Previously, identification of promoters regulated by mammalian transcription factors has relied upon overexpression studies. Here we present the identification of a large set of promoters that are bound by E2F in physiological conditions. Probing a human CpG microarray with chromatin immunoprecipitated using an antibody to E2F4, we have identified 68 unique target loci; 15% are bidirectional promoters and 25% recruit E2F via a mechanism distinct from the defined consensus site. Interestingly, although E2F has been shown previously to regulate genes involved in cell cycle progression, many of the new E2F target genes encode proteins involved in DNA repair or recombination. We suggest that human CpG microarrays, in combination with chromatin immunoprecipitation, will allow rapid identification of target promoters for many mammalian transcription factors.

/pdf/isolating-human-transcription-factor-targets-by-coupling-15otew59g8.pdf

Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis

Gastric cancer (GC) is one of the most common malignancies worldwide and it is the fourth leading cause of cancer-related death. GC is a multifactorial disease, where both environmental and genetic factors can have an impact on its occurrence and development. The incidence rate of GC rises progressively with age; the median age at diagnosis is 70 years. However, approximately 10% of gastric carcinomas are detected at the age of 45 or younger. Early-onset gastric cancer is a good model to study genetic alterations related to the carcinogenesis process, as young patients are less exposed to environmental carcinogens. Carcinogenesis is a multistage disease process specified by the progressive development of mutations and epigenetic alterations in the expression of various genes, which are responsible for the occurrence of the disease.

Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies.

A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis

Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase.

Purpose: In an effort to examine the clinicopathological characteristics of GC and the status of its surgical treatment, the Korean Gastric Cancer Association (KGCA) conducted a nationwide survey targeting surgically-treated gastric cancer patients in 2009. Materials and Methods: A standardized electrical case report was sent to every member institution of the KGCA via E-mail with detailed instructions regarding the survey data. Completed data forms were retrieved from each institution and analyzed by the KGCA information committee. Results: Data on 14,658 patients was collected from 59 institutions. The mean patient age was 59.2±11.9 years with a male to female ratio of 2.05 : 1. Lower third cancer (56.0%) was the most common among all gastric cancers. The histological type revealed poorly differentiated adenocarcinoma (34.1%) to be the most common, and the Lauren classification revealed the intestinal type (50.0%) to be the most prevalent. Curative surgery was performed in 92.4% of patients with laparoscopic surgery in 25.8% of patients. A Billroth I reconstruction was performed most frequently after a distal gastrectomy (63.4% of distal gastrectomy). T1 cancers accounted for 57.6% of all cases, and 62.6% of patients showed no lymph node metastasis. Compared to previous reports, it was found that patients are becoming older, laparoscopic surgery is being performed increasingly, and the proportion of T1 cancer is increasing with time. Conclusions: This survey presented the clinicopathological characteristics and current status of the surgical treatment of gastric cancer in Korea. This survey is expected aid research studies as well as planning and evaluation programs targeting cancer control.

/pdf/clinicopathological-features-and-surgical-treatment-of-3i46kuaqci.pdf

Clinicopathological Features and Surgical Treatment of Gastric Cancer in South Korea: The Results of 2009 Nationwide Survey on Surgically Treated Gastric Cancer Patients

BACKGROUND: This clinicopathological study evaluated the utility of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 as predictors of locoregional recurrence and long-term disease-free survival in patients with gastric cancer.METHODS: During the period January 1989 to December 1994, 485 patients with primary gastric cancer were evaluated. Gastrectomies were performed in 434 patients. Prognostic factors were analyzed by the Kaplan-Meier method and multivariate analysis, using Cox regression.RESULTS: Elevated serum CEA and CA19-9 levels were observed in 92 of the 485 patients (19.0%), and in 95 of the 435 patients (21.8%), respectively, and both markers were elevated in 29 of these 435 patients (6.7%). Elevated serum CEA and CA19-9 levels correlated well with lymph node metastasis, lymphatic invasion, vessel invasion, stage grouping, depth of invasion, and curability. Patients with elevated serum CEA levels were at significantly higher risk of having all recurrence factors than were those with normal serum CEA levels. Patients with elevated serum CA19-9 levels were at significantly higher risk of having peritoneal metastases and distant metastases than were those with normal serum CA19-9 levels. A significant difference in the cumulative survival curves of patients was demonstrated between those with elevated and those with normal serum CEA or CA19-9 levels, even for patients at the same disease stage (stage III). Patients with elevated levels of both markers had a significantly worse prognosis than patients in whom the levels of both markers were normal. In patients who underwent gastrectomy, elevated serum CEA levels either preoperatively or within 3 weeks after gastrectomy were associated with significantly worse prognosis than were normal levels. When the cutoff level of serum CEA was increased to 10 ng/ml, serum CEA, age, lymph node metastasis, and surgical stage grouping were selected as independent prognostic factors by multivariate analysis of 14 prognostic factors, using Cox regression.CONCLUSION: Serum CEA and CA19-9 levels provide additional prognostic information in patients with primary gastric cancer. In particular, an elevated serum CEA level provides additional prognostic information and is a useful indicator of curability in patients who undergo gastrectomy. Serum CEA level is an independent prognostic factor in patients with primary gastric cancer.

/pdf/evaluation-of-serum-cea-and-ca19-9-levels-as-prognostic-zl9abhhnoq.pdf

Evaluation of serum CEA and CA19-9 levels as prognostic factors in patients with gastric cancer.

Thymidylate
synthase ( TS ) is thought to be one of the target genes
that the E2F1 transcription factor binds to and
regulates. However, the relationship between the expressions of
 TS and E2F1 in primary colon cancer
specimens remains unclear. The aim of this study was to define the
relation of TS and E2F1 gene expressions
in tumor samples from 23 colon cancer patients. TS and
 E2F1 gene expressions were measured by TaqMan reverse
transcription-PCR assay using glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) as an internal standard and expressed as a
 TS : GAPDH or
 E2F1 : GAPDH mRNA ratio. A close
relationship was found between TS gene expression and
 E2F1 gene expression ( r 2 = 0.598, P < 0.001) in 23 tumor samples analyzed.
Surprisingly, a high correlation between TS gene
expression and E2F1 gene expression was observed even in
advanced tumors from stage IV colon cancer patients. These results
suggest that transcription of the TS gene may be
regulated by E2F1 in primary colon cancer specimens and
that this gene-regulatory pathway from E2F1 to
 TS may be highly conserved during malignant progression.
Four of the 23 patients showed TS overexpression with
increased E2F1 expression. These results suggest that
the ability of a tumor to increase TS expression may
possibly be due to an overexpression of E2F1 . Although
the number of patients was relatively small, our study provides new
insights into the molecular mechanisms underlying the regulation of
 TS expression in colon cancers.

https://clincancerres.aacrjournals.org/content/clincanres/6/7/2707.full.pdf

Thymidylate synthase expression correlates closely with E2F1 expression in colon cancer.

Background: Delayed diagnosis, a high rate of histologically undifferentiated types of tumors, and rapid disease progression are frequently cited as the main reasons for the poor prognosis of gastric cancer in young patients. An improved prognosis has been anticipated for young gastric cancer patients because of recent improvements in digestive tract diagnostic techniques. This retrospective study was designed to determine whether these trends have had an impact on young Japanese patients with gastric cancer, and to further elucidate differences in clinicopathologic features between elderly and young patients. Methods: From 1984 to 1995, 1654 patients with gastric cancer were admitted to our hospital. Of these, 86 patients (5.2%) were less than 40 years of age (young group). The clinicopathologic features of this young group were reviewed retrospectively, using hospital records, and compared with those of older patients (n = 499 [29.4%], 60 to 69 years of age). Results: The young group contained significantly higher percentages of female patients, epigastric pain symptoms, depressed superficial type lesions, mucosal invasion, and poorly differentiated histology; percentages of hepatic metastasis and venous invasion were lower. Survival rates for all patients and for the resected cases were significantly better in the young group (p = 0.035 and 0.017 respectively). The percentage of early stage stomach cancers for the group less than 40 years of age was 49.0% in 1984–89, but had risen to 60.9% by 1990–95. Conclusions: Early diagnosis has improved the prognosis of young gastric cancer patients. Furthermore, these data show a recent shift in stage distribution; additional prognostic improvement is anticipated for young patients with early gastric cancer.

https://www.journalacs.org/article/S1072-7515(98)00268-3/pdf

Gastric cancer in young patients

Objective: To compare the outcome after limited and extended gastric resections to find out whether extended lymph node dissection is indicated for gastric cancer in elderly patients.Design: Retrospective study.Setting: University hospital, Japan.Subjects: 182 patients over 75 years of age with gastric cancer who had gastric resections from 1980 to 1995.Interventions: 161 patients had limited lymph node dissection (limited group) and 21 had extended lymph node dissection (extended group).Main outcome measures: Histopathological features, morbidity, mortality, and long-term survival.Results: Postoperative morbidity was 27% (n = 44) in the limited group and 57% (n = 12) in the extended group, and postoperative mortality was 1% (n = 2) in the limited group and 10% (n = 2) in the extended group; these differences are significant (p = 0.005 and p = 0.002). The 5-year survival did not differ significantly between the two groups. Only the T classification and presence of lymph node metastases had a significant i...

Mitsuko Kasahara

Papers

Evaluation of serum CEA and CA19-9 levels as prognostic factors in patients with gastric cancer.

Thymidylate synthase expression correlates closely with E2F1 expression in colon cancer.

Gastric cancer in young patients

Is extended lymph node dissection necessary for gastric cancer in elderly patients