Charles S. Rabkin

Interleukin-1 polymorphisms associated with increased risk of gastric cancer

Helicobacter pylori infection is associated with a variety of clinical outcomes including gastric cancer and duodenal ulcer disease. The reasons for this variation are not clear, but the gastric physiological response is influenced by the severity and anatomical distribution of gastritis induced by H. pylori. Thus, individuals with gastritis predominantly localized to the antrum retain normal (or even high) acid secretion, whereas individuals with extensive corpus gastritis develop hypochlorhydria and gastric atrophy, which are presumptive precursors of gastric cancer. Here we report that interleukin-1 gene cluster polymorphisms suspected of enhancing production of interleukin-1-beta are associated with an increased risk of both hypochlorhydria induced by H. pylori and gastric cancer. Two of these polymorphism are in near-complete linkage disequilibrium and one is a TATA-box polymorphism that markedly affects DNA–protein interactions in vitro. The association with disease may be explained by the biological properties of interleukin-1-beta, which is an important pro-inflammatory cytokine and a powerful inhibitor of gastric acid secretion. Host genetic factors that affect interleukin-1-beta may determine why some individuals infected with H. pylori develop gastric cancer while others do not.

Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

BACKGROUND & AIMS Genetic variations in proinflammatory and anti-inflammatory cytokine genes influence individual response to carcinogenic exposures. Polymorphisms in interleukin (IL)-1 beta and its endogenous receptor antagonist are associated with risk of Helicobacter pylori-related gastric cancer. The aim of this study was to evaluate the role of proinflammatory cytokine gene polymorphisms in gastric and esophageal cancers defined by anatomic subsite. METHODS We assessed polymorphisms of the IL-1 gene cluster and 4 other cytokine genes in a population-based case-control study of upper gastrointestinal cancers, including gastric cardia (n = 126) and noncardia adenocarcinoma (n = 188), esophageal squamous cell carcinoma (n = 53), and adenocarcinoma (n = 108), and frequency-matched controls (n = 212). ORs for the different cancers were computed from logistic regression models adjusted for potential confounding factors. RESULTS Proinflammatory genotypes of tumor necrosis factor alpha and IL-10 were each associated with more than doubling of the risk of noncardia gastric cancer. Carriage of multiple proinflammatory polymorphisms of IL-1B(o) IL-1 receptor antagonist, tumor necrosis factor A, and IL-10 conferred greater risk, with ORs (and 95% confidence intervals) of 2.8 (1.6-5.1) for one, 5.4 (2.7-10.6) for 2, and 27.3 (7.4-99.8) for 3 or 4 high-risk genotypes. In contrast, these polymorphisms were not consistently related to the risks of esophageal or gastric cardia cancers. Polymorphisms in IL-4 and IL-6 were not associated with any of the cancers studied. CONCLUSIONS A proinflammatory cytokine genetic profile increases the risk of noncardia gastric adenocarcinoma but not other upper gastrointestinal cancers, possibly by inducing a hypochlorhydric and atrophic response to gastric H. pylori infection.

Hematotoxicity in Workers Exposed to Low Levels of Benzene

Benzene is known to have toxic effects on the blood and bone marrow, but its impact at levels below the U.S. occupational standard of 1 part per million (ppm) remains uncertain. In a study of 250 workers exposed to benzene, white blood cell and platelet counts were significantly lower than in 140 controls, even for exposure below 1 ppm in air. Progenitor cell colony formation significantly declined with increasing benzene exposure and was more sensitive to the effects of benzene than was the number of mature blood cells. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, influenced susceptibility to benzene hematotoxicity. Thus, hematotoxicity from exposure to benzene occurred at air levels of 1 ppm or less and may be particularly evident among genetically susceptible subpopulations.

Monoclonal origin of multicentric Kaposi's sarcoma lesions

BACKGROUND Kaposis sarcoma has features of both hyperplastic proliferation and neoplastic growth. Multiple lesions, in which spindle cells are prominent, often arise synchronously over widely dispersed areas. We tested the hypothesis that the spindle cells in these multicentric lesions originate from a single clone of precursor cells. METHODS To determine whether Kaposis sarcoma is a monoclonal disorder, we assessed the methylation patterns of the androgen-receptor gene (HUMARA) in multiple lesions from women with the acquired immunodeficiency syndrome. In polyclonal tissues, about half the copies of each HUMARA allele are methylated, whereas in cells derived from a single clone all the copies of only one allele are methylated. To minimize contamination by normal DNA, we used microdissection to isolate areas composed primarily of spindle cells, the putative tumor cells. RESULTS Eight patients with a total of 32 tumors were studied. Of these tumors, 28 had highly unbalanced methylation patterns (i.e., predominant methylation of one HUMARA allele). In all the tumors that had unbalanced methylation from a given patient, the same allele predominated. CONCLUSIONS These data indicate that Kaposis sarcoma is a disseminated monoclonal cancer and that the changes that permit the clonal outgrowth of spindle cells occur before the disease spreads.

Age-Specific Trends in Incidence of Noncardia Gastric Cancer in US Adults

CONTEXT For the last 50 years, overall age-standardized incidence rates for noncardia gastric cancer have steadily declined in most populations. However, overall rates are summary measures that may obscure important age-specific trends. OBJECTIVE To examine effects of age at diagnosis on noncardia gastric cancer incidence trends in the United States. DESIGN, SETTING, AND PARTICIPANTS Descriptive study with age-period-cohort analysis of cancer registration data from the National Cancer Institutes Surveillance, Epidemiology, and End Results Program, which covers approximately 26% of the US population. From 1977 through 2006, there were 83,225 adults with incident primary gastric cancer, including 39,003 noncardia cases. MAIN OUTCOME MEASURES Overall and age-specific incidence rates, adjusted for period and cohort effects using age-period-cohort models. Results were stratified by race, sex, and socioeconomic status. RESULTS Overall age-standardized annual incidence per 100,000 population declined during the study period from 5.9 (95% confidence interval [CI], 5.7-6.1) to 4.0 (95% CI, 3.9-4.1) in whites, from 13.7 (95% CI, 12.5-14.9) to 9.5 (95% CI, 9.1-10.0) in blacks, and from 17.8 (95% CI, 16.1-19.4) to 11.7 (95% CI, 11.2-12.1) in other races. Age-specific trends among whites varied significantly between older and younger age groups (P < .001 for interaction by age): incidence per 100,000 declined significantly from 19.8 (95% CI, 19.0-20.6) to 12.8 (95% CI, 12.5-13.1) for ages 60 to 84 years and from 2.6 (95% CI, 2.4-2.8) to 2.0 (95% CI, 1.9-2.1) for ages 40 to 59 years but increased significantly from 0.27 (95% CI, 0.19-0.35) to 0.45 (95% CI, 0.39-0.50) for ages 25 to 39 years. Conversely, rates for all age groups declined or were stable among blacks and other races. Age-period-cohort analysis confirmed a significant increase in whites among younger cohorts born since 1952 (P < .001). CONCLUSIONS From 1977 through 2006, the incidence rate for noncardia gastric cancer declined among all race and age groups except for whites aged 25 to 39 years, for whom it increased. Additional surveillance and analytical studies are warranted to identify risk factors that may explain this unfavorable trend.

The role of interleukin-1 polymorphisms in the pathogenesis of gastric cancer.

This corrects the article DOI: 35006081

Meta-analysis Shows That Prevalence of Epstein–Barr Virus-Positive Gastric Cancer Differs Based on Sex and Anatomic Location

BACKGROUND & AIMS Epstein-Barr virus (EBV) has been causally associated with cancer; some gastric carcinomas have a monoclonal EBV genome in every cancer cell, indicating that they arose from a single infected progenitor cell. However, the proportion of EBV-positive gastric carcinomas is uncertain, and the etiologic significance is unknown. METHODS We conducted a meta-analysis of 70 studies including 15,952 cases of gastric cancer assessed by in situ hybridization for EBV-encoded small RNA. RESULTS The pooled prevalence estimate of EBV positivity was 8.7% (95% confidence interval [CI]: 7.5%-10.0%) overall, with a 2-fold difference by sex: 11.1% (95% CI: 8.7%-14.1%) of gastric cancer cases in males vs 5.2% (95% CI: 3.6%-7.4%) of cases in females. Tumors arising in the gastric cardia (13.6%) or corpus (13.1%) were more than twice as likely to be EBV-positive as those in the antrum (5.2%; P < .01 for both comparisons). EBV prevalence was 4 times higher (35.1%) for tumors in postsurgical gastric stump/remnants. Over 90% of lymphoepithelioma-like carcinomas were EBV positive, but only 15 studies reported any cases of this type; prevalence did not significantly differ between the more common diffuse (9.5%) [corrected] and intestinal (7.6%) [corrected] histologies. EBV prevalence was similar in cases from Asia (8.3%), Europe (9.2%), and the Americas (9.9%). CONCLUSIONS EBV-positive gastric cancers greatly differ from other gastric carcinomas based on sex, anatomic subsite, and surgically disrupted anatomy, indicating that it is a distinct etiologic entity. Epidemiologic studies comparing EBV-positive and -negative gastric cancers are warranted to investigate EBVs role in gastric carcinogenesis.

Interassay Correlation of Human Herpesvirus 8 Serologic Tests

To standardize human herpesvirus 8 (HHV-8) antibody assays for application to asymptomatic infection, a blinded comparison was done of seven immunofluorescence assays and ELISAs. Five experienced laboratories tested a serum panel from 143 subjects in 4 diagnostic groups. Except for a minor capsid protein ELISA, the other six tests detected HHV-8 antibodies most frequently in classic (80%-100%) and AIDS-related (67%-91%) Kaposis sarcoma, followed by human immunodeficiency virus-seropositive patients (27%-60%), and least frequently in healthy blood donors (0-29%). However, these six assays frequently disagreed on individual sera, particularly for blood donor samples. Current HHV-8 antibody tests have uncertain accuracy in asymptomatic HHV-8 infection and may require correlation with viral protein or nucleic acid detection. Antibody assays are useful for epidemiologic investigations, but the absolute prevalence of HHV-8 infection in the United States cannot yet be determined.

Sexual behaviour, STDs and risks for prostate cancer

A population-based case-control study was carried out among 981 men (479 black, 502 white) with pathologically confirmed prostate cancer and 1315 controls (594 black, 721 white). In-person interviews elicited information on sexual behaviour and other potential risk factors for prostate cancer. Blood was drawn for serologic studies in a subset of the cases (n = 276) and controls (n = 295). Prostate cancer risk was increased among men who reported a history of gonorrhoea or syphilis (odds ratio (OR) = 1.6; 95% confidence internal (CI) 1.2–2.1) or showed serological evidence of syphilis (MHA-TP) (OR = 1.8; 95% CI 1.0–3.5). Patterns of risk for gonorrhoea and syphilis were similar for blacks (OR = 1.7; 95% CI 1.2–2.2) and whites (OR = 1.6; 95% CI 0.8–3.2). Risks increased with increasing occurrences of gonorrhoea, rising to OR = 3.3 (95% CI 1.4–7.8) among subjects with three or more events (Ptrend= 0.0005). Frequent sexual encounters with prostitutes and failure to use condoms were also associated with increased risk. Syphilis, gonorrhoea, sex with prostitutes and unprotected sexual intercourse may be indicators of contact with a sexually transmissible factor that increases the risk of prostate cancer.

Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology

The 2001 World Health Organization classification scheme considers B‐cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age‐adjusted incidence rates (IRs) of CLL and SLL in the population‐based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age‐standardized to the 2000 US population, overall IRs were 3·83 per 100 000 person‐years for CLL (n = 15 676) and 1·31 for SLL (n = 5382) during 1993–2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1·98) than for SLL (1·67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal trends must be interpreted cautiously. CLL and SLL IRs increased exponentially with age among all gender/race groups, with CLL IRs increasing more steeply with advancing age than SLL. Avenues of future research include assessment of delayed‐ and under‐reporting to cancer registries and exploration of race, gender, and age effects in epidemiological studies.