Replication study of SNP associations for colorectal cancer in Hong Kong Chinese

Background:

Recent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC.

Methods:

An association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs.

Results:

Twelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10⁻⁵).

Conclusion:

These results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations.     

Combined analysis of three lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers

Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data‐sets was performed to better define this association. This cohort‐study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair‐wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log‐rank test; p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair‐wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair‐wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program.     

Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians

Genome‐wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS‐identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC‐specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian‐specific) and CRC risk was approximately twofold (highest vs . lowest quintile), and the shape of the dose–response was linear (p _trend = 1.24 × 10^?13 and 3.02 × 10^?14 for overall GRS and Asian‐specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (p _interaction = 0.007). Asian‐specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose–response was linear for CRC‐specific and all‐cause mortality (p _trend = 0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC‐specific and overall survival. We show that GRSs constructed using GWAS‐identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival.     

Association between single nucleotide polymorphisms on chromosome 17q and the risk of prostate cancer in a Chinese population

In European populations, 7 single nucleotide polymorphisms (SNPs) on chromosome 17q, 3 SNPs on 17q12, and 4 SNPs on 17q24.3 were recently identified to be closely related to the risk of prostate cancer by a genome-wide association study. In Japanese populations, the correlation between 2 SNPs on 17q and the risk of prostate cancer and tumor aggressiveness was also confirmed by a large-scale experiment. However, whether 17q is associated with prostate cancer and its clinical manifestations in Chinese populations is still unknown. Therefore, we conducted a case-control study in a northern Chinese population and tested 2 SNPs, rs4430796 and rs1859962, on 17q in 124 prostate cancer patients and 111 controls using polymerase chain reaction-high resolution melting curve (PCR-HRM) combined with sequencing. We analyzed the association of the 2 SNPs with the risk of prostate cancer as well as patients' lifestyles, onset ages, Gleason scores, PSA levels, and pathologic stages. We found a significant difference in the G allele of SNP rs1859962 (P = 0.035, OR = 1.51, 95% CI = 1.03-2.21) but not in the rs4430796 genotype frequency or allele frequency distribution between prostate cancer patients and the controls (P > 0.05). Neither of the SNPs was significantly associated with the onset age, Gleason score, PSA level, pathologic stage, or other clinical indicators of patients with prostate cancer (P > 0.05). Our results show that polymorphism of the G allele of SNP rs1859962 is associated with the risk of prostate cancer in a Chinese population.     

Genetic variants of adiponectin and risk of colorectal cancer

Circulating adiponectin has been associated with lower risk of colorectal cancer (CRC). Genome‐wide association studies have identified several single‐nucleotide polymorphisms (SNPs) associated with adiponectin levels. However, it is unclear whether these SNPs are associated with CRC risk. In addition, previous data on SNPs in the adiponectin pathway and their associations with CRC are inconsistent. Therefore, we examined 19 SNPs in genes related to adiponectin or its receptors and their associations with CRC using logistic regression among 7,020 cases and 7,631 controls drawn from ten studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium. Using data from a subset of two large cohort studies, we also assessed the contribution of individual SNPs and an adiponectin genetic score to plasma adiponectin after accounting for lifestyle factors among 2,217 women and 619 men. We did not find any statistically significant association between the 19 adiponectin‐associated SNPs and CRC risk (multivariable‐adjusted odds ratios ranged from 0.89 to 1.05, all p > 0.05). Each SNP explained less than 2.50% of the variance of plasma adiponectin, and the genetic score collectively accounted for 2.95 and 1.42% of the variability of adiponectin in women and men, respectively, after adjustment for age, body mass index, physical activity, smoking, alcohol consumption, regular use of aspirin or nonsteroidal anti‐inflammatory drug and postmenopausal hormone use. In conclusion, our findings do not support an association between known adiponectin‐related common SNPs and CRC incidence. However, known common SNPs account for only a limited proportion of the interindividual variance in circulating adiponectin. Further work is warranted to investigate the relationship between adiponectin and CRC while accounting for other components in the pathway.     

Genetic investigation of DNA-repair pathway genes PMS2, MLH1, MSH2, MSH6, MUTYH, OGG1 and MTH1 in sporadic colon cancer

Mutations in DNA repair genes have previously been identified as causative factors for hereditary nonpolyposis colon cancer (HNPCC). Recent evidence also supports an association between DNA sequence variation in these genes and sporadic colorectal carcinoma (CRC). Genetic investigation of DNA repair genes PMS2, MLH1, MSH2, MSH6, MUTYH, OGG1 and MTH1, as possible susceptibility factors for sporadic CRC, was done using both a haplotype tagging and a candidate (i.e. coding) single nucleotide polymorphism (SNP) approach. Some 1,068 patients with operated CRC (median age at diagnosis: 59 years) were compared to 738 sex-matched control individuals (median age: 67 years). Haplotype tagging SNPs, previously reported risk variants and all known coding SNPs with a minor allele frequency >0.005 were genotyped in PMS2 (N = 10), MLH1 (N = 11), MSH2 (N = 18), MSH6 (N = 15), MUTYH (N = 7), OGG1 (N = 11) and MTH1 (N = 3). No evidence for an association between CRC and any of the 7 genes was detected, neither with the tagging or coding SNPs nor in a sliding window haplotype analysis (all nominal p-values >0.05). The previously reported risk variants D132H in MLH1 and R154H in OGG1 were not even observed in the German population. Genetic CRC risk factors so far identified in DNA repair genes seem to be rare and population-specific. Their association with the disease could not be replicated in German CRC samples. It remains to be elucidated by more systematic, large-scale experiments whether common variants in the same genes, but present across populations, represent risk factors for sporadic CRC.     

Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer--a finding from Texas lung cancer genome-wide association study

Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value<10(-2), including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to -10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12 214 cases and 47 721 controls, and we found that only rs3181366 (r2=0.69 with the untyped rs2075533) was associated to lung cancer risk (P=0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer.     

Investigation of the colorectal cancer susceptibility region on chromosome 8q24.21 in a large German case-control sample

Human chromosome 8q24.21 has been implicated as a susceptibility region for colorectal cancer (CRC) as a result of genome-wide association and candidate gene studies. To assess the impact of molecular variants at 8q24.21 upon the CRC risk of German individuals and to refine the disease-associated region, a total of 2,713 patients with operated CRC (median age at diagnosis: 63 years) were compared with 2,718 sex-matched control individuals (median age at inclusion: 65 years). Information on microsatellite instability in tumors was available for 901 patients. Association analysis of SNPs rs10505477 and rs6983267 yielded allelic p-values of 1.42 x 10(-7) and 2.57 x 10(-7), respectively. For both polymorphisms, the odds ratio was estimated to be 1.50 (95% CI: 1.29-1.75) under a recessive disease model. The strongest candidate interval, outside of which significance dropped by more than 4 orders of magnitude, was delineated by SNPs rs10505477 and rs7014346 and comprised 17 kb. In a subgroup analysis, the disease association was found to be more pronounced in MSI-stable tumors (odds ratio: 1.71). Our study confirms the role of genetic variation at 8q24.21 as a risk factor for CRC and localizes the corresponding susceptibility gene to a 17 kb candidate region.     

两个单核苷酸多态位点与北方中国人前列腺癌的关联研究

背景与目的:近年来在不同人群的研究中,全基因组关联研究已经发现了许多与前列腺癌(prostate cancer,PCa)风险相关的单核苷酸多态性位点(single nucleotide polymorphisms,SNPs).本文探讨了两个SNPs,即rs17021918 (4q22)与rs 10090154 (8q24)和中国北方汉族人PCa的相关性.方法:采用病例对照的研究方法,本研究入选了124例PCa患者和111例健康对照者,采用聚合酶链反应-高分辨熔解曲线(PCRHRM)技术,并结合测序验证法,对rs17021918(4q22)与rs10090154 (8q24)进行基因型及等位基因频率的分析,并探讨其与确诊时的体重指数(body mass index,BMI)、Gleason评分、血清前列腺特异性抗原(prostate specific antigen,PSA)水平、肿瘤分期及年龄等临床特征之间的联系.结果:在风险等位基因、基因型及分层分析中,rs17021918虽然并未观察到有统计学意义的结果,但风险比(the odds ratio,OR)值多＜1,其中在BMI＞27.5 kg/m2(P=0.056; OR=0.292; 95％CI:0.078～1.095)和PSA浓度＜10.0 ng/mL组(P=0.068;OR=0.467; 95％CI:0.204～1.069),CC基因型携带者可能有较低的PCa发病风险;另外发现,rs10090154的T等位基因携带者与较低的肿瘤分期关联(P=0.012; OR=2.512; 95％CI:1.210～5.214),而在较高的肿瘤分期组,T等位基因携带者与非T等位基因携带者之间差异有统计学意义(P=0.039).结论:Rs17021918的CC基因型携带者可能与中国北方人PCa发病风险负关联;而rs10090154的T等位基因携带者可能与中国北方人PCa肿瘤分期正关联.     

Association of estrogen receptor beta variants and serum levels of estradiol with risk of colorectal cancer: a case control study

ABSTRACT: BACKGROUND: Endogenous estrogens may play a vital role in colorectal tumorigenesis. Estrogen receptor beta is the predominant subtype which mediates the biological effect of estrogens, while loss of expression of estrogen receptor beta has been indicated as a common step in the development of colorectal cancer (CRC). Epidemiological studies have revealed several functional polymorphisms of estrogen receptor beta (ESR2) for cancer risk, but relevant study in CRC is limited, particularly in men. This study aimed to investigate the association of circulating estradiol and variations of ESR2 with CRC risk in men. METHODS: We initiated a case-control study consisting of 390 patients with CRC and 445 healthy controls in men only. We genotyped ESR2 single nucleotide polymorphisms (SNPs) rs1256049 and rs4986938 and measured serum estradiol concentration using chemilluminescence immunoassay. Multivariable logistic regression model was performed to evaluate the associations between these variables and CRC risk. RESULTS: ESR2 rs1256049 CT/TT genotypes were associated with reduced risk of CRC (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5-1.0), while rs4986938 CT/TT genotypes were associated with increased risk of CRC (OR, 1.5, 95% CI, 1.0-2.1). In addition, the CRC risk increased with the number of risk genotypes of these two SNPs in a dose-response manner (Ptrend, 0.003). Specifically, subjects carrying risk genotypes of both SNPs had the highest risk of CRC (OR, 2.0, 95% CI, 1.3-3.3.). Moreover, serum estradiol concentration alone was associated with risk of CRC in men (OR, 1.2, 95% CI, 1.0-1.3). However, individuals presenting both rs4986938 CT/TT genotypes and high level of serum estradiol had a high risk of CRC (OR, 2.3, 95% CI, 1.4-3.9), compared with those presenting CC genotype and low level of serum estradiol. The similar joint results were not observed for SNP rs1256049. CONCLUSIONS: These results suggest that endogenous estrogen and genetic variations in ESR2 may individually, or more likely jointly, affect CRC risk in male Han Chinese population, while larger studies are needed to validate our findings.     

A genetic variant in microRNA target site of TGF-β signaling pathway increases the risk of colorectal cancer in a Chinese population

Evidence shows that single-nucleotide polymorphisms in microRNA (miRNA) target sites can create, destroy, or modify the miRNA/mRNA binding, therefore modulating gene expression and affecting cancer susceptibility. The transforming growth factor-β (TGF-β) signaling pathway plays a pivotal role in tumor initiation and progression. Intriguingly, recent advances of genome-wide association studies have identified multiple risk loci in this pathway to be associated with risk of colorectal cancer (CRC). To test the hypothesis that genetic variants in miRNA target sites in genes of the TGF-β signaling pathway may also be associated with CRC risk, we first systematically scanned the single-nucleotide polymorphisms (SNPs) in genes of TGF-β signaling pathway which potentially affect the miRNA/mRNA bindings. Through a series of filters, we narrowed down these candidates to four SNPs. Then, we conducted a case–control study with 600 CRC patients and 638 controls in Han Chinese population. We observed that compared with A carriers (AA?+?AG), the GG genotype of rs12997:ACVR1 is associated with a significantly higher risk of CRC (OR?=?1.52, 95 % confidence interval (95 % CI)?=?1.04–2.21, P?=?0.031), particularly in nonsmokers with a higher OR of 1.63 (95 % CI?=?1.04–2.55, P?=?0.032). Our study suggested that SNPs in miRNA target sites could contribute to the likelihood of CRC susceptibility and emphasized the important role of polymorphisms at miRNA-regulatory elements in carcinogenesis.     

Body mass index and colorectal cancer risk: A Mendelian randomization study

Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m²) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.     

Two genetic variants in prostate stem cell antigen and gastric cancer susceptibility in a chinese population

Genetic factors play important roles in pathogenesis of human cancer. A recent genome‐wide association study (GWAS) linked two single nucleotide polymorphisms (SNPs) in prostate stem cell antigen (PSCA), rs2294008C>T and rs2976392G>A, to risk of diffuse‐type of gastric cancer in Japanese and Korean populations. We hypothesized that these two SNPs are also associated with risk of gastric cancer in Chinese population. We examined genotypes and haplotypes of PSCA, rs2294008C/T and rs2976392G/A in 716 patients with cardia gastric carcinoma (CGC), 1020 patients with noncardia gastric carcinoma (NCGC), and 1020 controls. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an elevated risk for developing NCGC compared with those without this allele (OR = 1.35, 95% CI = 1.13–1.61). Individuals with at least one copy of the rs2976392A allele (GA or AA genotype) had nonsignificantly increased risk for NCGC compared with those without this allele (OR = 1.20, 95% CI = 1.01–1.43). Stratification analysis showed that the increased risk associated with the SNPs was restricted in female subjects. Moreover, the rs2294008T and rs2976392A allele carriers were predisposed to developing poorly differentiated and high stage NCGC at diagnosis. However, no such association was detected for CGC. In addition, we observed considerably lower allelic and genotype frequencies of these genetic variants in Chinese population compared with Japanese and Korean populations. These findings are in general consistent with previous GWAS and suggest that PSCA may play a role in the development of NCGC in Chinese population. © 2009 Wiley‐Liss, Inc.     

Impact of multiple Alcohol Dehydrogenase gene polymorphisms on risk of laryngeal,esophageal, gastric and colorectal cancers in Chinese Han population

Alcohol intake is positively associated with the risk of upper aerodigestive tract (UADT) cancers; but its effect on gastric or colorectal cancer is controversial. Previous study had identified several single nucleotide polymorphisms (SNPs) of Alcohol Dehydrogenase (ADH) genes associated with UADT cancers in European and Japanese populations. We sought to determine if these SNPs associated with laryngeal, esophageal, gastric or colorectal cancer in Chinese population. We conducted a case-control study among 1577 cases and 1013 healthy controls from northwest China. Five SNPs associated with UADT cancers risk were selected from previous genome-wide association studies and genotyped using Sequenom Mass-ARRAY technology. Odds ratios and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and gender. We identified that the minor alleles of rs1789924 and rs971074 were associated with decreased risk of laryngeal cancer (OR = 0.311; 95% CI = 0.161-0.602; P < 0.001) and esophagus cancer (OR = 0.711; 95% CI = 0.526-0.962; P = 0.027) in allelic model analysis, respectively. In the genetic model analysis, we found the “C/T” genotype of rs1789924 was associated with decreased laryngeal cancer risk in codominant model (P = 0.046) and overdominant model (P = 0.013); the “C/T-T/T” genotype of rs1789924 was associated with reduced risk of laryngeal cancer under dominant model (P = 0.013). Additionally, none of the SNPs was associated with gastric or colorectal cancer in our study. Our data shed new light on the association between ADH SNPs and respiratory and digestive tract cancers susceptibility in the Han Chinese population.     

Estimation of heritability for nine common cancers using data from genome‐wide association studies in Chinese population

The familial aggregation indicated the inheritance of cancer risk. Recent genome‐wide association studies (GWASs) have identified a number of common single‐nucleotide polymorphisms (SNPs). Following heritability analyses have shown that SNPs could explain a moderate amount of variance for different cancer phenotypes among Caucasians. However, little information was available in Chinese population. We performed a genome‐wide complex trait analysis for common cancers at nine anatomical sites in Chinese population (14,629 cancer cases vs. 17,554 controls) and estimated the heritability of these cancers based on the common SNPs. We found that common SNPs explained certain amount of heritability with significance for all nine cancer sites: gastric cancer (20.26%), esophageal squamous cell carcinoma (19.86%), colorectal cancer (16.30%), lung cancer (LC) (15.17%), and epithelial ovarian cancer (13.31%), and a similar heritability around 10% for hepatitis B virus‐related hepatocellular carcinoma, prostate cancer, breast cancer and nasopharyngeal carcinoma. We found that nearly or less than 25% change was shown when removing the regions expanding 250 kb or 500 kb upward and downward of the GWAS‐reported SNPs. We also found strong linear correlations between variance partitioned by each chromosome and chromosomal length only for LC (R² = 0.641, p = 0.001) and esophageal squamous cell cancer (R² = 0.633, p = 0.002), which implied us the complex heterogeneity of cancers. These results indicate polygenic genetic architecture of the nine common cancers in Chinese population. Further efforts should be made to discover the hidden heritability of different cancer types among Chinese.     

Novel colon cancer susceptibility variants identified from a genome‐wide association study in African Americans

Genome‐wide association studies (GWAS) in ethnic/racial minority populations can help to fine‐map previously identified risk regions or discover new risk loci because of the genetic diversity in these populations. We conducted a GWAS of colorectal cancer (CRC) in 6,597 African Americans (1,894 cases and 4,703 controls) (Stage 1) and followed up the most promising markers in a replication set of 2,041 participants of African descent (891 cases and 1,150 controls) (Stage 2). We identified a novel variant, rs56848936 in the gene SYMPK at 19q13.3, associated with colon cancer risk (odds ratio 0.61 for the risk allele G, p = 2.4 × 10^?8). The frequency of the G allele was 0.06 in African Americans, compared to <0.01 in Europeans, Asians and Amerindians in the 1000 Genomes project. In addition, a variant previously identified through fine‐mapping in this GWAS in the region 19q13.1, rs7252505, was confirmed to be more strongly associated with CRC in the African American replication set than the variant originally reported in Europeans (rs10411210). The association between rs7252505 and CRC was of borderline significance (p = 0.05) in a Hispanic population GWAS with 1,611 CRC cases and 4,330 controls. With the three datasets combined, the odds ratio was 0.84 for the risk allele A (95% confidence interval 0.79–0.89, p = 3.7 × 10^?8). This study further highlights the importance of conducting GWAS studies in diverse ancestry populations.     

CASP8 variants D302H and -652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population

Polymorphisms in CASP8 at 2q33.1 have been associated with the risk of developing cancer, specifically, the D302H variant (rs1045485) with breast cancer in the European population and the -652 6N ins/del promoter variant (rs3834129) with multiple tumours including colorectal cancer (CRC) in the Chinese population. We evaluated the relationship between -652 6N ins/del and D302H variants and risk of developing CRC in the UK population by genotyping 4016 cases and 3749 controls. Both variants showed no evidence of an association with risk of developing CRC (P=0.42 and 0.22, respectively). In contrast, the recently identified CRC susceptibility allele rs6983267 mapping to 8q24 was significantly associated with disease risk (P=8.94 x 10(-8)). It is thus very unlikely that variation in CASP8 defined by -652 6N ins/del or D302H influences the risk of CRC in European populations. The implications of our findings both in terms of population-specific effects and publication bias are discussed.     

RPSA Gene Mutants Associated with Risk of Colorectal Cancer among the Chinese Population

The primary aim of this study was to evaluate the relationship of single nucleotide polymorphisms (SNPs) inribosomal protein SA (RPSA) gene with colorectal cancer (CRC). A case-control study including 388 controls and387 patients with CRC was conducted in a Chinese population. Information about socio-demography and livingbehavior factors was collected by a structured questionnaire. Three SNPs (rs2133579, rs2269349, rs7641291)in RPSA gene were genotyped by Illumina SnapShot method. Multiple logistic regression models were used forassessing the joint effects between tea consumption and SNPs on CRC. The subjects with rs2269349 CC genotypehad a decreased risk for CRC (OR=0.60; 95%CI = 0.37-0.99), compared with TT/CT genotype after adjustmentfor covariates. A similar association of rs2269349 with rectal cancer was observed (OR=0.49; 95%CI=0.24-1.00).Further analyses indicated that this SNP could modify the protective effect of tea drinking on CRC. Amongthe subjects with rs2269349 TT/CT or rs2133579 AA/GA, there was a marginal significantly lower risk of CRC(OR and 95%CI: 0.63 and 0.39-1.01 for rs2269349; 0.64 and 0.40-1.02 for rs2133579) in tea-drinking subjects incomparison to non-tea-drinking subjects. Mutants in the RPSA gene might be associated with genetic susceptibilityto CRC and influence the protective effect of tea consumption in the Chinese population.     

Dietary fatty acids and colorectal cancer risk in men: A report from the Shanghai Men's Health Study and a meta‐analysis

Evidence from animal models suggests that dietary fatty acids have both anticancer and tumor‐promoting effects. Whether dietary fatty acids are associated with colorectal cancer (CRC) in humans remains inconclusive. We investigated associations between dietary fatty acids and risk of CRC among 59 986 men who participated in the Shanghai Men's Health Study (SMHS), an ongoing population‐based prospective cohort study. We identified 876 incident CRC cases in the SMHS during a mean follow‐up of 9.8 years. Associations between dietary fatty acid intake and CRC risk were evaluated by Cox proportional hazard regression analyses. Consumption of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) was not significantly associated with CRC risk. Multivariate hazard ratios (HRs) and respective 95% confidence intervals (CIs) for Quartile 4 vs Quartile 1 were 0.92 (0.74‐1.14; P_trend = 0.47) for SFA, 0.95 (0.79‐1.16; P_trend = 0.74) for MUFA and 1.18 (0.95‐1.46; P_trend = 0.21) for PUFA. No significant associations were found for total n‐6 PUFA or total n‐3 PUFA. Additionally, we performed a meta‐analysis to summarize results from the present study and 28 reports from 26 additional cohorts, which supported the overall null association between dietary fatty acid intake and CRC risk among men. Docosahexanoic acid and eicosapentaenoic acid were associated with 11% to 12% reduced risk, and linoleic acid a 19% increased risk, of CRC in the meta‐analysis of combined sexes. In conclusion, this population‐based prospective study and meta‐analysis of cohort studies found little evidence that dietary fatty acid intake was associated with risk of CRC in men.     

Prevalence and spectrum of germline cancer susceptibility gene variants and somatic second hits in colorectal cancer

Colorectal cancer (CRC) is one of the most heritable cancers, and genetic factors play an important role in the increased CRC risk. However, the well-established CRC-risk genes were limited for explaining the increased risk of CRC individuals. Germline mutations in DNA damage repair (DDR) genes have also been reported to be implicated in CRC heritability. Here, we aimed to determine the prevalence and significance of germline DDR and well-established CRC-risk gene variants in CRCs with paired somatic analyses. Next-generation sequencing (NGS) was performed on tumor tissues and paired white blood cells collected from 2160 Chinese patients with CRC using well-designed 381- or 733-cancer gene panel. Germline/somatic variations were identified and assessed for pathogenicity and likely pathogenicity. Of 2160 CRCs, 136 pathogenic germline mutations in 133 patients (133/2160, 6.1%) were identified in 21 genes, including 19 out of 32 examined DDR genes. Compared with non-carriers, individuals with germline variants were prone to a higher level of microsatellite instability (MSI) and tumor mutational burden (TMB), and an earlier age of onset. Somatic sequencing identified second hits in 24/133 (18%) patients with germline variants. Among the mismatch repair (MMR) genes with germline mutations, the second hit significantly increased MSI and TMB, particularly apparent in MSH6. All MMR germline variation carriers further with a second hit were all MSI-H and had an extraordinarily high level of TMB. Collectively, approximately 6.1% of CRC patients carried pathogenic germline variants, and additional somatic second hit increases the genomic instability in CRC, whereas the more clinical significance warrants further study.