Masoud Babaei

A Form of the Metabolic Syndrome Associated with Mutations in DYRK1B

BACKGROUND Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome. METHODS We identified three large families with coinheritance of early-onset coronary artery disease, central obesity, hypertension, and diabetes. We used linkage analysis and whole-exome sequencing to identify the disease-causing gene. RESULTS A founder mutation was identified in DYRK1B, substituting cysteine for arginine at position 102 in the highly conserved kinase-like domain. The mutation precisely cosegregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Functional characterization of the disease gene revealed that nonmutant protein encoded by DYRK1B inhibits the SHH (sonic hedgehog) and Wnt signaling pathways and consequently enhances adipogenesis. Furthermore, DYRK1B promoted the expression of the key gluconeogenic enzyme glucose-6-phosphatase. The R102C allele showed gain-of-function activities by potentiating these effects. A second mutation, substituting proline for histidine 90, was found to cosegregate with a similar clinical syndrome in an ethnically distinct family. CONCLUSIONS These findings indicate a role for DYRK1B in adipogenesis and glucose homeostasis and associate its altered function with an inherited form of the metabolic syndrome. (Funded by the National Institutes of Health.).

Low Helicobacter pylori eradication rates with 4- and 7-day regimens in an Iranian population.

Background: In Iran, there is insufficient information on the efficacy of Helicobacter pylori eradication regimens shorter than 10 days. This study aims at assessing the efficacy of 4‐ and 7‐day H. pylori eradication regimens in a high‐incidence area of gastric cancer in Iran.

Neglected role of hookah and opium in gastric carcinogenesis: a cohort study on risk factors and attributable fractions

A recent study showed an association between hookah/opium use and gastric cancer but no study has investigated the relationship with gastric precancerous lesions. We examined the association between hookah/opium and gastric precancerous lesions and subsequent gastric cancer. In a population‐based cohort study, 928 randomly selected, healthy, Helicobacter pylori‐infected subjects in Ardabil Province, Iran, were followed for 10 years. The association between baseline precancerous lesions and lifestyle risk factors (including hookah/opium) was analyzed using logistic regression and presented as odds ratios (ORs) and 95% confidence intervals (CIs). We also calculated hazard ratios (HRs) and 95% CIs for the associations of lifestyle risk factors and endoscopic and histological parameters with incident gastric cancers using Cox regression models. Additionally, the proportion of cancers attributable to modifiable risk factors was calculated. During 9,096 person‐years of follow‐up, 36 new cases of gastric cancer were observed (incidence rate: 3.96/1,000 persons‐years). Opium consumption was strongly associated with baseline antral (OR: 3.2; 95% CI: 1.2–9.1) and body intestinal metaplasia (OR: 7.3; 95% CI: 2.5–21.5). Opium (HR: 3.2; 95% CI: 1.4–7.7), hookah (HR: 3.4; 95% CI: 1.7–7.1) and cigarette use (HR: 3.2; 95% CI: 1.4–7.5), as well as high salt intake, family history of gastric cancer, gastric ulcer and histological atrophic gastritis and intestinal metaplasia of body were associated with higher risk of gastric cancer. The fraction of cancers attributable jointly to high salt, low fruit intake, smoking (including hookah) and opium was 93% (95% CI: 83–98). Hookah and opium use are risk factors for gastric cancer as well as for precancerous lesions. Hookah, opium, cigarette and high salt intake are important modifiable risk factors in this high‐incidence gastric cancer area.

Comparison of breast cancer survival in two populations: Ardabil, Iran and British Columbia, Canada

BackgroundPatterns in survival can provide information about the burden and severity of cancer, help uncover gaps in systemic policy and program delivery, and support the planning of enhanced cancer control systems. The aim of this paper is to describe the one-year survival rates for breast cancer in two populations using population-based cancer registries: Ardabil, Iran, and British Columbia (BC), Canada.MethodsAll newly diagnosed cases of female breast cancer were identified in the Ardabil cancer registry from 2003 to 2005 and the BC cancer registry for 2003. The International Classification of Disease for Oncology (ICDO) was used for coding cancer morphology and topography. Survival time was determined from cancer diagnosis to death. Age-specific one-year survival rates, relative survival rates and weighted standard errors were calculated using life-tables for each country.ResultsBreast cancer patients in BC had greater one-year survival rates than patients in Ardabil overall and for each age group under 60.ConclusionThese findings support the need for breast cancer screening programs (including regular clinical breast examinations and mammography), public education and awareness regarding early detection of breast cancer, and education of health care providers.

Comparison of Two Diverse Populations, British Columbia, Canada, and Ardabil, Iran, Indicates Several Variables Associated with Gastric and Esophageal Cancer Survival

BackgroundGeographic variation and temporal trends in the epidemiology of esophageal and gastric cancers vary according to both tumor morphology and organ subsite. This study compares 1-year survival of gastric and esophageal cancers between two distinct populations: British Columbia (BC), Canada, and Ardabil, Iran.MethodsData for invasive primary esophageal and gastric cancer patients were obtained from the population-based cancer registries for BC and Ardabil. The relative survival rate was calculated using WHO Statistical Information System (WHOSIS) life-tables for each country. Chi-square and Fisher’s exact tests were used to compare survival differences between BC and Ardabil. T-tests, chi-square tests, and Fisher’s exact test were used to compare patient characteristics and tumor factors between the populations.ResultsThe overall 1-year age-standardized relative survivals for gastric cancer were 48% and 21% in BC and Ardabil, respectively (p < 0.01). The overall 1-year age-standardized relative survival for esophageal cancer was 33% and 17% in BC and Ardabil, respectively (p < 0.05). Overall and separately for each gender, age group, tumor location, and histology, there was greater 1-year survival of the gastric cancer patients in BC compared to Ardabil. For esophageal cancer; patients under age 65, patients with tumors in the middle or upper third of esophagus, and patients with squamous cell carcinoma had significantly better survival in BC than in Ardabil.ConclusionFindings of this study point to differences in disease characteristics and patient factors, not solely differences in healthcare systems, as being responsible for the survival difference in these populations.

Serum Ghrelin; A New Surrogate Marker of Gastric Mucosal Alterations in Upper Gastrointestinal Carcinogenesis

Background A few studies have indicated inverse relationships between serum ghrelin and gastric and esophageal cancers but those associations have been restricted to specific populations, including smokers and overweight individuals. We examined the association between ghrelin and gastroesophageal cancers and atrophic gastritis in a population-based setting. Methods In total 220 gastroesophageal cancers, comprising non-cardia and cardia gastric cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma (SCC) and age and gender-matched controls were recruited. Serum ghrelin, pepsinogen I/II ratio (PGI/II) and anti-H.pylori IgG antibodies were measured. Relationships between ghrelin and gastroesophageal cancers, after adjustment for PGI/II ratio, H.pylori status and smoking, were tested using logistic regression. Furthermore, in 125 endoscopically normal volunteers, with and without histological atrophic gastritis, the relationship with ghrelin was compared. Results Serum ghrelin (lowest vs. highest quintile) was inversely associated with gastric cancer: OR (95% CI) 8.71 (1.70–44.59) for cardia and 6.58 (1.26–34.46) for non-cardia cancer. Lower serum ghrelin was also associated with esophageal SCC: OR (95% CI) 5.69 (1.36–23.78), but not with esophageal adenocarcinoma. A similar association was observed between gastric cancer (cardia and non-cardia) and esophageal SCC when serum ghrelin was analysed as a continuous scaled variable. In endoscopically-normal volunteers, extensive atrophic gastritis was associated with low serum ghrelin [OR (95% CI) 0.25 (0.10–0.64)]. Conclusion Inverse associations between ghrelin and some gastroesophageal cancers suggest a potential role for serum ghrelin as a biomarker of upper gastrointestinal cancers and atrophic gastritis. In areas with a high incidence of gastric and/or esophageal cancer, screening might be more effectively targeted to individuals with low serum ghrelin in addition to the PGI/II ratio.

Estimating the Completeness of Gastric Cancer Registration in Ardabil/Iran by a Capture-Recapture Method using Population-Based Cancer Registry Data

BACKGROUND Knowledge of cancer incidences is essential for cancer prevention and control programs. Capture-recapture methods have been recommended for reducing bias and increasing the accuracy of cancer incidence estimations. This study aimed to estimate the completeness of gastric cancer registration by the capture-recapture method based on Ardabil population-based cancer registry data. MATERIALS AND METHODS All new cases of gastric cancer reported by three sources, pathology reports, death certificates and medical records that reported to Ardabil population-based cancer registry in 2006 and 2008 were enrolled in the study. The duplicate cases based on the similarity of first name, surname and fathers names were identified between sources. The estimated number of gastric cancers was calculated by the log-linear method using Stata 12 software. RESULTS A total of 857 new cases of gastric cancer were reported from three sources. After removing duplicates, the reported incidence rates for the years 2006 and 2008 were 35.3 and 32.5 per 100,000 population, respectively. The estimated completeness calculated by log-linear method for these years was 36.7 and 36.0, respectively. CONCLUSIONS These results indicate that none of the sources of pathology reports, death certificates and medical records individually or collectively fully cover the incident cases of gastric cancer. We can obtain more accurate estimates of incidence rates using the capture-recapture method.

Estimating the Esophagus Cancer Incidence Rate in Ardabil, Iran: A Capture-Recapture Method

Background: Accurate cancer registry and awareness of cancer incidence rate is essential in order to define strategies for cancer prevention and control programs. Capture-recapture methods have been recommended for reducing bias and increase the accuracy of cancer incidence estimation. Objectives: This study aimed to estimate the esophagus cancer incidence by capture-recapture method based on Ardabil population-based cancer registry data. Patients and Methods: Total new cases of esophagus cancer reported by three sources of pathology reports, medical records, and death certificates to Ardabil province cancer registry center in 2006 and 2008 were enrolled in the study. All duplicated cases between three sources were identified and removed using Excel software. Some characteristics such as name, surname, father’s name, date of birth and ICD codes related to their cancer type were used for data linkage and finding the common cases among three sources. The incidence rate per 100,000 was estimated based on capture-recapture method using the log-linear models. We used BIC, G2 and AIC statistics to select the best-fit model. Results: After removing duplicates, total 471 new cases of esophagus cancer were reported from three sources. The model with linkage between pathology reports, medical record sources and independence with the death certificates source was the best fitted model. The reported incidence rate for the years 2006 and 2008 was 18.77 and 18.51 per 100,000, respectively. In log-linear analysis, the estimated incidence rate for the years 2006 and 2008 was 49.71 and 53.87 per 100,000 populations, respectively. Conclusions: Based on the obtained results, it can be concluded that none of the sources of pathology reports, death certificates and medical records individually or collectively were fully covered the incidence cases of esophagus cancer and need to apply some changes in data abstracting and case finding.

Mo1565 Helicobacter pylori Infection and Development of Gastric Cancer a 10-Year Follow-up Population-Based Study in a High Incidence Area

Backgrounds & Aim: H. pylori (HP) infection is the most important etiology of gastric cancer (GC) in the world but it causes GC in only a minority of those infected .Eradication of HP can decrease the development of GC only in the subgroup of HP infected subjects without precancerous lesions. Strategies of HP eradication is still not well defined in countries with high mortality rates secondary to GC with almost universal HP infection in adults. The aim of the present study was to investigate the predictors of GC in an adult population with almost universal HP infection in an area with highest rate of gastric cancer in the world. Methods: 1011 healthy subjects 40 years and older, permanent residents of Ardabil and Meshkinshahr districts in northwest Iran, were randomly selected and enrolled in an endoscopic screening study during 2000 to 2001 year. Data on demographics and potential risk factors were collected using a well-structured questionnaire. Upper gastrointestinal endoscopy with multiple biopsy sampling was performed to detect HP infection and endoscopic precancerous lesions.Participants have been followed up until 2011. During followup period data on the occurrence of GC, mortality, and cause of death were obtained from cancer and death registries, and when neccessary by direct contacting to participants, and their families. The cumulative incidence and person-time incidence rate were calculated. The effect of other risk factors in addition to H. pylori infection on the risk of GC development were estimated by fitting multivariate hazard model using Cox proportional regression analysis, and were presented as hazard ratio (HR) and corresponding 96% confidence interval (95%CI). Results: During 10-year follow up, 36 participants (3.6%) developed GC yielding an incidence rate of 3.6 per 1000 person-years. The significant risk factors of GC included age over 50 (HR 4.8; 95%CI 1.4-16.2), a positive family history of stomach cancer (6.4; 3.1-13.1), smoking (5.7; 2.5-12.6), gastric atrophy (2.3; 1.0-5.1), intestinal metaplasia (4.5; 2.3-8.9) and presence of gastric ulcer (4.8; 1.9-11.5). Joint presence of precancerous lesion and one of the other risk factors significantly increased risk of stomach cancer as (46.5; 10.8-98.6) for a positive family history of stomach cancer; (27.6; 6.5-116.4) for smoking and (25.1; 16.3-105.3) for age>50. Conclusion: Combining the information on family history, lifestyle risk factors and the type of precancerous lesion may be helpful in order to identify high risk HP infected patients who need more intensive surveillance for early detection of GC. Key words: Stomach cancer, Precancerous lesions, Risk factors, H. pylori, Ardabil,Iran.

Importance of tumor location and histology in familial risk of upper gastrointestinal cancers: a nationwide cohort study

Background Familial clustering of upper gastrointestinal (UGI) cancers and the significance of family history has been addressed previously. We aimed to elucidate the familial risk based on the specified tumor location and histology. Method In the Swedish Family-Cancer Database, we determined the familial risk of UGI cancer patients diagnosed (1958–2015) with esophageal and gastric cancer by tumor location using standardized incidence ratios (SIRs). Results Risk of esophageal cancer in first-degree relatives (FDRs) of patients with esophageal cancer increased 2.4-fold (SIR 95% CI 2.0–2.8), whereas risk of esophageal cancer in cases with family history of cancer in the middle third of the esophagus increased 3.4-fold (SIR 95% CI 2.1–5.1). Risk of gastric cancer in FDRs increased 1.6-fold (SIR 95% CI 1.5–1.7), occurrence of concordant subsite gastric cancer in the antrum, body, and cardia was 5.5-fold (SIR 95% CI 2.4–11), 4.6-fold (SIR 95% CI 2.6–7.4), and 1.7-fold (SIR 95% CI 1.1–2.5), respectively. Familial risk of concordant histological subtype in esophageal cancer was 4.1-fold for squamous cell carcinoma (SIR 95% CI 3.2–5.2) and 3.6-fold for adenocarcinoma (SIR 95% CI 2.5–5.1). The risk of concordant gastric adenocarcinoma was 1.6-fold for one affected FDR (SIR 95% CI 1.5–1.7), 6.1-fold for two FDRs (SIR 95% CI 4.4–8.4), and 8.6-fold among twins (SIR 95% CI 2.3–22). Conclusion Family history of cancer in the lower third of the esophagus and stomach cancer in specific locations such as the antrum, body, and cardia can be considered as important predictive evidence for cancer in the same location in relatives. Our findings might guide endoscopy-based surveillance by introducing subgroups of populations with a higher risk for UGI cancer with particular attention to concordance of location of lesions, which could be a reasonable strategy for early detection, and thus help save more lives.