Impact of changing US cigarette smoking patterns on incident cancer: Risks of 20 smoking-related cancers among the women and men of the NIH-AARP cohort

Background: Historically, US women started smoking at a later age than men and had lower relative risks for smoking-related cancers. However, more recent birth cohorts of women and men have similar smoking histories and have now reached the high-risk age for cancer. The impact of these changes on cancer incidence has not been systematically examined. Methods: Relative risks (RR), 95% confidence intervals (CI) and attributable fractions were calculated for cigarette smoking and incidence of 20 smoking-related cancers in 186 057 women and 266 074 men of the National Institutes of Health-AARP cohort, aged 50 to 71 years in 1995 and followed for 11 years. Results: In the cohort, which included participants born between 1924 and 1945, most women and men started smoking as teenagers. RRs for current vs never smoking were similar in women and men for the following cancers: lung squamous-cell (RR women: 121.4, 95% CI: 57.3–257.4; RR men:114.6, 95% CI: 61.2–214.4), lung adenocarcinoma (RR women: 11.7, 95% CI: 9.8–14.0; RR men: 15.6, 95% CI: 12.5–19.6), laryngeal (RR women: 37.0, 95% CI: 14.9–92.3; RR men: 13.8, 95% CI: 9.3–20.2), oral cavity-pharyngeal (RR women:4.4, 95% CI: 3.3–6.0; RR men: 3.8, 95% CI: 3.0–4.7), oesophageal squamous cell (RR women: 7.3, 95% CI: 3.5–15.5; RR men: 6.2, 95% CI: 2.8–13.7), bladder (RR women: 4.7, 95% CI: 3.7–5.8; RR men: 4.0, 95% CI: 3.5–4.5), colon (RR women: 1.3, 95% CI: 1.2–1.5; RR men: 1.3, 95% CI: 1.1–1.4), and at other sites, with similar attributable fractions. Conclusions: RRs for current smoking and incidence of many smoking-related cancers are now similar in US women and men, likely reflecting converging smoking patterns

Food group intake and risk of subtypes of esophageal and gastric cancer

Incidence rates for adenocarcinomas of the esophagus and gastric cardia have been increasing rapidly, while rates for non‐cardia gastric adenocarcinoma and esophageal squamous cell carcinoma have declined. We examined food group intake as a risk factor for subtypes of esophageal and gastric cancers in a multicenter, population‐based case–control study in Connecticut, New Jersey and western Washington state. Associations between food groups and risk were estimated using adjusted odds ratios (OR), based on increasing intake of one serving per day. Total vegetable intake was associated with decreased risk of esophageal adenocarcinoma (OR = 0.85, 95% CI = 0.75, 0.96). Conversely, total meat intake was associated with increased risk of esophageal adenocarcinoma (OR = 1.43, 95% CI = 1.11, 1.83), gastric cardia adenocarcinoma (OR = 1.37, 95% CI = 1.08, 1.73) and noncardia gastric adenocarcinoma (OR = 1.39, 95% CI = 1.12, 1.71), with red meat most strongly associated with esophageal adenocarcinoma risk (OR = 2.49, 95% CI = 1.39, 4.46). Poultry was most strongly associated with gastric cardia adenocarcinoma (OR = 1.89, 95% CI = 1.15, 3.11) and noncardia gastric adenocarcinoma (OR = 1.90, 95% CI = 1.19, 3.03). High‐fat dairy was associated with increased risk of both esophageal and gastric cardia adenocarcinoma. Higher intake of meats, particularly red meats, and lower intake of vegetables were associated with an increased risk of esophageal adenocarcinoma, while higher intake of meats, particularly poultry, and high‐fat dairy was associated with increased risk of gastric cardia adenocarcinoma

Food group intake and risk of subtypes of esophageal and gastric cancer

Incidence rates for adenocarcinomas of the esophagus and gastric cardia have been increasing rapidly, while rates for non‐cardia gastric adenocarcinoma and esophageal squamous cell carcinoma have declined. We examined food group intake as a risk factor for subtypes of esophageal and gastric cancers in a multicenter, population‐based case–control study in Connecticut, New Jersey and western Washington state. Associations between food groups and risk were estimated using adjusted odds ratios (OR), based on increasing intake of one serving per day. Total vegetable intake was associated with decreased risk of esophageal adenocarcinoma (OR = 0.85, 95% CI = 0.75, 0.96). Conversely, total meat intake was associated with increased risk of esophageal adenocarcinoma (OR = 1.43, 95% CI = 1.11, 1.83), gastric cardia adenocarcinoma (OR = 1.37, 95% CI = 1.08, 1.73) and noncardia gastric adenocarcinoma (OR = 1.39, 95% CI = 1.12, 1.71), with red meat most strongly associated with esophageal adenocarcinoma risk (OR = 2.49, 95% CI = 1.39, 4.46). Poultry was most strongly associated with gastric cardia adenocarcinoma (OR = 1.89, 95% CI = 1.15, 3.11) and noncardia gastric adenocarcinoma (OR = 1.90, 95% CI = 1.19, 3.03). High‐fat dairy was associated with increased risk of both esophageal and gastric cardia adenocarcinoma. Higher intake of meats, particularly red meats, and lower intake of vegetables were associated with an increased risk of esophageal adenocarcinoma, while higher intake of meats, particularly poultry, and high‐fat dairy was associated with increased risk of gastric cardia adenocarcinoma

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 disease1. 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 secretion2, whereas individuals with extensive corpus gastritis develop hypochlorhydria and gastric atrophy3, which are presumptive precursors of gastric cancer4. 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 cytokine5 and a powerful inhibitor of gastric acid secretion6,7. 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

AbstractBackground & Aims:Genetic variations in proinflammatory and anti-inflammatory cytokine genes influence individual response to carcinogenic exposures. Polymorphisms in interleukin (IL)-1β 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 α and IL-10 were each associated with more than doubling of the risk of noncardia gastric cancer. Carriage of multiple proinflammatory polymorphisms of IL-1Bo 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

Cigarette smoking, body mass index, gastro-esophageal reflux disease, and non-steroidal anti-inflammatory drug use and risk of subtypes of esophageal and gastric cancers by P53 overexpression

A number of risk factors for esophageal and gastric cancers have emerged, yet little is known whether risk factors map to molecular tumor markers such as overexpression of the tumor suppressor TP53. Using a US multicenter, population-based case-control study (170 cases of esophageal adenocarcinomas, 147 gastric cardia adenocarcinomas, 220 non-cardia gastric adenocarcinomas, and 112 esophageal squamous cell carcinomas), we examined whether the risk associated with cigarette smoking, body mass index (BMI), gastroesophageal reflux disease (GERD), and non-steroidal anti-inflammatory drug (NSAID) use varied by P53 overexpression. We defined P53 overexpression through immunohistochemistry of paraffin-embedded tumor tissues, using cutpoints based on percent of cells positive. Polytomous logistic regression was used to assess differences between each case group (defined by tumor subtype and P53 expression) and the control group by risk factors. The proportion of cases overexpressing P53 by tumor subtype was 72% for esophageal adenocarcinoma, 69% for gastric cardia adenocarcinoma, 52% for non-cardia gastric adenocarcinoma, and 67% for esophageal squamous cell carcinoma. For most tumor subtypes, we found little difference in risk factors by tumor P53 overexpression. For non-cardia gastric cancer however, an association with cigarette smoking was suggested for tumors that do not overexpress P53, while larger BMI was related with tumors that overexpress P53 verses no overexpression. Overall, this study did not find a clear relationship between P53 protein overexpression and known risk factors for subtypes of esophageal and gastric cancers. Further research with these tumors is needed to identify molecular markers associated with variations in the risk factor profiles

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

BACKGROUND AND AIMS: TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis. METHODS: We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. RESULTS: TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4). CONCLUSIONS: Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Large-Scale Pathway-Based Analysis of Bladder Cancer Genome-Wide Association Data from Five Studies of European Background

Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways (‘Aromatic amine metabolism’ [PGSEA = 0.0100, PARTP = 0.0020], ‘NAD biosynthesis’ [PGSEA = 0.0018, PARTP = 0.0086], ‘NAD salvage’ [PARTP = 0.0068], ‘Clathrin derived vesicle budding’ [PARTP = 0.0018], ‘Lysosome vesicle biogenesis’ [PGSEA = 0.0023, PARTP<0.00012], ’Retrograde neurotrophin signaling’ [PGSEA = 0.00840], and ‘Mitotic metaphase/anaphase transition’ [PGSEA = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis

Occupational exposure to formaldehyde, hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells - Response

There are concerns about the health effects of formaldehyde exposure, including carcinogenicity, in light of elevated indoor air levels in new homes and occupational exposures experienced by workers in health care, embalming, manufacturing and other industries. Epidemiological studies suggest that formaldehyde exposure is associated with an increased risk of leukemia. However, the biological plausibility of these findings has been questioned because limited information is available on formaldehyde’s ability to disrupt hematopoietic function. Our objective was to determine if formaldehyde exposure disrupts hematopoietic function and produces leukemia-related chromosome changes in exposed humans. We examined the ability of formaldehyde to disrupt hematopoiesis in a study of 94 workers in China (43 exposed to formaldehyde and 51 frequency-matched controls) by measuring complete blood counts and peripheral stem/progenitor cell colony formation. Further, myeloid progenitor cells, the target for leukemogenesis, were cultured from the workers to quantify the level of leukemia-specific chromosome changes, including monosomy 7 and trisomy 8, in metaphase spreads of these cells. Among exposed workers, peripheral blood cell counts were significantly lowered in a manner consistent with toxic effects on the bone marrow and leukemia-specific chromosome changes were significantly elevated in myeloid blood progenitor cells. These findings suggest that formaldehyde exposure can have an adverse impact on the hematopoietic system and that leukemia induction by formaldehyde is biologically plausible, which heightens concerns about its leukemogenic potential from occupational and environmental exposures