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SummaryIntroductionIndigenous people have disproportionally worse health and lower life expectancy than their non-indigenous counterparts in high-income countries. Cancer data for indigenous people are scarce and incidence has not previously been collectively reported in Australia, New Zealand, Canada, and the USA. We aimed to investigate and compare, for the first time, the cancer burden in indigenous populations in these countries. MethodsWe derived incidence data from population-based cancer registries in three states of Australia (Queensland, Western Australia, and the Northern Territory), New Zealand, the province of Alberta in Canada, and the Contract Health Service Delivery Areas of the USA. Summary rates for First Nations and Inuit in Alberta, Canada, were provided directly by Alberta Health Services. We compared age-standardised rates by registry, sex, cancer site, and ethnicity for all incident cancer cases, excluding non-melanoma skin cancers, diagnosed between 2002 and 2006. Standardised rate ratios (SRRs) and 95% CIs were computed to compare the indigenous and non-indigenous populations of each jurisdiction, except for the Alaska Native population, which was compared with the white population from the USA. FindingsWe included 24 815 cases of cancer in indigenous people and 5 685 264 in non-indigenous people from all jurisdictions, not including Alberta, Canada. The overall cancer burden in indigenous populations was substantially lower in the USA except in Alaska, similar or slightly lower in Australia and Canada, and higher in New Zealand compared with their non-indigenous counterparts. Among the most commonly occurring cancers in indigenous men were lung, prostate, and colorectal cancer. In most jurisdictions, breast cancer was the most common cancer in women followed by lung and colorectal cancer. The incidence of lung cancer was higher in indigenous men in all Australian regions, in Alberta, and in US Alaska Natives than in their non-indigenous counterparts. For breast cancer, rates in women were lower in all indigenous populations except in New Zealand (SRR 1·23, CI 95% 1·16–1·32) and Alaska (1·14, 1·01–1·30). Incidence of cervical cancer was higher in indigenous women than in non-indigenous women in most jurisdictions, although the difference was not always statistically significant. InterpretationThere are clear differences in the scale and profile of cancer in indigenous and non-indigenous populations in Australia, New Zealand, Canada, and the USA. Our findings highlight the need for much-improved, targeted programmes of screening, vaccination, and smoking cessation, among other prevention strategies. Governments and researchers need to work in partnership with indigenous communities to improve cancer surveillance in all jurisdictions and facilitate access to cancer data. FundingInternational Agency for Research on Cancer–Australia Fellowship.

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) show promise in colorectal cancer prevention, but there have been concerns about potential toxicity. Pharmacogenetic studies to establish an individual's risk– benefit ratio might allow tailoring of chemoprevention. Key Points Non-steroidal anti-inflammatory drugs (NSAIDs) are effective chemopreventive agents against colorectal neoplasia. NSAID use is associated with a reduced risk of several other types of malignancies, but randomized controlled trials for primary or secondary prevention are still needed. A key mechanism for NSAID efficacy is cyclooxygenase (COX) inhibition and reduced production of prostaglandins. COX2-specific inhibitors (COXibs) might be less toxic to the gastrointestinal tract than NSAIDs that target both COX1 and COX2. However, cardiovascular toxicity associated with COXibs raises concerns. Inherited genetic factors can explain some inter-individual differences in NSAID metabolism and prostaglandin synthesis. Initial epidemiological studies indicate that only in a genetically defined subset of the population will NSAIDs prevent colorectal neoplasia, which suggests pharmacogenetic effects. Pharmacogenetic investigations are expected to help establish the individual risk–benefit ratio for NSAID use and therefore allow tailoring of chemoprevention. In general, a multi-agent, multi-targeted approach to chemoprevention is to be recommended. However, NSAIDs are effective as single agents because they work early in carcinogenesis across multiple pathways. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) show indisputable promise as chemopreventive agents. Possible targets include cancers of the colon, stomach, breast and lung. However, recent studies raise concern about potential cardiovascular toxicity associated with the use of NSAIDs that specifically target the enzyme cyclooxygenase 2. These findings, and others that show that inherited genetic characteristics might determine preventive success, argue for new strategies that are tailored to individual medical history and genetic make-up.

Aims/hypothesis The aims of the study were to evaluate the association between type 2 diabetes and the risk of death from any cancer and specific cancers in East and South Asians. Methods Pooled analyses were conducted of 19 prospective population-based cohorts included in the Asia Cohort Consortium, comprising data from 658,611 East Asians and 112,686 South Asians. HRs were used to compare individuals with diabetes at baseline with those without diabetes for the risk of death from any cancer and from site-specific cancers, including cancers of the oesophagus, stomach, colorectum, colon, rectum, liver, bile duct, pancreas, lung, breast, endometrium, cervix, ovary, prostate, bladder, kidney and thyroid, as well as lymphoma and leukaemia. Results During a mean follow-up of 12.7 years, 37,343 cancer deaths (36,667 in East Asians and 676 in South Asians) were identified. Baseline diabetes status was statistically significantly associated with an increased risk of death from any cancer (HR 1.26; 95% CI 1.21, 1.31). Significant positive associations with diabetes were observed for cancers of the colorectum (HR 1.41; 95% CI 1.26, 1.57), liver (HR 2.05; 95% CI 1.77, 2.38), bile duct (HR 1.41; 95% CI 1.04, 1.92), gallbladder (HR 1.33; 95% CI 1.10, 1.61), pancreas (HR 1.53; 95% CI 1.32, 1.77), breast (HR 1.72; 95% CI 1.34, 2.19), endometrium (HR 2.73; 95% CI 1.53, 4.85), ovary (HR 1.60; 95% CI 1.06, 2.42), prostate (HR 1.41; 95% CI 1.09, 1.82), kidney (HR 1.84; 95% CI 1.28, 2.64) and thyroid (HR 1.99; 95% CI 1.03, 3.86), as well as lymphoma (HR 1.39; 95% CI 1.04, 1.86). Diabetes was not statistically significantly associated with the risk of death from leukaemia and cancers of the bladder, cervix, oesophagus, stomach and lung. Conclusions/interpretation Diabetes was associated with a 26% increased risk of death from any cancer in Asians. The pattern of associations with specific cancers suggests the need for better control (prevention, detection, management) of the growing epidemic of diabetes (as well as obesity), in order to reduce cancer mortality.

ObjectiveTo discover and confirm blood-based colon cancer early-detection markers.DesignWe created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.ResultsIn the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.ConclusionsA panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.

This study presents pooled analyses of the associations between BMI and risk of death in more than 1.1 million people from 19 cohorts in Asia after a mean follow-up of 9.2 years. Underweight was associated with a substantially increased risk of death in all Asian populations. Over the past few decades, there has been a dramatic increase in the prevalence of obesity in many countries. The World Health Organization (WHO) estimates that more than 1 billion adults worldwide are overweight; of these, at least 300 million are obese. 1 A large number of epidemiologic studies have evaluated the associations between body weight and, more often, the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and a wide range of health outcomes. Obesity is associated with multiple chronic diseases, including type 2 diabetes, hypertension, coronary heart disease, stroke, and several . . .

Constipation and laxative use have been hypothesized to increase colorectal cancer (CRC) risk, but existing epidemiologic studies have been inconclusive. To address this issue, the authors prospectively examined the association between CRC incidence and constipation, non-fiber laxative use, and fiber laxative use among 75,214 participants of the VITamins And Lifestyle study. Information on bowel movement frequency as well as average 10-year non-fiber laxative use, fiber laxative use, and constipation was ascertained by means of a questionnaire. Patients were followed from the time of receipt of the baseline questionnaire (2000-2002) until 2008 for CRC incidence, over which time 558 incident CRC cases occurred. Cox proportional hazard models were used to estimate the multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CI). Compared with individuals who used non-fiber laxatives less than once per year, the HRs associated with low (1-4 times per year) and high (≥5 times per year) use were 1.49 (95% CI: 1.04-2.14) and 1.43 (95% CI: 0.82-2.28), respectively (Ptrend=0.05). HRs for CRC were statistically significantly decreased and lowest in individuals who reported using fiber laxatives often (4+ days per week for 4+ years) vs. those who reported no use (HR=0.44; 95% CI: 0.21-0.95), although the trend was not significant (Ptrend=0.19). No statistically significant associations between bowel movement frequency or constipation and CRC risk were observed. Findings from this study suggest that risk for CRC increases with non-fiber laxative use and decreases with fiber laxative use. However, further observational and experimental studies are needed to clarify these relationships before drawing conclusions about the preferred treatment of constipation.

Findings of polymerase chain reaction (PCR) studies of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) and breast cancer vary, making it difficult to determine whether either, both, or neither virus is causally associated with breast cancer. We investigated CMV and EBV in paired samples of breast cancer and normal breast tissue from 70 women using quantitative PCR. A serum sample from each woman was tested for CMV and EBV IgG. To place our results in context, we reviewed the existing literature and performed a meta-analysis of our results together with previous PCR studies of EBV, CMV, and breast cancer. Of the serology samples, 67 of 70 (96%) were EBV IgG positive and 49 of 70 (70%) were CMV IgG positive. QPCR detected EBV in 24 (34%) of the tumour and 9 (13%) of the paired normal specimens and CMV in 0 (0%) of the tumour and 2 (3%) of the paired normal specimens. Our findings, together with earlier results summarised in the meta-analysis, suggest several possibilities: variable findings may be due to limitations of molecular analyses; 'hit and run' oncogenesis may lead to inconsistent results; one or both viruses has a role at a later stage in breast cancer development; infection with multiple viruses increases breast cancer risk; or neither virus has a role. Future studies should focus on ways to investigate these possibilities, and should include comparisons of breast cancer tissue samples with appropriate normal tissue samples.

The occurrence of diabetes has greatly increased in low- and middle-income countries, particularly in Asia, as has the prevalence of overweight and obesity; in European-derived populations, overweight and obesity are established causes of diabetes. The shape of the association of overweight and obesity with diabetes risk and its overall impact have not been adequately studied in Asia. A pooled cross-sectional analysis was conducted to evaluate the association between baseline body mass index (BMI, measured as weight in kg divided by the square of height in m) and self-reported diabetes status in over 900,000 individuals recruited in 18 cohorts from Bangladesh, China, India, Japan, Korea, Singapore and Taiwan. Logistic regression models were fitted to calculate cohort-specific odds ratios (OR) of diabetes for categories of increasing BMI, after adjustment for potential confounding factors. OR were pooled across cohorts using a random-effects meta-analysis. The sex- and age-adjusted prevalence of diabetes was 4.3% in the overall population, ranging from 0.5% to 8.2% across participating cohorts. Using the category 22.5-24.9 Kg/m.sup.2 as reference, the OR for diabetes spanned from 0.58 (95% confidence interval [CI] 0.31, 0.76) for BMI lower than 15.0 kg/m.sup.2 to 2.23 (95% CI 1.86, 2.67) for BMI higher than 34.9 kg/m.sup.2 . The positive association between BMI and diabetes prevalence was present in all cohorts and in all subgroups of the study population, although the association was stronger in individuals below age 50 at baseline (p-value of interaction<0.001), in cohorts from India and Bangladesh (p<0.001), in individuals with low education (p-value 0.02), and in smokers (p-value 0.03); no differences were observed by gender, urban residence, or alcohol drinking. This study estimated the shape and the strength of the association between BMI and prevalence of diabetes in Asian populations and identified patterns of the association by age, country, and other risk factors for diabetes.

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer ( p value range 0.02 to 1.8 × 10 −8 ). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p  < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10 −5 ). In a region on 5p33.15, which includes the coding regions of the TERT - CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10 −4 ). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.

Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest. We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan-accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y. Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary.