DNA甲基化与胃癌的相关性

在胃癌的发展过程中常发现肿瘤相关基因的异常甲基化存在,其中包括全基因组的低甲基化和某些抑癌基因的高甲基化.另外,DNA甲基化水平似乎还与胃癌的预后密切相关.近年来为揭示DNA甲基化与胃癌的相关性进行了大量研究.     

Primary tumor classification according to methylation pattern is prognostic in patients with early stage ER-negative breast cancer

Breast cancer patients with similar clinical stage may experience different disease outcomes. Aberrant DNA methylation of primary breast tumors can have impact on the clinical outcome. This study aimed to assess clinical utility of tumor-specific methylated sequences (MINT17, 31) and tumor-related gene (RARβ2) methylation classification in primary breast tumors. Absolute quantitative assessment of methylated alleles (AQAMA) was used to determine the methylation index (MI) of MINT17, MINT31, and RARß2 in 242 primary tumors of early stage breast cancer patients. Patients were classified into three methylation groups: meth-N, with normal methylation levels of all biomarkers; meth-L, with one biomarker hypermethylation; and meth-H, with hypermethylation of >1 biomarker. Disease outcome of methylation groups was compared during follow-up. MI of all biomarkers was successfully obtained in 237 tumors of which 79 (33%) were classified as meth-N, 86 (36%) as meth-L, and 72 (30%) as meth-H. Meth-H status was a risk factor for distant recurrence (DR) (log-rank P = 0.007) and shorter disease-free survival (DFS) (log-rank P = 0.039). Methylation classification had strongest prognostic value for patients with ER-negative tumors. In multivariate analysis (n = 222), ER-negative meth-H patients had a 4.1-fold increased risk of DR (95% CI 1.80–9.59; meth-N HR 1.0, P = 0.001), a 4.2-fold increased risk of overall recurrence (OR) (95% CI 1.88–9.47; meth-N HR 1.0, P = 0.001), and a 3.1-fold shorter DFS (95% CI 1.57–5.98; meth-N HR 1.0, P = 0.003). Methylation classification of primary breast cancer is an independent prognostic factor for disease outcome in patients with ER-negative tumors. The study’s findings will have to be confirmed in an independent dataset.     

Pretreatment anemia is associated with poorer survival in patients with stage I and II gastric cancer

BACKGROUND AND OBJECTIVES: A negative correlation between anemia and outcome has been demonstrated in various cancers treated with radiotherapy. However, it is rarely studied whether this correlation may exist in surgical setting. Our aim was to investigate the relationship between pretreatment anemia and survival in surgically treated patients with gastric cancer. METHODS: A total of 1,688 patients who had undergone curative resection for gastric cancer between 1991 and 1995 were reviewed. Anemia was defined as a hemoglobin level <12.0 g/dl. The influence of anemia on patient overall survival was evaluated by univariate and multivariate analysis. RESULTS: Pretreatment anemia was present in 39.9% of the patients. The 10-year overall survival rate in anemic patients was 48.2% as compared with 62.6% in nonanemic patients (P < 0.001). In subgroup analysis according to the stage, the significant difference in 10-year overall survival rate between anemic and nonanemic patients was found in stage I and II gastric cancer (76.1% vs. 83.5% in stage I, P = 0.030; 55.1% vs. 67.2% in stage II, P = 0.043). On multivariate analysis, anemia was an independent prognostic predictor in patients with stage I and II disease (P = 0.007; RR, 1.466; 95% CI, 1.109-1.937). CONCLUSIONS: Pretreatment anemia was found to have an independent relationship to the long-term survival of patients with stage I and II gastric cancer.     

Aberrant intracellular localization of RCAS1 is associated with tumor progression of gastric cancer

A novel tumor-associated antigen, RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is expressed at a high frequency in human uterine and ovarian cancer cells as well as in other mammalian cancer cells. We investigated a relationship between RCAS1 expression and clinicopathological features in gastric cancer. Immunohistochemically, RCAS1 was detected in 98.4% of gastric carcinomas. However, its expression was also observed in non-cancerous gastric epithelial cells including gastric adenomas (100%), gastric ulcers (66.7%) and normal gastric epithelia (100%). Striking difference was observed in the pattern of RCAS1 expression between benign and malignant cells. In cases of normal gastric mucosae, gastric ulcers and gastric adenomas, RCAS1 was localized only in the perinuclear region of the mucosal epithelial cells (PN pattern), while, in most of gastric cancers (83.9%), it was detected diffusely in the cytoplasm and cell membranes of the tumor cells (DC pattern). In semi-quantitative RT-PCR analysis, RCAS1 mRNA levels in gastric adenocarcinoma tissues were significantly higher than those in non-neoplastic tissues (p=0.038). The PN pattern of RCAS1 expression was more frequently observed in well differentiated adenocarcinoma (25%) than in moderately differentiated adenocarcinoma (0%) (p=0.01). In addition, it is noteworthy that DC pattern of RCAS1 expression was more frequently recognized in carcinomas which invaded beyond the submucosa (100%) compared to intramucosal carcinoma (67.7%) (p=0.0026). These findings suggest that altered intracellular distribution of RCAS1 is strictly associated with tumor progression of gastric cancer and is a useful marker for the diagnosis and prognosis in gastric cancer.     

抑癌基因甲基化与胃癌研究进展

DNA甲基化是基因表达调控的一种方式，抑癌基因启动子高甲基化可以使其表达受抑，这与肿瘤的发生关系密切。胃癌的发生是由多因素多基因多阶段异常累计的结果，其中抑癌基因甲基化与胃癌的发生具有重要的关系。     

CpG island methylation of microRNAs is associated with tumor size and recurrence of non-small-cell lung cancer

We investigated whether the CpG island methylation of certain microRNAs was associated with the clinicopathological features and the prognosis of non-small-cell lung cancer. The methylation of mir-152, -9-3, -124-1, -124-2, and -124-3 was analyzed in 96 non-small-cell lung cancer specimens using a combined bisulfite restriction analysis. The median observation period was 49.5 months. The methylation of mir-9-3, -124-2, and -124-3 was individually associated with an advanced T factor independent of age, sex, and smoking habit. Moreover, the methylation of multiple microRNA loci was associated with a poorer progression-free survival in a univariate analysis. Our result enlightens the accumulation of aberrant DNA methylation which occurs in concordance with the tumor progression.     

PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma

Loss of heterozygosity and mutations in the PTEN (MMAC1) tumor suppressor gene are frequent in endometrial carcinoma. Promoter hypermethylation has recently been identified as an alternative mechanism of tumor suppressor gene inactivation in cancer, but its importance in the PTEN gene in endometrial carcinoma is unknown. The purpose of our study was to assess the frequency of promoter methylation of the PTEN gene and to determine its correlation with clinicopathologic variables in a prospective and population-based series of endometrial carcinomas with complete follow-up. Presence of PTEN promoter methylation was seen in 26 of 138 patients (19%). Methylation was significantly associated with metastatic disease (p = 0.01) and a microsatellite unstable phenotype (p = 0.006). In conclusion, we find that PTEN promoter methylation is relatively frequent in endometrial carcinoma. Its association with metastatic disease and microsatellite instability implicates its importance in the development of this tumor type.     

DNA ploidy is associated with growth potential in gastric carcinoma

To correlate growth potential with DNA ploidy 109 patients with early gastric carcinoma and 132 patients with advanced gastric carcinoma were studied. Early gastric carcinomas were classified by growth potential into the small mucosal type, the superficially spreading (super) type, or the expansively penetrating (Pen A)/infiltratively penetrating (Pen B) types. Advanced gastric carcinomas were classified into funnel, column, or mountain types, each of which was divided further into expanding and infiltrative types. Cell nuclear DNA content was measured by microspectrophotometric study and classified as either low or high ploidy according to the degree of dispersion on the DNA histogram. Super type early and funnel type advanced carcinomas, characterized by superficially spreading growth, were more likely to have low DNA ploidy. In contrast, Pen A type early and column-expanding type advanced carcinomas, characterized by expansively penetrating growth, were more likely to have high DNA ploidy.     

循环肿瘤DNA甲基化在卵巢癌中的研究进展

卵巢癌是最致命的妇科恶性肿瘤,对卵巢癌的早期诊断、治疗监测和预后判断尤为重要。越来越多的证据表明DNA甲基化在致癌过程中发挥重要的作用。肿瘤中发现的基因启动子异常甲基化,可以反映在从肿瘤释放到外周血的循环肿瘤DNA（circulating tumor DNA,ctDNA）,与原发肿瘤有一致性改变,从而使ctDNA甲基化成为基于血液检测的非侵入性分子标志物。本文将介绍ctDNA甲基化及其检测方法,卵巢癌中常见的ctDNA甲基化标志物,并重点阐述ctDNA甲基化在卵巢癌中的研究进展。