lynch syndrome is associated with early onset of cancer and the development of multiple cancer types, particularly colon and endometrial cancer. METHODS The current status of knowledge regarding Lynch syndrome-associated endometrial cancer and methods for diagnosis, screening, and prevention of cancers is reviewed. RESULTS The lifetime cumulative risk of endometrial cancer for women with Lynch syndrome is 40% to 60%, which equals or exceeds their risk of colorectal cancer. No current evidence suggests either a survival advantage or disadvantage to endometrial cancer that is associated with Lynch syndrome when these cases are compared with sporadic cases. A combination of family and personal medical history and tumor testing provides an efficient basis for diagnosing Lynch syndrome in women with endometrial cancer. Current gynecologic cancer screening guidelines for women with Lynch syndrome include annual endometrial sampling and transvaginal ultrasonography beginning at age 30 to 35 years. CONCLUSIONS Diagnosing endometrial cancer patients with Lynch syndrome has important clinical implications for the individual and family members. Screening and prevention practices can decrease the likelihood of developing additional cancers.
Collapse
Affiliation(s)
- Larissa A Meyer
- Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230, USA
| | | | | |
Collapse
|
|
5
|
Holmes K, Egan B, Swan N, O’Morain C. Genetic Mechanisms and Aberrant Gene Expression during the Development of Gastric Intestinal Metaplasia and Adenocarcinoma. Curr Genomics 2007; 8:379-397. [PMID: 19412438 PMCID: PMC2671722 DOI: 10.2174/138920207783406460] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2007] [Revised: 09/21/2007] [Accepted: 09/28/2007] [Indexed: 02/07/2023] Open
Abstract
Gastric adenocarcinoma occurs via a sequence of molecular events known as the Correa's Cascade which often progresses over many years. Gastritis, typically caused by infection with the bacterium H. pylori, is the first step of the cascade that results in gastric cancer; however, not all cases of gastritis progress along this carcinogenic route. Despite recent antibiotic intervention of H. pylori infections, gastric adenocarcinoma remains the second most common cause of cancer deaths worldwide. Intestinal metaplasia is the next step along the carcinogenic sequence after gastritis and is considered to be a precursor lesion for gastric cancer; however, not all patients with intestinal metaplasia develop adenocarcinoma and little is known about the molecular and genetic events that trigger the progression of intestinal metaplasia into adenocarcinoma. This review aims to highlight the progress to date in the genetic events involved in intestinal-type gastric adenocarcinoma and its precursor lesion, intestinal metaplasia. The use of technologies such as whole genome microarray analysis, immunohistochemical analysis and DNA methylation analysis has allowed an insight into some of the events which occur in intestinal metaplasia and may be involved in carcinogenesis. There is still much that is yet to be discovered surrounding the development of this lesion and how, in many cases, it develops into a state of malignancy.
Collapse
Affiliation(s)
- K Holmes
- Department of Clinical Medicine, Trinity College Dublin, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland
| | | | | | | |
Collapse
|
|
6
|
Hong SJ, Kim YH, Choi YD, Min KO, Choi SW, Rhyu MG. Relationship between the extent of chromosomal losses and the pattern of CpG methylation in gastric carcinomas. J Korean Med Sci 2005; 20:790-805. [PMID: 16224153 PMCID: PMC2779276 DOI: 10.3346/jkms.2005.20.5.790] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The extent of unilateral chromosomal losses and the presence of microsatellite instability (MSI) have been classified into high-risk (high- and baseline-level loss) and low-risk (low-level loss and MSI) stem-line genotypes in gastric carcinomas. A unilateral genome-dosage reduction might stimulate compensation mechanism, which maintains the genomic dosage via CpG hypomethylation. A total of 120 tumor sites from 40 gastric carcinomas were examined by chromosomal loss analysis using 40 microsatellite markers on 8 chromosomes and methylation analysis in the 13 CpG (island/non-island) regions near the 10 genes using the bisulfite-modified DNAs. The high-level-loss tumor (four or more losses) showed a tendency toward unmethylation in the Maspin, CAGE, MAGE-A2 and RABGEF1 genes, and the other microsatellite-genotype (three or fewer losses and MSI) toward methylation in the p16, hMLH1, RASSF1A, and Cyclin D2 genes (p<0.05). The non-island CpGs of the p16 and hMLH1 genes were hypomethylated in the high-level-loss and hypermethylated in the non-high-level-loss sites (p<0.05). Consequently, hypomethylation changes were related to a high-level loss, whereas the hypermethylation changes were accompanied by a baseline-level loss, a low-level loss, or a MSI. This indicates that hypomethylation compensates the chromosomal losses in the process of tumor progression.
Collapse
Affiliation(s)
- Seung-Jin Hong
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young-Ho Kim
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young-Deok Choi
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Ouk Min
- Department of Clinical Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sang-Wook Choi
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mun-Gan Rhyu
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| |
Collapse
|
|
7
|
Niwa T, Yamashita S, Tsukamoto T, Kuramoto T, Nomoto T, Wakazono K, Fujita H, Matsushima T, Tatematsu M, Sugimura T, Ushijima T. Whole-genome analyses of loss of heterozygosity and methylation analysis of four tumor-suppressor genes in N-methyl-N'-nitro-N-nitrosoguanidine-induced rat stomach carcinomas. Cancer Sci 2005; 96:409-13. [PMID: 16053512 PMCID: PMC11158422 DOI: 10.1111/j.1349-7006.2005.00068.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced rat stomach carcinomas are considered to be a good model for differentiated-type human stomach carcinomas. However, as for their molecular basis, only infrequent mutations of Catnb (beta-catenin) and Trp53 (p53) have been observed. Here, we carried out a whole-genome analysis of loss of heterozygosity (LOH) using 21 stomach carcinomas induced by MNNG in F(1) hybrids of ACI and BUF rats, and also analyzed promoter methylation of four tumor-suppressor genes. LOH analysis was performed using 130 polymorphic markers covering rat chromosomes 1-20 with an average interval of 20 Mbp. Despite adapting conditions so that LOH could be detected with up to a 50% contamination of stromal cells, no LOH was detected at any loci. CpG islands in putative promoter regions of four tumor-suppressor genes, Cdh1 (E-cadherin), Cdkn2a (p16), Mlh1, and Rassf1a, were analyzed by methylation-specific polymerase chain reaction (PCR). However, no methylation was detected. In contrast, the promoter region of Pgc (pepsinogen C), which lacks a CpG island, was methylated in all 21-cancer samples. These results indicated that LOH spanning a chromosomal region larger than 30-40 Mbp or silencing of Cdh1, Cdkn2a, Mlh1, and Rassf1a, was not involved in MNNG-induced rat stomach carcinomas. The search for other genes involved in these carcinomas needs to be continued.
Collapse
Affiliation(s)
- Tohru Niwa
- Carcinogenesis Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
|
|
9
|
N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:965-968. [DOI: 10.11569/wcjd.v12.i4.965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2023] Open
|