Gwen Murphy

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.

Sex disparities in colorectal cancer incidence by anatomic subsite, race and age.

Although incidence of colorectal cancer (CRC) in the United States has declined in recent years, rates remain higher in men than in women and the male‐to‐female incidence rate ratio (MF IRR) increases progressively across the colon from the cecum to the rectum. Rates among races/ethnicities other than Whites or Blacks have not been frequently reported. To examine CRC rates by sex across anatomic subsite, age and racial/ethnic groups, we used the National Cancer Institutes Surveillance, Epidemiology and End Results (SEER) program for cases diagnosed among residents of 13 registries during 1992–2006. Incidence rates were expressed per 100,000 person‐years and age‐adjusted to the 2000 US Standard Population; MF IRR and 95% confidence intervals were also calculated. Among each racial/ethnic group, the MF IRR increased fairly monotonically from close to unity for cecal cancers to 1.81 (Hispanics) for rectal cancers. MF IRRs increased with age most rapidly for distal colon cancers from <1.0 at ages <50 years to 1.4–1.9 at older ages. The MF IRR for rectal cancers also rose with age from about 1.0 to 2.0. For proximal cancer, the MF IRR was consistently <1.5; among American Indian/Alaska Natives, it was <1.0 across all ages. The MF IRRs for CRC vary markedly according to subsite and age but less by racial/ethnic group. These findings may partially reflect differences in screening experiences and access to medical care but also suggest that etiologic factors may be playing a role.

The Polyp Prevention Trial–Continued Follow-up Study: No Effect of a Low-Fat, High-Fiber, High-Fruit, and -Vegetable Diet on Adenoma Recurrence Eight Years after Randomization

The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), and low-fat (20% of total energy) diet on the recurrence of adenomatous polyps in the large bowel over a period of 4 years. Although intervention participants reported a significantly reduced intake of dietary fat, and increased fiber, fruit, and vegetable intakes, their risk of recurrent adenomas was not significantly different from that of the controls. Since the PPT intervention lasted only 4 years, it is possible that participants need to be followed for a longer period of time before treatment differences in adenoma recurrence emerge, particularly if diet affects early events in the neoplastic process. The PPT-Continued Follow-up Study (PPT-CFS) was a post-intervention observation of PPT participants for an additional 4 years from the completion of the trial. Of the 1,905 PPT participants, 1,192 consented to participate in the PPT-CFS and confirmed colonoscopy reports were obtained on 801 participants. The mean time between the main trial end point colonoscopy and the first colonoscopy in the PPT-CFS was 3.94 years (intervention group) and 3.87 years (control group). The baseline characteristics of 405 intervention participants and 396 control participants in the PPT-CFS were quite similar. Even though the intervention group participants increased their fat intake and decreased their intakes of fiber, fruits, and vegetables during the PPT-CFS, they did not go back to their prerandomization baseline diet (P < 0.001 from paired t tests) and intake for each of the three dietary goals was still significantly different from that in the controls during the PPT-CFS (P < 0.001 from t tests). As the CFS participants are a subset of the people in the PPT study, the nonparticipants might not be missing completely at random. Therefore, a multiple imputation method was used to adjust for potential selection bias. The relative risk (95% confidence intervals) of recurrent adenoma in the intervention group compared with the control group was 0.98 (0.88-1.09). There were no significant intervention-control group differences in the relative risk for recurrence of an advanced adenoma (1.06; 0.81-1.39) or multiple adenomas (0.92; 0.77-1.10). We also used a multiple imputation method to examine the cumulative recurrence of adenomas through the end of the PPT-CFS: the intervention-control relative risk (95% confidence intervals) for any adenoma recurrence was 1.04 (0.98-1.09). This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1745–52)

Serum Macrophage Inhibitory Cytokine-1 (MIC-1/GDF15): A Potential Screening Tool for the Prevention of Colon Cancer?

Background: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) mediates nonsteroidal anti-inflammatory drug (NSAID) protection from colonic polyps in mice and is linked to the development of colorectal carcinoma in humans. Therefore, changes in serum MIC-1/GDF15 levels could predict the presence of premalignant colonic polyposis and assist in population screening strategies. Methods: Serum MIC-1/GDF15 levels were measured in subjects in the Polyp Prevention Trial, in which NSAID use and colon cancer risk factors were defined. Subjects had an initial adenoma removed, a repeat colonoscopy removing previously unidentified polyps, and serum MIC-1/GDF15 estimation. Three years later recurrent adenomas were identified and serum MIC-1/GDF15 levels reestimated. The relationship between serum MIC-1/GDF15 levels and adenoma presence or recurrence was examined. Results: Serum MIC-1/GDF15 levels differed by adenoma status and were significantly related to colon cancer risk factors. In addition, mean serum MIC-1/GDF15 levels rose with increasing numbers of adenomas present and high-risk adenoma recurrence. NSAID users had higher serum MIC-1/GDF15 concentrations, which were related to protection from adenoma recurrence. Furthermore, adjusted serum MIC-1/GDF15 levels at final follow-up were related to adenoma recurrence (highest quartile MIC-1/GDF15; OR = 14.7, 95% CI: 3.0–73). Conclusions: These data suggest that MIC-1/GDF15 mediates at least some of the protection afforded by NSAIDs against human colonic polyposis. Furthermore, serum MIC-1/GDF15 levels vary with the development of adnenomatous colonic polyps. Impact: Serum MIC-1/GDF15 determination may hold promise as the first serum screening test to assist the detection of premalignant adenomatous colonic polyposis. Cancer Epidemiol Biomarkers Prev; 21(2); 337–46. ©2011 AACR.

Cancer Risk After Pernicious Anemia in the US Elderly Population

BACKGROUND & AIMS Pernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B12 deficiency, affecting 2% to 5% of the elderly population. Treatment with vitamin B12 cures the anemia, but not the gastritis. Findings from small studies have indicated that patients with pernicious anemia could have an increased risk of cancer. METHODS We performed a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, comparing 1,138,390 cancer cases (age, 66-99 y) with 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, and models were adjusted for sex, age, and calendar year of diagnosis and selection. RESULTS Compared with controls, we found individuals with pernicious anemia to be at increased risk for noncardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94-2.45) and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90-14.69). In addition, people with pernicious anemia have an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40-2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35-2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76-2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32-2.02), liver cancer (OR, 1.49; 95% CI, 1.28- 1.73), myeloma (OR, 1.55; 95% CI, 1.37-1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46-1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53-3.26). People with pernicious anemia have a lower risk of rectal cancer than the general population (OR, 0.82; 95% CI, 0.74- 0.92). CONCLUSIONS In a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, we found individuals with pernicious anemia to have significantly increased risks of gastric carcinoid tumors, adenocarcinomas, and other cancers located throughout the body.

The Relationship Between Serum Ghrelin and the Risk of Gastric and Esophagogastric Junctional Adenocarcinomas

BACKGROUND Cancers of the upper gastrointestinal tract remain a substantial cause of morbidity and mortality worldwide. Ghrelin is a hormone produced in the oxyntic glands of the stomach, and under conditions of chronic inflammation and atrophy, serum ghrelin concentrations decrease. However, the relationship between ghrelin and the risk of gastric and esophagogastric junctional cancers has not been investigated. METHODS We conducted a nested case-control study within the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to examine the relationship between serum ghrelin concentration and the risk of gastric noncardia adenocarcinoma (GNCA) and esophagogastric junctional adenocarcinoma (EGJA). Data from 261 GNCA patients, 98 EGJA patients, and 441 control subjects were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for potential confounders. Lag analysis was also performed to investigate the temporal nature of the associations between baseline serum pepsinogen I and ghrelin in GNCA and EGJA patients. All statistical tests were two-sided. RESULTS Lower concentrations of serum ghrelin were statistically significantly associated with an increased risk of both GNCA (adjusted OR = 1.75, 95% CI = 1.49 to 2.04; P < .001) and EGJA (adjusted OR = 1.56, 95% CI = 1.28 to 1.89, P < .001). A multivariable model found that the risk of both GNCA and EGJA were statistically significantly increased for those individuals in the lowest quartile of serum ghrelin levels compared with those in the highest quartile (OR of GNCA = 5.63, 95% CI = 3.16 to 10.03; OR of EGJA = 4.90, 95% CI = 2.11 to 11.35). The statistical significance of these associations remained even after restricting the analysis to those patients who developed cancer more than 10 years after baseline serum ghrelin measurements. CONCLUSION Low baseline concentrations of serum ghrelin were associated with a statistically significant increase in the risk of GNCA and EGJA, suggesting a potential role for gastric hormones in carcinogenesis.

Association of gastric disease with polymorphisms in the inflammatory-related genes IL-1B, IL-1RN, IL-10, TNF and TLR4.

Objectives This study aimed to investigate if single nucleotide polymorphisms (SNPs) in a series of inflammatory genes were associated with the development of the most common pathologies thought to precede gastric cancer development namely; Helicobacter pylori (H. pylori)-associated gastritis and intestinal metaplasia. Methods A total of 250 patients were genotyped for 11 SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes. The study population comprised H. pylori uninfected (‘normal’) control patients (n=96), H. pylori-positive gastritis (n=91) and intestinal metaplasia patients (n=63). Genotyping was performed using Taqman allelic discrimination assays. Odds ratios for gastric disease groups were adjusted for potential confounding factors. Results No differences were identified in frequency of carriage, or homozygosity, for any of the ‘risk’ alleles investigated across the patient groups. No evidence was found to suggest an association with increased risk of developing either chronic gastritis or intestinal metaplasia with SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes or haplotypes tested. Conclusion This study found no evidence of an association with increased risk of developing either chronic gastritis or intestinal metaplasia with the SNPs or haplotypes tested.

Hyperplastic Polyps and the Risk of Adenoma Recurrence in the Polyp Prevention Trial

BACKGROUND AND AIMS Recent studies have suggested that some hyperplastic polyps may be associated with an increased risk of colorectal cancer. Prospective information on the risk of adenoma recurrence associated with hyperplastic polyps is limited. We sought to investigate whether the coexistence of hyperplastic polyps with adenomas increases the risk of adenoma recurrence. METHODS We used unconditional logistic regression models to examine the association between baseline hyperplastic polyps and subsequent adenoma recurrence during a 3-year follow-up evaluation, among 1637 participants in the Polyp Prevention Trial. RESULTS A total of 437 participants (26.7%) had hyperplastic polyps coexisting with adenomas at baseline. Of these, 132 (30.2%) had at least one hyperplastic polyp in the proximal colon, whereas 305 (69.8%) had only distal hyperplastic polyps. When compared with subjects without any hyperplastic polyps at baseline, there was no statistically significant association between the presence of baseline hyperplastic polyps and recurrence of any adenoma (odds ratio [OR], 1.19; 95% confidence interval [CI], 0.94-1.51) or advanced adenoma (OR, 1.25; 95% CI, 0.78-2.03). Also, there was no association between hyperplastic polyp location and adenoma recurrence (OR, 1.01; 95% CI, 0.69-1.48) for any proximal hyperplastic polyp (OR, 1.26; 95% CI, 0.96-1.65) and for distal hyperplastic polyps. CONCLUSIONS The coexistence of hyperplastic polyps with adenomas, irrespective of location, does not confer an increased risk of adenoma recurrence beyond that of adenomas alone within 3 years of follow-up evaluation. Prospective long-term studies on adenoma recurrence risk associated with hyperplastic polyps in screening populations are needed.

Serum Adiponectin, Leptin, C-Peptide, Homocysteine, and Colorectal Adenoma Recurrence in the Polyp Prevention Trial

Background: Serum adiponectin, leptin, C-peptide, and homocysteine are indicators for obesity, hyperinsulinemia, and chronic inflammation, which have all been associated with colorectal cancer. Aims: To determine whether serum adiponectin, leptin, C-peptide, and homocysteine are associated with fat, fiber, fruit and vegetable, flavonol, or dry bean intake and colorectal adenoma recurrence. Methods: Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (95% CI) for adenoma recurrence in 627 participants from the control arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Results: Serum concentrations of C-peptide and homocysteine were inversely related to fiber, fruit and vegetable, and flavonol intake and positively related to percentage of calories from fat (all Ptrend ≤0.01). High homocysteine concentrations were associated with any (4th versus 1st quartile: OR, 2.26; 95% CI, 1.30-3.94) and more than one adenoma recurrence (OR, 2.11; 95% CI, 1.01-4.40). Individuals in the highest, versus lowest, tertile of serum leptin concentration had a decreased risk of advanced adenoma recurrence (OR, 0.22; 95% CI, 0.06-0.79). Conclusion: Our results suggest that serum homocysteine may serve as an indicator of dietary exposure, including a low-fat and high-fiber, high-fruit and vegetable, and high-flavonol diet, as well as colorectal adenoma recurrence. Impact: Discovering biomarkers that are both modifiable and can predict cancer risk is critical. We identified serum homocysteine as a novel indicator that is modified by diet and predicts risk of adenoma recurrence. Cancer Epidemiol Biomarkers Prev; 19(6); 1441–52. ©2010 AACR.

Association of seropositivity to Helicobacter species and biliary tract cancer in the ATBC study

Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention (ATBC) Study. We included 64 biliary cancers, 122 liver cancers, and 224 age‐matched controls which occurred over the course of 22 years. Helicobacter pylori seropositivity was defined as those positive to ≥4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors. Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of ampula of Vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (95% confidence interval [CI]: 0.79‐62.33), 2.21 (0.19‐25.52), 10.67 (0.76‐150.08), and 1.20 (0.42‐3.45), respectively, with an OR of 5.47 (95% CI: 1.17‐25.65) observed for the biliary tract cancers combined. ORs above 1 were observed for many of the investigated antigens, although most of these associations were not statistically significant. Conclusion: Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence the risk of biliary tract cancer. (Hepatology 2014;60:1962–1970)