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.
Several polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC) in European descendants. We used genome‐wide association study (GWAS) data from 22 702 cases ...and 212 486 controls of Asian ancestry to develop PRSs and validated them in two case‐control studies (1454 Korean and 1736 Chinese). Eleven PRSs were derived using three approaches: GWAS‐identified CRC risk SNPs, CRC risk variants identified through fine‐mapping of known risk loci and genome‐wide risk prediction algorithms. Logistic regression was used to estimate odds ratios (ORs) and area under the curve (AUC). PRS115‐EAS, a PRS with 115 GWAS‐reported risk variants derived from East‐Asian data, validated significantly better than PRS115‐EUR derived from European descendants. In the Korea validation set, OR per SD increase of PRS115‐EAS was 1.63 (95% CI = 1.46‐1.82; AUC = 0.63), compared with OR of 1.44 (95% CI = 1.29‐1.60, AUC = 0.60) for PRS115‐EUR. PRS115‐EAS/EUR derived using meta‐analysis results of both populations slightly improved the AUC to 0.64. Similar but weaker associations were found in the China validation set. Individuals among the highest 5% of PRS115‐EAS/EUR have a 2.52‐fold elevated CRC risk compared with the medium (41‐60th) risk group and have a 12% to 20% risk of developing CRC by age 85. PRSs constructed using results from fine‐mapping and genome‐wide algorithms did not perform as well as PRS115‐EAS and PRS115‐EAS/EUR in risk prediction, possibly due to a small sample size. Our results indicate that CRC PRSs are promising in predicting CRC risk in East Asians and highlights the importance of using population‐specific data to build CRC risk prediction models.
What's new?
Several polygenic risk scores (PRS) have been developed to predict colorectal cancer risk in European‐ancestry populations. Using data from large genome‐wide association studies, here the authors developed and validated PRSs for colorectal cancer risk prediction in East Asians. The PRS derived from this study showed a similar discriminatory ability in classifying cases and controls as that previously reported in European‐ancestry populations. The findings support the utility of PRSs in identifying high‐risk individuals for colorectal cancer prevention in Asians and highlight the importance of using population‐specific data to build colorectal cancer risk prediction models.
Summary Background Population-based cancer survival data, a key indicator for monitoring progress against cancer, are not widely available from countries in Africa, Asia, and Central America. The aim ...of this study is to describe and discuss cancer survival in these regions. Methods Survival analysis was done for 341 658 patients diagnosed with various cancers from 1990 to 2001 and followed up to 2003, from 25 population-based cancer registries in 12 countries in sub-Saharan Africa (The Gambia, Uganda), Central America (Costa Rica), and Asia (China, India, Pakistan, Philippines, Saudi Arabia, Singapore, South Korea, Thailand, Turkey). 5-year age-standardised relative survival (ASRS) and observed survival by clinical extent of disease were determined. Findings For cancers in which prognosis depends on stage at diagnosis, survival was highest in China, South Korea, Singapore, and Turkey and lowest in Uganda and The Gambia. 5-year ASRS ranged from 76–82% for breast cancer, 63–79% for cervical cancer, 71–78% for bladder cancer, and 44–60% for large-bowel cancers in China, Singapore, South Korea, and Turkey. Survival did not exceed 22% for any cancer site in The Gambia; in Uganda, survival did not exceed 13% for any cancer site except breast (46%). Variations in survival correlated with early detection initiatives and level of development of health services. Interpretation The wide variation in cancer survival between regions emphasises the need for urgent investments in improving awareness, population-based cancer registration, early detection programmes, health-services infrastructure, and human resources. Funding Association for International Cancer Research (AICR; St Andrews, UK), Association pour la Recherche sur le Cancer (ARC, Villejuif, France), and the Bill & Melinda Gates Foundation (Seattle, USA).
There is limited evidence on the interaction by alcohol dehydrogenase 2 (ADH1B) (rs1229984) and aldehyde dehydrogenase 2 (ALDH2) (rs671) regarding the associations of alcohol and a methyl diet (low ...folate and high alcohol intake) with cancer risk, partly because of rare polymorphisms in Western populations.
In a case-control study, we estimated the ORs and 95 % CIs to evaluate the associations of ADH1B and ALDH2 genotypes with colorectal cancer (CRC) and the joint association between methyl diets and ADH1B and ALDH2 polymorphisms with CRC risk using logistic regression models.
A hospital-based case-control study.
In total, 1001 CRC cases and 899 cancer-free controls admitted to two university hospitals.
We found that alcohol intake increased the risk of CRC; OR (95 % CI) was 2·02 (1·41, 2·87) for ≥60 g/d drinkers compared with non-drinkers (Ptrend < 0·001). The associations for two polymorphisms with CRC were not statistically significant. However, we found a potential interaction of ALDH2 with methyl diets and CRC. We observed a 9·08-fold (95 % CI 1·93, 42·60) higher risk of CRC for low-methyl diets compared with high-methyl diets among individuals with an A allele of ALDH2, but the association was not apparent among those with ALDH2 GG (Pinteraction = 0·02).
Our data support the evidence that gene-methyl diet interactions may be involved in CRC risk in East Asian populations, showing that a low-methyl diet increased the risk of CRC among individuals with an A allele of ALDH2.
Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.
We performed a genome-wide association study (GWAS) of ...colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.
An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at
× 10
in Asians (
per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (
= 7.7 × 10
). Of the remaining 59 variants, 12 showed an association at
< 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at
< 5 × 10
and two variants with an association near the genome-wide significance level (rs60911071,
= 5.8 × 10
; rs62558833,
= 7.5 × 10
) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.
In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.
Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.
Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)—nearly one third of these loci were initially associated with CRC in studies ...conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.
We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.
A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10–8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%–75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.
We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for ...cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population‐based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2); normal (18.5‐22.9 kg/m2); overweight (23‐24.9 kg/m2); and obese (25+ kg/m2). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 CI 1.02‐1.38 for males, HR 1.30 1.14‐1.49 for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.
What's new?
In biliary tract cancer, obesity is considered a probable risk factor while cholelithiasis is an established risk factor. Although obesity is also an established risk factor for cholelithiasis, previous studies of obesity and biliary tract cancer have not fully accounted for cholelithiasis. Here, the authors conducted a pooled analysis of 905 530 subjects from 21 population‐based cohort studies participating in the Asia Cohort Consortium. Results confirmed the association of body mass index with biliary tract cancer risk in Asians. Moreover, while obesity affected biliary tract cancer risk through symptomatic cholelithiasis, it could also increase biliary tract cancer risk without cholelithiasis.
Background: Total or red meat intake has been shown to be associated with a higher risk of mortality in Western populations, but little is known of the risks in Asian populations.Objective: We ...examined temporal trends in meat consumption and associations between meat intake and all-cause and cause-specific mortality in Asia.Design: We used ecological data from the United Nations to compare country-specific meat consumption. Separately, 8 Asian prospective cohort studies in Bangladesh, China, Japan, Korea, and Taiwan consisting of 112,310 men and 184,411 women were followed for 6.6 to 15.6 y with 24,283 all-cause, 9558 cancer, and 6373 cardiovascular disease (CVD) deaths. We estimated the study-specific HRs and 95% CIs by using a Cox regression model and pooled them by using a random-effects model.Results: Red meat consumption was substantially lower in the Asian countries than in the United States. Fish and seafood consumption was higher in Japan and Korea than in the United States. Our pooled analysis found no association between intake of total meat (red meat, poultry, and fish/seafood) and risks of all-cause, CVD, or cancer mortality among men and women; HRs (95% CIs) for all-cause mortality from a comparison of the highest with the lowest quartile were 1.02 (0.91, 1.15) in men and 0.93 (0.86, 1.01) in women.Conclusions: Ecological data indicate an increase in meat intake in Asian countries; however, our pooled analysis did not provide evidence of a higher risk of mortality for total meat intake and provided evidence of an inverse association with red meat, poultry, and fish/seafood. Red meat intake was inversely associated with CVD mortality in men and with cancer mortality in women in Asian countries.
IMPORTANCE: Understanding birth cohort–specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking ...across Asian populations. OBJECTIVES: To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations. DESIGN, SETTING, AND PARTICIPANTS: This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India. EXPOSURES: Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking. MAIN OUTCOMES AND MEASURES: Country or region and birth cohort–specific mortality and the population attributable risk for deaths from all causes and from lung cancer. RESULTS: Of 1 002 258 participants (51.1% women and 48.9% men; mean SD age at baseline, 54.6 10.4 years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions. CONCLUSIONS AND RELEVANCE: In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.
The etiology of colorectal cancer is not fully understood.
Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic ...prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis.
Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk Benjamini-Hochberg FDR (BH-FDR) < 0.05 in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60-2.36, P = 2.6 × 10-11; OREUR: 1.01, 95% CI, 0.99-1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer.
This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data.
The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.
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