New Insights into the Genetics of Fetal Megacystis: ACTG2 Mutations, Encoding γ-2 Smooth Muscle Actin in Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (Berdon Syndrome).

OBJECTIVE: To identify the molecular basis for prenatally suspected cases of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) (MIM 249210) in 3 independent families with clinical and radiographic evidence of MMIHS. METHODS: Whole-exome sequencing (WES) and Sanger sequencing of the ACTG2 gene. RESULTS: We identified a novel heterozygous de novo missense variant in ACTG2 c.770G>A (p.Arg257His) encoding x03B3;-2 smooth muscle actin (ACTG2) in 2 siblings with MMIHS, suggesting gonadal mosaicism of one of the parents. Two additional de novo missense variants (p.Arg257Cys and p.Arg178His) in ACTG2 were identified in 2 additional MMHIS patients. All of our patients had evidence of fetal megacystis and a normal or slightly increased amniotic fluid volume. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. ACTG2 immunostaining of the intestinal tissue showed an altered muscularis propria, a markedly thinned longitudinal muscle layer, and a reduced amount and abnormal distribution of ACTG2. CONCLUSION: Our study demonstrates that de novo mutations in ACTG2 are a cause of fetal megacystis in MMIHS and that gonadal mosaicism may be present in a subset of cases. These findings have implications for the counseling of families with a diagnosis of fetal megacystis with a preserved amniotic fluid volume and associated gastrointestinal findings.

Alcohol dehydrogenase 3 and risk of esophageal and gastric adenocarcinomas.

OBJECTIVES: Alcohol increases esophageal squamous carcinoma risk but has been less consistently associated with esophageal adenocarcinoma. Alcohol dehydrogenase catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a carcinogen. The alcohol dehydrogenase gene has several polymorphisms which may lead to faster conversion of ethanol to acetaldehyde, which may increase cancer risk. METHODS: We undertook a study to examine whether a common polymorphism in the alcohol dehydrogenase 3 gene was associated with a higher risk of esophageal adenocarcinoma using data and biological samples collected for the Esophageal and Gastric Cancer Study (n = 114 esophageal and gastric cardia adenocarcinoma, n = 60 non-cardia gastric carcinoma, n = 23 cases of esophageal squamous cell carcinoma and 160 controls). RESULTS: Individuals homozygous for ADH ( 3 ) (1-1) had a higher risk of each tumor type compared to individuals who had ADH ( 3 ) (2-2) or ADH ( 3 ) (1-2) genotype (OR = 1.7, 95% CI = 1.0-2.9 for esophageal and gastric cardia adenocarcinomas; OR = 1.7, 95% CI = 0.7-4.3 for esophageal squamous cell carcinoma; and OR = 2.8, 95% CI = 1.5-5.1 for non-cardia gastric cancer). The elevation in risk from homozygosity of the ADH ( 3 ) (1) allele was seen in drinkers and nondrinkers, although the risk estimate was only significant for drinkers, particularly of liquor. CONCLUSION: These data suggest ADH3 genotype may be associated with risk of esophageal and gastric cardia adenocarcinomas.

Carbonated soft drink consumption and risk of esophageal adenocarcinoma.

Carbonated soft drinks (CSDs) have been associated with gastroesophageal reflux, an established risk factor for esophageal adenocarcinoma. As both CSD consumption and esophageal adenocarcinoma incidence have sharply increased in recent decades, we examined CSD as a risk factor for esophageal and gastric cancers in a U.S. multicenter, population-based case-control study. Associations between CSD intake and risk were estimated by adjusted odds ratios (ORs), comparing the highest versus lowest quartiles of intake. All statistical tests were two-sided. Contrary to the proposed hypothesis, CSD consumption was inversely associated with esophageal adenocarcinoma risk (highest versus lowest quartiles, OR = 0.47, 95% confidence interval = 0.29 to 0.76; Ptrend = .005), due primarily to intake of diet CSD. High CSD consumption did not increase risk of any esophageal or gastric cancer subtype in men or women or when analyses were restricted to nonproxy interviews. These findings indicate that CSD consumption (especially diet CSD) is inversely associated with risk of esophageal adenocarcinoma, and thus it is not likely to have contributed to the rising incidence rates.

Demographic and lifestyle predictors of survival in patients with esophageal or gastric cancers.

BACKGROUND AND AIMS: Risk factors for subtypes of esophageal and gastric cancer recently have been identified, but their effect on survival is unknown. METHODS: Incident cases (n = 1142) from a population-based case-control study were followed-up from diagnosis (1993-1995) until 2000. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for esophageal and gastric cancer in relation to prediagnostic factors. RESULTS: Relative to distant stage, esophageal adenocarcinoma (EA) patients with localized disease had a decreased risk for death (HR, .22; 95% CI, .15-.31), followed by those with regional spread (HR, .32; 95% CI, .23-.45). Similar patterns were seen for the other tumor types. Except for other (non-cardia) gastric adenocarcinomas (OGA), higher household income (> or =15,000 US dollars/y vs. <15,000 US dollars/y) was associated with a 33%-38% decrease in risk for death. Prediagnosis body mass index (BMI) between 25 and 29.9 kg/m 2 was associated with longer survival for EA and OGA patients (EA: HR, .67; 95% CI, .51-.88) vs. BMI <25 kg/m(2). Women with esophageal squamous cell carcinoma (ES) and OGA experienced longer survival compared with men. Age, education, cigarette smoking, alcohol intake, gastroesophageal reflux disease, and nonsteroidal anti-inflammatory drug use did not consistently predict survival. CONCLUSIONS: Predictors of lengthened esophageal and gastric cancer survival included higher income (except in OGA), overweight (among EA and OGA patients), and female sex (among ES and OGA patients).