Epstein�CBarr virus antibody level and gastric cancer risk in Korea: a nested case�Ccontrol study

Background:

Few cohort studies have investigated Epstein–Barr virus (EBV) infection before the occurrence of gastric cancer.

Methods:

Among 14 440 cohort participants, 100 incident gastric cancer cases were individually matched to two controls. Epstein–Barr virus antibodies IgG and IgA against viral capsid antigen (VCA), EBV nuclear antigen (EBNA) antibody IgG, and early antigen (EA) antibody IgG were measured using enzyme immunoassays (EIAs).

Results:

The highest titres of VCA IgG (odds ratio (OR): 1.37, 95% confidence interval (CI): 0.62–3.06) or EBNA IgG (OR: 0.87, 95% CI: 0.51–1.46) were not associated with gastric cancer risk.

Conclusion:

Higher levels of VCA IgG or EBNA IgG were not associated with increased risk of gastric adenocarcinoma in Koreans.     

Plasma pepsinogens, antibodies against Helicobacter pylori, and risk of gastric cancer in the Shanghai Women's Health Study Cohort

Background:

Circulating pepsinogens can indicate atrophic gastritis, a precursor of gastric cancer. We tested the association between gastric cancer and plasma pepsinogens and antibodies against Helicobacter pylori in a case–control study nested in a prospective cohort.

Methods:

We selected 141 gastric cancer cases and 282 incidence-density sampled controls. Plasma concentrations of pepsinogens 1 and 2 were measured using ELISA kits, and anti-H. pylori antibodies were measured using a kit specific to Chinese strains. Associations were estimated using conditional logistic regression models adjusted for potential confounders.

Results:

Gastric cancer subjects were more likely to be anti-H. pylori positive than controls, 97 vs 92%. A plasma pepsinogen 1 (PG1) concentration <50 ng ml^–1 (15% of cases) was associated with a significantly increased risk of gastric cancer (OR 4.23; (95% CI: 1.86–9.63), whereas a plasma pepsinogen 2 (PG2) concentration >6.6 ng ml^–1 (75% of cases) was also associated with a significantly increased risk of gastric cancer (OR 3.62; (95% CI: 1.85–7.09). We also found that the PG1 : 2 ratio had a nearly linear association with gastric cancer risk.

Conclusion:

Lower plasma PG1 : 2 ratios are associated with a higher risk of gastric cancer. Furthermore, it appears that circulating pepsinogens 1 and 2 may be independently associated with the risk of gastric cancer.     

Leg length, sitting height and postmenopausal breast cancer risk

Background:

Tallness has consistently been associated with an increased risk of breast cancer. We investigated the association further by decomposing height into leg length and sitting height.

Methods:

From the prospective Danish cohort ‘Diet, Cancer and Health'', 23 864 postmenopausal women enrolled during 1993–1997 were followed for a diagnosis of breast cancer in the Danish Cancer Registry through 2009.

Results:

The incidence rate ratios for breast cancer were 1.11 (95% CI=1.06–1.16) for each 5 cm increase in total height and 1.09 (95% CI=1.01–1.17) and 1.14 (95% CI=1.04–1.25) for each 5 cm increase in leg length and sitting height, respectively. There was no statistical significant difference between the associations for leg length and sitting height (P=0.47).

Conclusion:

Leg length does not seem to be more strongly associated with breast cancer among postmenopausal women than sitting height.     

Alcohol intake and risk of thyroid cancer in the NIH-AARP Diet and Health Study

Background:

Certain studies suggest that alcohol may reduce the risk of thyroid cancer in women, but the effect in men remains unclear.

Methods:

We analysed the association between alcohol and thyroid cancer in a large (n=490 159) prospective NIH-AARP Diet and Health Study with self-reported beer, wine, and liquor intakes.

Results:

Over 7.5 years of follow-up (median), 170 men and 200 women developed thyroid cancer. Overall, the thyroid cancer risk decreased with greater alcohol consumption (⩾2 drinks per day vs none, relative risk=0.57, 95% CI 0.36–0.89, P-trend=0.01).

Conclusions:

These results suggest a potential protective role for alcohol consumption in thyroid cancer.     

Circulating tumour markers can define patients with normal colons, benign polyps, and cancers

Background:

Early diagnosis represents the best opportunity for cure of colorectal cancer. Current screening programmes use faecal occult blood testing for screening, which has limited sensitivity and poor specificity.

Methods:

In this study we looked at a series of previously described diagnostic markers utilising circulating free DNA (cfDNA), with a preparation method allowing small DNA fragments to be isolated. The Circulating free DNA was isolated from samples obtained from 85 patients, including 35 patients without endoscopic abnormality, a group of 26 patients with benign colorectal adenomas, and 24 patients with colorectal carcinomas. In each case, polymerase chain reaction (PCR) was performed for Line1 79 bp, Line1 300 bp, Alu 115 bp, Alu 247 bp, and mitochondrial primers. In addition, carcinoembryonic antigen (CEA) was measured by ELISA. Each marker was analysed between normal, polyp, and cancer populations, and the best performing analysed in combination by logistic regression.

Results:

The best model was able to discriminate normal from populations with adenoma or carcinoma using three DNA markers and CEA, showing an area under the receiver operator characteristic (ROC) curve of 0.855 with a positive predictive value of 81.1% for polyps and cancer diagnosis.

Conclusion:

These circulating markers in combination with other markers offer the prospect of a simple blood test as a possible secondary screen for colorectal cancers and polyps in patients with positive faecal occult blood tests.     

Epigenetic status of LINE-1 predicts clinical outcome in early-stage rectal cancer

Background:

We evaluated the clinical prognostic value of methylation of two non-coding repeat sequences, long interspersed element 1 (LINE-1) and Alu, in rectal tumour tissues. In addition to DNA methylation, expression of histone modifications H3K27me3 and H3K9Ac was studied in this patient cohort.

Methods:

LINE-1 and Alu methylation were assessed in DNA extracted from formalin-fixed paraffin-embedded tissues. A pilot (30 tumour and 25 normal tissues) and validation study (189 tumour and 53 normal tissues) were performed. Histone modifications H3K27me3 and H3K9Ac were immunohistochemically stained on tissue microarrays of the study cohort.

Results:

In early-stage rectal cancer (stage I-II), hypomethylation of LINE-1 was an independent clinical prognostic factor, showing shorter patient survival (P=0.014; HR: 4.6) and a higher chance of tumour recurrence (P=0.001; HR: 9.6). Alu methylation did not show any significant correlation with clinical parameters, suggesting an active role of LINE-1 in tumour development. Expression of H3K27me3 (silencing gene expression) and H3K9Ac (activating gene expression) in relation to methylation status of LINE-1 and Alu supported this specific role of LINE-1 methylation.

Conclusion:

The epigenetic status of LINE-1, but not of Alu, is prognostic in rectal cancer, indicating an active role for LINE-1 in determining clinical outcome.     

Mammographic density and its interaction with other breast cancer risk factors in an Asian population

Background:

Joint effects of mammographic density and other risk factors on breast cancer risk remain unclear.

Methods:

From The Singapore Breast Screening Project, we selected 491 cases and 982 controls. Mammographic density was measured quantitatively. Data analysis was by conditional logistic regression.

Results:

Density was a significant risk factor, adjusting for other factors. Density of 76–100% had an odds ratio of 5.54 (95% CI 2.38–12.90) compared with 0–10%. Density had significant interactions with body mass index and oral contraceptive use (P=0.02).

Conclusions:

Percent density increases breast cancer risk in addition to effects of other risk factors, and modifies the effects of BMI and OCs.     

Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies

Background:

Whether red and processed meat consumption is a risk factor for pancreatic cancer remains unclear. We conducted a meta-analysis to summarise the evidence from prospective studies of red and processed meat consumption and pancreatic cancer risk.

Methods:

Relevant studies were identified by searching PubMed and EMBASE databases through November 2011. Study-specific results were pooled using a random-effects model.

Results:

Eleven prospective studies, with 6643 pancreatic cancer cases, were included in the meta-analysis. An increase in red meat consumption of 120 g per day was associated with an overall relative risk (RR) of 1.13 (95% confidence interval (CI)=0.93–1.39; P_{heterogeneity}<0.001). Red meat consumption was positively associated with pancreatic cancer risk in men (RR=1.29; 95% CI=1.08–1.53; P_{heterogeneity}=0.28; five studies), but not in women (RR=0.93; 95% CI=0.74–1.16; P_{heterogeneity}=0.21; six studies). The RR of pancreatic cancer for a 50 g per day increase in processed meat consumption was 1.19 (95% CI=1.04–1.36; P_{heterogeneity}=0.46).

Conclusion:

Findings from this meta-analysis indicate that processed meat consumption is positively associated with pancreatic cancer risk. Red meat consumption was associated with an increased risk of pancreatic cancer in men. Further prospective studies are needed to confirm these findings.     

Red and processed meat consumption and risk of ovarian cancer: a dose-response meta-analysis of prospective studies

Background:

During the last decade, the epidemiological evidence on consumption of meat and risk of ovarian cancer has accumulated.

Methods:

We assessed the relationship between red and processed meat consumption and risk of ovarian cancer with a dose-response meta-analysis. Relevant prospective cohort studies were identified by searching the PubMed and EMBASE databases through 21 January 2011, and by reviewing the reference lists of retrieved articles. Study-specific relative risk (RR) estimates were combined using a random-effects model.

Results:

Eight cohort studies were included in the meta-analysis. The summary RR for an intake increment of 100 g per week was 1.02 (95% confidence interval (CI), 0.99–1.04) for red meat and 1.05 (95% CI, 0.98–1.14) for processed meat. For an intake increment of four servings per week, the summary RR of ovarian cancer was 1.07 (95% CI, 0.97–1.19) for red meat (100 g per serving) and 1.07 (95% CI, 0.97–1.17) for processed meat (30 g per serving).

Conclusion:

Results from this dose-response meta-analysis suggest that red and processed meat consumption is not associated with risk of ovarian cancer. Although a lower consumption of red and processed meat may offer protection against other types of cancer, other interventions are needed to reduce the risk of ovarian cancer.     

Fish consumption and the risk of colorectal cancer: the Ohsaki Cohort Study

Background:

Evidence from laboratory and animal studies suggests that high fish consumption may reduce the risk of colorectal cancer, but the results of studies in humans have been inconsistent. The objective of this study was to prospectively examine the association between fish consumption and the risk of colorectal cancer incidence in Japan, where fish is widely consumed.

Methods:

We analysed data from 39 498 men and women registered in the Ohsaki National Health Insurance Cohort Study who were 40–79 years old and free of cancer at the baseline. Fish consumption was assessed at the baseline using a self-administered food frequency questionnaire.

Results:

During 9 years of follow-up, we identified 566 incident cases of colorectal cancer (379 men and 187 women). The hazard ratios and 95% confidence intervals (CIs) for colorectal cancer incidence in the highest quartile of fish consumption compared with the lowest quartile were 1.07 (95% CIs; 0.78–1.46, P-trend=0.43) for men, and 0.96 (95% CIs; 0.61–1.53, P-trend=0.69) for women.

Conclusion:

The results of this prospective cohort study revealed no association between fish consumption and the risk of colorectal cancer.     

Salt intake and gastric cancer risk according to Helicobacter pylori infection, smoking, tumour site and histological type

Background:

Although salt intake is considered a probable risk factor for gastric cancer, relevant studies have provided heterogeneous results, and the magnitude of the association has not been accurately quantified.

Methods:

To quantify gastric cancer risk in relation to dietary salt exposure according to Helicobacter pylori infection status and virulence, smoking, tumour site, and histological type, we evaluated 422 gastric cancer cases and 649 community controls. Salt exposure was estimated in the year before the onset of symptoms through: sodium intake (estimated by a food frequency questionnaire (FFQ)); main food items/groups contributing to dietary sodium intake; visual analogical scale for salt intake preference; use of table salt; and duration of refrigerator ownership.

Results:

Comparing subjects with the highest with those with the lowest salt exposure (3rd vs 1st third), sodium intake (OR=2.01, 95% CI: 1.16–3.46), consumption of food items with high contribution to sodium intake (OR=2.54, 95% CI: 1.56–4.14) and salt intake evaluated by visual analogical scale (OR=1.83, 95% CI: 1.28–2.63) were associated with an increased gastric cancer risk. Subjects owning a refrigerator for >50 years had a lower risk for gastric cancer (OR=0.28, 95% CI: 0.14–0.57). These associations were observed regardless of H. pylori infection status and virulence, smoking, tumour site or histological type.

Conclusion:

Our results support the view that salt intake is an important dietary risk factor for gastric cancer, and confirms the evidence of no differences in risk according to H. pylori infection and virulence, smoking, tumour site and histological type.     

Hepatitis B virus infection is associated with gastric cancer in China: an endemic area of both diseases

Background:

Hepatitis B virus (HBV) infection was demonstrated to be a risk factor of several cancers of the digestive system. In addition, liver cirrhosis, which could possibly result from chronic HBV infection, was associated with a higher risk of gastric cancer. However, the association of HBV infection and gastric cancer has not been investigated.

Methods:

A retrospective case–control study with 580 cases and 580 controls matched for age, sex and year of diagnosis was conducted. The associations between gastric cancer and HBV infection were explored with univariate and multivariate unconditional logistic regression analysis.

Results:

Hepatitis B surface antigen (HBsAg) was positively associated with gastric cancer (AOR (95% CI): 1.49 (1.06–2.10)). This association remained significant in patients without family history of gastric cancer (AOR (95% CI): (1.06–2.11)). For HBsAg-negative population, being anti-HBc positive/anti-HBs negative, which possibly indicated occult HBV infection, was also found to have some associations with gastric cancer. In addition, some synergistic effects between HBV infection and blood type A in gastric cancer were identified.

Conclusions:

The HBV infection was positively related with gastric cancer, especially for patients without family history of gastric cancer. Further prospective studies are warranted to confirm this relationship.     

EBV-associated gastric carcinoma in high- and low-incidence areas for nasopharyngeal carcinoma

Background:

Approximately 10% of gastric carcinomas are associated with Epstein–Barr virus (EBV). The Inuit in Greenland have a high incidence of EBV-associated nasopharyngeal carcinoma.

Methods:

We conducted a population-based case–control study comparing gastric carcinomas in Greenland and in Denmark.

Results:

The prevalence rate of EBV-associated gastric carcinomas was 8.5% in both populations.

Conclusion:

The findings of this study argue against a general susceptibility to EBV-associated carcinomas among the Inuit.     

Inflammation marker and risk of pancreatic cancer: a nested case-control study within the EPIC cohort

Background:

Established risk factors for pancreatic cancer include smoking, long-standing diabetes, high body fatness, and chronic pancreatitis, all of which can be characterised by aspects of inflammatory processes. However, prospective studies investigating the relation between inflammatory markers and pancreatic cancer risk are scarce.

Methods:

We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition, measuring prediagnostic blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble receptors of tumour necrosis factor-α (sTNF-R1, R2) in 455 pancreatic cancer cases and 455 matched controls. Odds ratios (ORs) were estimated using conditional logistic regression models.

Results:

None of the inflammatory markers were significantly associated with risk of pancreatic cancer overall, although a borderline significant association was observed for higher circulating sTNF-R2 (crude OR=1.52 (95% confidence interval (CI) 0.97–2.39), highest vs lowest quartile). In women, however, higher sTNF-R1 levels were significantly associated with risk of pancreatic cancer (crude OR=1.97 (95% CI 1.02–3.79)). For sTNF-R2, risk associations seemed to be stronger for diabetic individuals and those with a higher BMI.

Conclusion:

Prospectively, CRP and IL-6 do not seem to have a role in our study with respect to risk of pancreatic cancer, whereas sTNF-R1 seemed to be a risk factor in women and sTNF-R2 might be a mediator in the risk relationship between overweight and diabetes with pancreatic cancer. Further large prospective studies are needed to clarify the role of proinflammatory proteins and cytokines in the pathogenesis of exocrine pancreatic cancer.     

LINE-1 methylation in leukocyte DNA,interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk

Background:

Aberrant global DNA methylation is shown to increase cancer risk. LINE-1 has been proven a measure of global DNA methylation. The objectives of this study were to assess the association between LINE-1 methylation level and bladder cancer risk and to evaluate effect modification by environmental and genetic factors.

Methods:

Bisulphite-treated leukocyte DNA from 952 cases and 892 hospital controls was used to measure LINE-1 methylation level at four CpG sites by pyrosequencing. Logistic regression model was fitted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Interactions between LINE-1 methylation levels and environmental and genetic factors were assessed.

Results:

The risk of bladder cancer followed a nonlinear association with LINE-1 methylation. Compared with subjects in the middle tertile, the adjusted OR for subjects in the lower and the higher tertiles were 1.26 (95% CI 0.99–1.60, P=0.06) and 1.33 (95% CI 1.05–1.69, P=0.02), respectively. This association significantly increased among individuals homozygous for the major allele of five single-nucleotide polymorphisms located in the phosphatidylethanolamine N-methyltransferase gene (corrected P-interaction<0.05).

Conclusions:

The findings from this large-scale study suggest that both low and high levels of global DNA methylation are associated with the risk of bladder cancer.     

Reproductive factors and risk of oesophageal and gastric cancer in the Million Women Study cohort

Background:

Hormonal factors may influence risk for upper gastrointestinal cancers in women. We examined risk of oesophageal and gastric cancers in relation to reproductive factors in a large UK cohort, the Million Women Study.

Methods:

Among 1 319 409 women aged on average 56 years at recruitment, 1186 incident cancers of the oesophagus and 1194 of the stomach were registered during 11.9 million person-years'' observation. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.

Results:

Risks of both oesophageal and gastric cancer were significantly higher in postmenopausal than in pre- or peri-menopausal women (RRs 1.46, 1.07–2.00 and 1.59, 1.15–2.20, respectively; P⩽0.01 for both); and, among postmenopausal women, risk was higher the younger women were at menopause (RR, 95% CI per 5 years younger at menopause 1.18, 1.05–1.34 for oesophageal cancer and 1.18, 1.04–1.34 for stomach cancer, P_trend=0.01 for both). For factors relating to childbearing, including women''s age at first birth, their number of children, and breastfeeding history, the only significant association was a higher risk of oesophageal cancer in nulliparous, compared with parous, women (RR 1.31, 1.11–1.55; P=0.002). When risks for squamous cell and adenocarcinomas of the oesophagus were compared, most did not differ significantly, but statistical power was limited.

Conclusion:

Both oesophageal and gastric cancer risks appeared to be related to menopausal status and age at menopause, but there was little consistent evidence for associations with factors related to childbearing.     

Identification of macrophage migration inhibitory factor and human neutrophil peptides 1�C3 as potential biomarkers for gastric cancer

Background:

Proteomic methods have the potential to meet the urgent need for better cancer biomarkers. We have used a range of proteomic analyses of serum and tissue from gastric cancer patients and relevant controls to discover biomarkers for gastric cancer.

Methods:

Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI) and antibody arrays were used to compare protein expression in 21 pairs of gastric cancer tissue and adjacent normal mucosa and serum from 51 gastric cancer patients and 29 patients with benign gastric diseases. Expression differences were confirmed by enzyme-linked immunosorbent assay.

Results:

Tissue analysis shows human neutrophil peptides 1–3 (HNPs 1–3) elevated 10-fold (P=0.001) in gastric cancer relative to adjacent normal mucosa. Macrophage migration inhibitory factor (MIF) was increased five-fold (P=1.84 × 10⁻⁷) in the serum of gastric cancer patients relative to individuals with benign gastric disease. The large increase in MIF concentration in serum gives an area under the receiver operating characteristic curve of 0.85.

Conclusions:

Proteomic analyses of serum and tissue indicate that HNPs 1–3 and MIF have potential as biomarkers for gastric cancer. In particular MIF may be useful, either alone or in combination with other markers, for diagnosing and monitoring gastric cancer.     

Height and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial

Background:

The relationship between prostate cancer and height is uncertain.

Methods:

We prospectively examined the association of height with prostate cancer among 34268 men in the prostate, lung, colorectal, and ovarian cancer trial. Anthropometry was assessed at baseline and 2144 incident prostate cancer cases were identified upto 8.9 years of follow-up.

Results:

Overall, tallness was not associated with the risk of prostate cancer or with the risk of non-aggressive disease, but the risk for aggressive prostate cancer tended to be greater in taller men (Gleason score ⩾7 or stage ⩾III; P trend=0.05; relative risk (RR) for 190 cm+ vs ⩽170 cm=1.39, 95% confidence interval (95% CI): 0.96–2.01). This association was largely limited to men below the age of 65 years (P trend=0.008; RR for 190 cm+ vs ⩽170 cm=1.76, 95% CI: 1.06–2.93; P for interaction=0.009), although the number of cases was small and risk estimates were somewhat unstable.

Conclusion:

The results of this large prospective prostate cancer screening trial suggest that tallness is associated with increased risk for younger onset aggressive prostate cancer.     

Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis

Background:

Prostate-specific antigen (PSA) screening has low specificity. Assessment of methylation status in body fluids may complement PSA screening if the test has high specificity.

Method:

The purpose of this study was to conduct a meta-analysis of the sensitivity and specificity for prostate cancer detection of glutathione-s-transferase–π (GSTP1) methylation in body fluids (plasma, serum, whole blood, urine, ejaculate, and prostatic secretions). We conducted a comprehensive literature search on Medline (Pubmed). We included studies if they met all four of the following criteria: (1) measurement of DNA methylation in body fluids; (2) a case-control or case-only design; (3) publication in an English journal; and (4) adult subjects. Reviewers conducted data extraction independently using a standardised protocol. Twenty-two studies were finally included in this paper. Primer sequences and methylation method in each study were summarised and evaluated using meta-analyses. This paper represents a unique cross-disciplinary approach to molecular epidemiology.

Results:

The pooled specificity of GSTP1 promoter methylation measured in plasma, serum, and urine samples from negative-biopsy controls was 0.89 (95% CI, 0.80–0.95). Stratified analyses consistently showed a high specificity across different sample types and methylation methods (include both primer sequences and location). The pooled sensitivity was 0.52 (95% CI, 0.40–0.64).

Conclusions:

The pooled specificity of GSTP1 promoter methylation measures in plasma, serum, and urine was excellent and much higher than the specificity of PSA. The sensitivity of GSTP1 was modest, no higher than that of PSA. These results suggest that measurement of GSTP1 promoter methylation in plasma, serum, or urine samples may complement PSA screening for prostate cancer diagnosis.     

Body mass index and smoking-related lung cancer risk in the Singapore Chinese Health Study

Background:

Smokers with low body mass index (BMI) may be more susceptible to lung cancer.

Methods:

We prospectively examined the association between baseline BMI and lung cancer risk in the Singapore Chinese Health Study, a cohort of 63 257 Chinese enrolled between 1993 and 1998.

Results:

After adjustment for smoking intensity and duration, BMI was inversely associated with risk of lung cancer among current smokers (P for trend=0.0004). Current smokers at different dosage of smoking with low BMI had significantly higher risk for lung cancer than those with high BMI. Hazard ratios (95% confidence intervals) of lung cancer for heavy smokers with BMI of ⩾28, 24–<28, 20–<24, and <20 kg m⁻² were 6.37 (2.10–19.30), 9.01 (5.04–16.10), 8.53 (6.35–11.5), and 11.12 (6.60–18.70), respectively, as compared with nonsmokers. BMI had no modifying effects on lung cancer risk among nonsmokers and former smokers.

Conclusion:

Smokers with lower BMI may experience an enhanced risk of lung cancer. The findings have significant public-health implication given the increase in smoking prevalence in developing countries, where people still have relatively low BMI.