Denggui Wen

Association of MTHFR C677T and SHMT1 C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China

ObjectiveTo assess the association between the C to T transition in the methylenetetrahydro folate reductase gene (MTHFR C677T) and the C to T transition in the serine hydroxymethyltransferase1gene (SHMT1 C1420T) and the increased risk of carcinogenesis of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a population of high incident region of Northern China.MethodsThe polymorphisms were genotyped by polymerase chain reaction–restriction fragment length polymorphism and PCR-confronting two-pair primers analysis respectively among 1051 cancer patients (584 ESCC and 467 GCA) and 540 healthy controls.ResultsThe MTHFR 677T/T genotype significantly increased susceptibility to both ESCC and GCA compared with the C/C genotype, the adjusted OR was 2.13 (95% CI = 1.50–3.02) and 1.28 (95% CI = 1.07–1.53, respectively. For the SHMT1 C1420T polymorphism, the C/C genotype was significantly associated with the increased risk of ESCC and GCA, compared with the C/T genotype (the adjusted OR = 1.43 and 1.35, 95% CI = 1.02–2.00 and 1.11–1.63, respectively). The interactive influence of the MTHFR and SHMT1 polymorphisms in the risk of ESCC and GCA was also observed.ConclusionThe association between the MTHFR C677T and SHMT1 C1420T polymorphisms and the risk of ESCC and GCA was demonstrated.

Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal squamous cell carcinoma in a German Caucasian and a northern Chinese population

Purpose Folate deficiency is considered to increase the risk of developing esophageal cancer. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. A single C → T substitution at nucleotide 677 of the MTHFR cDNA influences enzyme activity. The purpose of this study is to compare the association of the MTHFR C677T polymorphism with susceptibility to esophageal squamous cell carcinoma (ESCC).Methods Using real-time PCR and melting curve analysis, the MTHFR C677T genotypes were determined in 430 patients with ESCC (241 German Caucasians and 189 northern Chinese) and 397 unrelated healthy controls (256 German Caucasians and 141 northern Chinese).Results A significant difference in MTHFR C677T genotype distribution was observed between German Caucasian controls (C/C, 41.8%, C/T, 44.9%, T/T, 13.3%) and northern Chinese controls (C/C, 17.7%, C/T, 38.3%, T/T, 44.0%) (χ2=52.19, P<0.001). The distribution of the MTHFR C677T genotypes among German ESCC patients (C/C, 39.0%, C/T, 48.1%, T/T, 12.9%) was not significantly different from that among healthy controls (χ2=0.531, P=0.767). In contrast, the frequency of the C/C genotype among Chinese ESCC patients (8.5%) was significantly lower than among Chinese healthy controls (17.7%) (χ2=6.37, P=0.012). The C/C genotype was correlated with a significantly reduced risk for the development of ESCC as compared to the combination of C/T and T/T genotypes (adjusted OR=0.38, 95% CI=0.16–0.88).Conclusions Our results suggest that, in contrast to German Caucasians, the MTHFR 677CC homozygous wild-type plays a protective role in the development of ESCC in the northern Chinese population.

Aberrant CpG Island Hypermethylation of RASSF1A in Gastric Cardia Adenocarcinoma

Ras-association domain family 1A (RASSF1A) gene, a candidate tumor suppressor gene, is inactivated in several human tumors, usually by hypermethylation of its promoter region. RASSF1A induces cell cycle arrest through inhibition of cyclin D1 accumulation. In this work, the promoter methylation status of the RASSF1A in 92 gastric cardia adenocarcinoma (GCA) and corresponding normal tissues were investigated using Methylation-specific PCR (MSP) approach, immunohistochemistry method and RT-PCR were used respectively to examine the protein expression and mRNA expression of RASSF1A in tumors and corresponding normal tissues. Cyclin D1 expression was examined by immunohistochemistry. RASSF1A was methylated in 54/92 (58.7%) tumor specimens, which was significantly higher than that in corresponding normal tissues (p <.001). Methylation frequencies of stage III and IV tumor tissues were significantly higher than that in stage I and II tumor tissues (p <.05). By immunostaining, 43/92 (46.7%) tumor tissues demonstrated heterogeneous, positive immunostaining of tumor tissues was significantly reduced with comparison to matched normal tissues (p <.001). mRNA expressions of RASSF1A in GCA tumor tissues were reduced significantly with comparison to the corresponding normal tissues (OD value: 0.2376 ± 0.2315 vs 0.6874 ± 0.2668, p <.001). RASSF1A mRNA expression in methylation group of GCA was significantly different from that in unmethylation group (p <.001). Cyclin D1 hyper-expression was found in 72/92 (78.3%) cases and correlated with RASSF1A methylation (p <.05). Our data suggested that epigenetic silencing of RASSF1A gene expression by promoter hypermethylation may play an important role in GCA.

PTEN polymorphisms and the risk of esophageal carcinoma and gastric cardiac carcinoma in a high incidence region of China

PTEN, as a tumor suppressor gene, plays an important role in regulating cell growth, proliferation, and apoptosis. Two common polymorphisms, -9C/G and IVS4 (-/+), may alter susceptibility to the disease. To test the hypothesis that the genetic variations of PTEN play a role in the etiology of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA), a population-based case-control study was conducted in 350 ESCC patients, 257 GCA patients, and 634 healthy controls from a high-incidence region of Hebei province, China. The PTEN polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). The results showed that the family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing ESCC and GCA (the age, gender and smoking status adjusted OR = 1.73 and 1.67; 95% CI = 1.29-2.32 and 1.28-2.19, respectively). The overall distribution of the PTEN -9C/G genotype was not significantly different between cancer patients and controls. Compared with the PTEN IVS4-/- genotype, the IVS4+/+ genotype significantly decreased the risk of ESCC and GCA development, the adjusted OR was 0.64 (95% CI = 0.44-0.94) and 0.63 (95% CI = 0.41-0.98), respectively. Stratification analysis by gender, age, smoking status and family history of UGIC showed that the PTEN IVS4-/+ genotype only reduced the risk of ESCC (adjusted OR = 0.55, 95%CI = 0.34-0.90) among subjects with family history of UGIC. While the IVS4+/+ genotype decreased the susceptibility to both ESCC and GCA (adjusted OR = 0.61 and 0.57, 95% CI = 0.37-0.98 and 0.34-0.98, respectively) among male subjects, the IVS4+/+ genotype only decreased the risk of ESCC development among subjects younger than 55 years (adjusted OR = 0.43, 95% CI = 0.21-0.85). In addition, the haplotype analysis found that the -9C/IVS4- haplotype increased the risk of developing ESCC and GCA (OR = 1.31 and 1.24, 95% CI = 1.08-1.58 and 1.001-1.53). Our results suggested that the PTEN IVS4+/+ homozygote may play a protective role in the development of ESCC and GCA, while the haplotype -9C/IVS4- might be the risk factor of the development of ESCC and GCA in the high incidence region population of Hebei province, China.

Helicobacter pylori infection may be implicated in the topography and geographic variation of upper gastrointestinal cancers in the Taihang Mountain high-risk region in northern China.

Backgrounds:  Helicobacter pylori infection is prevalent in China. Chronic infection of the bacterial not only causes distal stomach cancer, but also confers risk to gastric cardia adenocarcinoma. Because H. pylori infection is inversely associated with esophageal adenocarcinoma, globally the infection rate is significantly correlated with the ratio of squamous carcinoma to adenocarcinoma of the esophagus. These agree with the topography of upper gastrointestinal cancer observed in the Taihang Mountain high‐risk region where both gastric cardia and non‐cardia adenocarcinoma coincide with esophageal squamous cancer, but with almost no distal esophageal adenocarcinoma. Moreover, as altitude increases from plain to mountains, we observed progressively increasing incidence rates of gastric adenocarcinomas in recent years in the region. Because H. pylori infection is a definite carcinogen to gastric adenocarcinoma and is more prevalent in the mountain than in plain areas due to undeveloped living conditions, the observation gives the impression as though H. pylori infection is implicated.

A positive family history of esophageal/gastric cardia cancer with gastric cardia adenocarcinoma is associated with a younger age at onset and more likely with another synchronous esophageal/gastric cardia cancer in a Chinese high-risk area

BACKGROUND To find a genetic component in gastric cardia adenocarcinomas (GCA). METHODS Age at onset (AO) and rate of another synchronous primary upper gastrointestinal carcinoma (RASPUGIC) were compared among the three GCA groups with positive (N = 766), negative (N = 2167), and missing family history of upper gastrointestinal cancer (FHUGIC) (N = 198). These 3131 GCAs were diagnosed on 3128 primary GCA patients of a consecutive surgical cohort treated from 1973 through 1994 at the Department of Thoracic Surgery in the 4th Hospital of Hebei Medical University in a high-risk region in northern China. RESULTS Overall, GCAs of positive FHUGIC showed a significantly younger AO and a significantly higher RASPUGIC than the negative group (54.68 ± 7.35 vs 55.94 ± 7.47 years old, Pt-test = 0.000; 3.1% vs 1.3%, χ2 = 11.02, P = 0.001). The difference in AO and RASPUGIC between the positive and the negative FHUGIC GCAs is significant or nearly significant in most subgroups; minimizing the possibility of a false association due to bias or confounding (e.g. significant stage-specific differences in AO between familial and sporadic GCAs observed in the subgroup of T2,3N0M0 (P = 0.000) and T2,3,4N1M0 (P = 0.03) exclude the possibility of ascertainment bias towards an earlier diagnosis in familial cases), and the association between FHUGIC and RASPUGIC is statistically significant for GCAs of younger AO (<55 yr old, RASPUGIC 3.8% vs 1.6% vs 1.1% for the positive, negative and missing FHUGIC GCAs respectively, χ2 = 6.50, P = 0.04), but not significant for the later onset GCAs (≥55 yr old, RASPUGIC 2.5%, 1.1%, 1.9% for the positive, negative and missing FHUGIC respectively, χ2 = 4.22, P = 0.12). CONCLUSION These findings suggest a genetic component in GCA in the Chinese high-risk region, and genetic predisposition may determine the age at onset and number of primary upper gastrointestinal cancer.

Incidence and mortality rate of esophageal cancer has decreased during past 40 years in Hebei Province, China

BACKGROUND Hebei province is located in North of China with of approximately 6% of whole national population. It is known as a high-risk area for esophageal cancer in China and worldwide. The aim of our study was to estimate the esophageal cancer burden and trend in Hebei Province. METHODS Eight cancer registries in Hebei Province submitted cancer registry data to the Hebei Provincial Cancer Registry Center. All data were qualified and compiled for cancer statistics in 2011. The pooled data were stratified by gender and age group (0, 1-4, 5-9, 10-14…80+). Incidence and mortality rates were age-standardized to World Segis population standard and expressed per 100,000 persons. In addition, proportions and cumulative incidence/mortality rates for esophageal cancer were calculated. Esophageal cancer mortality data during the periods 1973-1975, 1990-1992, and 2004-2005 were extracted from the national death surveys. Mortality and incidence rate data from Cixian and Shexian were obtained from population-based cancer registries in each county. RESULTS The estimated number of newly diagnosed esophageal cancer cases and deaths in 2011 in Hebei Province was 24,318 and 18,226, respectively. The crude incidence rate of esophageal cancer was 33.37/100,000 (males, 42.18/100,000 and females, 24.31/100,000). The age-standardized rate by world standard population (ASRW) was 28.09/100,000, ranking third among all cancers. The esophageal cancer mortality rate was 25.01/100,000 (males, 31.40/100,000 and females, 18.45/100,000), ranking third in deaths among all cancers. The mortality rates of esophageal cancer displayed a significant decreasing trend in Hebei Province from 1973-1975 (ASRW =48.69/100,000) to 2004-2005 (ASRW =28.02/100,000), with a decreased rate of 42.45%. In Cixian, the incidence of esophageal cancer decreased from 250.76/100,000 to 106.74/100,000 in males and from 153.86/100,000 to 75.41/100,000 in females, with annual percentage changes (APC) of 2.13 and 2.16, while the mortality rates declined with an APC of 2.46 for males and 3.10 for females from 1988 to 2011. In Shexian, the incidence rate decreased from 116.90/100,000 to 74.12/100,000 in males and from 46.98/100,000 to 40.64/100,000 in females, while the mortality rates declined, with an APC of 4.89 in males from 2003 to 2011. CONCLUSIONS Although the incidence and mortality rates of esophageal cancer remain high, an obvious decreasing trend has been observed in Hebei Province, as well as in high-risk regions, such as Cixian and Shexian, over the past 40 years.

Lung cancer burden has increased during the last 40 years in Hebei Province, China.

In 2011, Hebei Province, located in North China with a population of 71 794 239, accounted for approximately 6% of the national population. It is well known as a heavily air polluted area. This study reports the lung cancer burden and mortality trend in Hebei Province from 1973 to 2011.

Estimated cancer incidence and mortality in Hebei province, 2012

Objective This study estimates the numbers of new cancer cases and cancer deaths in Hebei province using incidence and mortality data from 9 population-based cancer registries in 2012. Methods The data of new diagnosed cancer cases and cancer deaths in 2012 were collected from 9 population-based cancer registries of Hebei province in 2015. All the data met the National Central Cancer Registry of China (NCCR) criteria of data quality. The pooled data analysis was stratified by areas (urban/rural), gender, age group (0, 1.4, 5.9, 10.14, …, 85+) and cancer type. New cancer cases and deaths in Hebei province were estimated using age-specific rates and corresponding provincial population in 2012. The 10 most common cancers in different groups and the cumulative rates were calculated. Chinese population census in 2000 and Segi’s population were used for age-standardized incidence/mortality rates. Results All cancer registries covered 4,986,847 populations, 6.84% of Hebei provincial population (2,098,547 in urban and 2,888,300 in rural areas). The percentage of cases morphologically verified (MV%) and death certificate-only cases (DCO%) were 76.40% and 4.72%, respectively. The mortality to incidence rate ratio (M/I) was 0.64. In 2012, it is estimated that there were about 187,900 new diagnosed cancer cases and 119,800 cancer deaths in Hebei province. The incidence rate of cancer was 258.12/100,000 (275.75/100,000 in males, 239.78/100,000 in females), and the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 210.65/100,000 and 208.50/100,000, with the cumulative incidence rates (0.74 years old) of 24.46%. The cancer incidence and ASIRC were 256.99/100,000 and 211.32/100,000 in urban areas and 258.94/100,000 and 209.99/100,000 in rural areas, respectively. The cancer mortality rate was 164.63/100,000 (201.85/100,000 in males, 125.92/100,000 in females). Agestandardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 137.30/100,000 and 137.39/100,000 with the cumulative mortality rate (0.74 years old) of 14.58%, respectively. The cancer mortality rate in rural areas (167.16/100,000) was higher than that in urban areas (161.16/100,000). The most common cancers were lung cancer, stomach cancer, breast cancer, esophageal cancer, liver cancer and colorectal cancer, which accounted for 72.31% of all cancer cases. Lung cancer, stomach cancer, liver cancer, esophageal cancer and colorectal cancer were the major causes of cancer death in Hebei province, which accounted for 75.24% of all cancer deaths. The cancer spectrum differs between urban and rural, males and females in both incidence and mortality rates. Conclusions The most common cancers were lung cancer, stomach cancer, esophageal cancer, breast cancer, liver cancer and colorectal cancer in Hebei province.

Urban rural disparity in female breast cancer incidence rate in China and the increasing trend in parallel with socioeconomic development and urbanization in a rural setting: Westernization and BC prevention

Worldwide breast cancer incidence correlates with socioeconomic status and increases in parallel with westernization, however urban–rural disparity and trends have not been adequately investigated in China.