Association studies on 11 published colorectal cancer risk loci

Background:

Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort.

Methods:

The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype–phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed.

Results:

Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q23.1, 16q22.1, 19q13.1 and 20p12.3 showed weak trends but somehow similar to what was previously published. The loci 9p24 and 14q22.2 could not be confirmed. We show a higher number of risk alleles in affected individuals compared to controls. Four statistically significant genotype–phenotype associations were found; the G allele of rs6983267 was associated to older age, the G allele of rs1075668 was associated with a younger age and sporadic cases, and the T allele of rs10411210 was associated with younger age.

Conclusions:

Our study, using a Swedish population, supports most genetic variants published in GWAS. More studies are needed to validate the genotype–phenotype correlations.     

Using linkage studies combined with whole-exome sequencing to identify novel candidate genes for familial colorectal cancer

Colorectal cancer (CRC) is a complex disorder for which the majority of the underlying germline predisposition factors remain still unidentified. Here, we combined whole-exome sequencing (WES) and linkage analysis in families with multiple relatives affected by CRC to identify candidate genes harboring rare variants with potential high-penetrance effects. Forty-seven affected subjects from 18 extended CRC families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. Suggestive linkage peaks were identified on chromosomes 1q22–q24.2 (maxSNP = rs2134095; LODlinear = 2.38, LODexp = 2.196), 7q31.2–q34 (maxSNP = rs6953296; LODlinear = 2.197, LODexp = 2.149) and 10q21.2–q23.1 (maxSNP = rs1904589; LODlinear = 1.445, LODexp = 2.195). These linkage signals were replicated in 10 independent sets of random markers from each of these regions. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 89 rare variants predicted to be deleterious from 78 genes under the linkage intervals. This analysis showed significant segregation of rare variants with CRC in 18 genes (weighted p-value > 0.0028). Protein network analysis and functional evaluation were used to suggest a plausible candidate gene for germline CRC predisposition. Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data. This approach can be used with already available NGS data from families with several sequenced members to further identify candidate genes involved germline predisposition to disease. This approach resulted in one candidate gene associated with increased risk of CRC but needs evidence from further studies.     

Genome‐wide association study and meta‐analysis in Northern European populations replicate multiple colorectal cancer risk loci

Genome‐wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome‐wide association study in 1,701 CRC cases and 14,082 cancer‐free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single‐nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10⁻⁴; OR, 1.14; 95% CI, 1.06–1.23), and it was genome‐wide significant in combined analysis (p = 1.50 × 10⁻⁹; OR, 1.12; 95% CI, 1.08–1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.     

MTHFR基因多态和饮酒习惯与结直肠癌易感相关性的研究

目的:探讨亚甲基四氢叶酸还原酶(MTHFR)与结直肠癌(CRC)风险的关系。方法:进行了以医院为基础的结直肠癌病例对照研究(结直肠癌新发病例300例,对照300例)。对叶酸代谢相关基因MTHFRC677T和A1298C多态性进行了检测,并与结直肠癌风险关联进行了分析。结果:未观察到MTH-FR677和1298多态单独对CRC发生的影响,但发现MTHFR-677CT/1298AC组合型发生结直肠癌的风险增加,OR值为2.32(95%CI,1.10～4.92,P=0.027)。未发现MTHFR单倍型和双体型基因与CRC的风险之间存在统计学的显著关联。MTHFRC677T和A1298C基因与吸烟程度之间存在交互作用(似然比检验,P=0.002,P=0.001),在吸烟<16包年者中,MTHFR-677T等位基因患结直肠癌的风险增加2.09(95%CI,1.07～4.04),而在吸烟≥16包年者中,MTHFR-1298AA基因型患结直肠癌的风险明显下降,OR值为0.37(95%CI,0.17～0.80)。MTHFRC677T多态与饮酒之间存在交互作用(似然比检验,P=0.000)。结论:MTHFR-677CT/1298AC组合型基因是CRC的危险因素,MTHFR与吸烟、饮酒之间存在一定的交互作用。     

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (P_interaction < 5 × 10⁻⁸). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10⁻⁷). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (P_interaction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10⁻⁶). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.     

Genome-wide association study identifies two new susceptibility loci for colorectal cancer at 5q23.3 and 17q12 in Han Chinese

Genome-wide association studies (GWAS) have reported a number of loci harboring common variants that influence risk of colorectal cancer (CRC) in European descent. But all the SNPs identified explained a small fraction of total heritability. To identify more genetic factors that modify the risk of CRC, especially Chinese Han specific, we conducted a three-stage GWAS including a screening stage (932 CRC cases and 966 controls) and two independent validations (Stage 2: 1,759 CRC cases and 1,875 controls; Stage 3: 943 CRC cases and 1,838 controls). In the combined analyses, we discovered two novel loci associated with CRC: rs12522693 at 5q23.3 (CDC42SE2-CHSY3, OR = 1.31, P = 2.08 × 10⁻⁸) and rs17836917 at 17q12 (ASIC2-CCL2, OR = 0.75, P = 4.55 × 10⁻⁸). Additionally, we confirmed two previously reported risk loci, rs6983267 at 8q24.21 (OR = 1.17, P = 7.17 × 10⁻⁷) and rs10795668 at 10p14 (OR = 0.86, P = 2.96 × 10⁻⁶) in our cohorts. These results bring further insights into the CRC susceptibility and advance our understanding on etiology of CRC.     

DNA损伤修复基因XRCC3 Thr241Met多态与肺癌易感性关系的Meta分析

目的:探讨DNA损伤修复基因X射线交叉互补修复基因3(XRCC3)Thr241Met多态性与肺癌易感性的关系。方法:查找中国医学文献数据库和PubMed,以得到XRCC3基因Thr241Met多态与肺癌易感性关系的病例-对照研究,根据纳入和排除标准筛选符合条件的研究进行Meta分析,合并XRCC3基因Thr241Met多态与肺癌易感性关系的OR值,然后进行亚组分析、敏感性分析和文献的发表偏倚检验。结果:本次Meta分析共纳入13篇文献,累计病例2 986例,对照4 495例,显性模型下TM+MM基因型相对于TT(TM=Thr/Met)基因型OR值为0.96(95%CI为0.86~1.06),差异无统计学意义。结论:尚无足够证据证明XRCC3基因Thr241Met多态同肺癌易感性有关。     

DNA修复基因XPD XPC XRCC4基因多态性与结直肠癌易感性的关联性研究

  目的  探讨DNA修复基因XPD rs13181（codon751A/C,Lys751Gln）、rs238406（codon156C/A,Arg156Arg）、XPC rs2279017（i11C/A）和XRCC4 rs3734091（codon247T/C,Ala247Ser）的单核苷酸多态性与结直肠癌易感性的关系。  方法  采用TaqMan技术对2013年4月至2016年1月北京肿瘤医院收治的338例结直肠癌患者（病例组）和315例健康者（对照组）进行多态位点基因型的检测。  结果  XPD rs13181基因型GT和等位基因G增加个体结直肠癌的发病风险（GT>TT,adjusted OR=1.69,95%CI:1.15~2.47,P=0.007;G>T,adjusted OR=1.77,95%CI:1.19~2.64,P=0.005）;XRCC4 rs3734091基因型GT和等位基因T增加个体结直肠癌的易感性（GT>GG,adjusted OR=9.02,95%CI:5.61~14.50,P＜0.001;T>G,adjusted OR=4.06,95%CI:2.49~6.61,P＜0.001）;XPD rs13181和rs238406的单倍体型GT显著降低结直肠癌的发病风险（adjusted OR=0.39,95%CI:0.18~0.85,P=0.018）。XPCrs2279017等位基因G和XRCC4 rs3734091等位基因T的联合效应（adjusted OR=28.43,95%CI:6.85~117.95,P＜0.001）以及XPD rs13181等位基因G和XRCC4 rs3734091等位基因T的联合效应（adjusted OR=10.24,95%CI:4.69~22.35,P＜0.001）显著增加个体结直肠癌的易感性。  结论  XPD rs13181和XRCC4 rs3734091位点的多态性与结直肠癌的易感性相关。      

Genetic variants in SLC22A3 contribute to the susceptibility to colorectal cancer

Previous a genome-wide association study (GWAS) of colorectal cancer in Japanese population has identified a risk region at the chromosome 6q26-q27 associated with colorectal cancer risk. However, the causal gene at this locus remained unclear. In our study, we enrolled a total of 14 candidate functional single nucleotide polymorphisms (SNPs) at 6q26-q27 (318 kb), and then genotyped them by TaqMan method in a Chinese population including 1,147 colorectal cancer cases and 1,203 controls. Among that, 5 SNPs were identified statistical association with colorectal cancer risk by logistic regression analysis. Of which, SNP rs420038 G > A in SLC22A3 was related to decreased risk of colorectal cancer (adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.67–0.94, p = 0.007), and also associated with lower expression of SLC22A3 (p = 0.040) using expression quantitative trait loci (eQTL) analysis. Moreover, by the luciferase assays, we found that compared to the G allele of rs420038, the A allele could suppress the activity of the promoter in SLC22A3. Furthermore, the expression of SLC22A3 was significantly higher in colorectal cancer tissues than that in paired normal tissues (p < 0.001). Meanwhile, the phenotypes of proliferation, migration, invasion, cell cycle and apoptosis of colorectal cancer cell were significantly affected by SLC22A3 in vitro. Our results revealed a novel susceptible locus, rs420038 in SLC22A3, which may be involved in colorectal cancer development and progression.     

Macronutrients and colorectal cancer: a Swiss case-control study.

BACKGROUND: A role of energy and various nutrients, including protein, sugar, saturated and unsaturated fats, in colorectal cancer risk has been suggested, but should be better defined. PATIENTS AND METHODS: The association between dietary intake of various macronutrients and colorectal cancer risk was analysed using data from a case-control study conducted between 1992 and 2000 in the Swiss Canton of Vaud. The study comprised 286 case subjects (174 males, 112 females; median age 65 years) with incident, histologically confirmed colon (n = 149) or rectal (n = 137) cancer, and 550 control subjects (269 males, 281 females; median age 59 years) admitted to the same University Hospital for a wide spectrum of acute non-neoplastic conditions. Dietary habits were investigated using a validated food frequency questionnaire, including questions on 79 foods or recipes and on individual fat intake pattern. Multivariate odds ratios (OR) were obtained after allowance for age, sex, education, physical activity and energy intake. RESULTS: The risk of colon and rectal cancer increased with total energy intake (OR in highest and lowest tertile, 2.0 and 2.2, respectively). There was no significant relation with starches or proteins, a significant inverse relation with sugars (OR for the highest tertile, 0.5), a direct trend in risk of borderline significance for saturated fats (OR = 1.4 for the highest tertile), and significant inverse trends for monounsaturated (OR = 0.6) and polyunsaturated fats (OR = 0.6). CONCLUSIONS: These findings confirm that energy intake is directly related to colorectal cancer risk, and that different types of fat may have different roles in colorectal carcinogenesis.     

SULT1A1 genotype and susceptibility to colorectal cancer

Several procarcinogens that are present in cooked red meat and tobacco smoke are substrates for sulfotransferase 1A1 (SULT1A1). The association between environmental exposures and colorectal cancer risk may be modified by individual differences in the metabolism. Thus, we investigated the effect of a common polymorphism in the SULT1A1 gene associated with decreased enzyme activity on the susceptibility to colorectal cancer in a population-based case-control study. Patients (505) and 604 age- and sex-matched controls provided detailed risk factor information and were genotyped for SULT1A1 G638A using a fluorescence-based melting curve analysis method. Multivariate logistic regression analysis was used to estimate colorectal cancer risk associated with environmental exposures by SULT1A1 genotype. SULT1A1 genotype was not an independent risk factor for colorectal cancer. Risk of colorectal cancer associated with frequent consumption of red meat was significantly elevated among carriers of the SULT1A1*2 allele but not increased among subjects with the SULT1A1*1/*1 genotype (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-4.1 and OR 1.0, 95% CI 0.5-2.1, respectively). Colorectal cancer risk associated with 30+ pack-years of active smoking was higher among carriers of the SULT1A1*2 allele (OR 1.7, 95% CI 1.0-3.2) than among individuals with the SULT1A1*1/*1 genotype (OR 1.1, 95% CI 0.6-2.1). Our results do not support a main effect of SULT1A1 genotype with regard to colorectal cancer but suggest that individuals with the low activity SULT1A1*2 allele may be at higher risk following carcinogen exposure than those with the SULT1A1*1/*1 genotype.     

散发性大肠腺癌与谷胱甘肽转硫酶M1、T1基因型的关系

 目的　探讨中国浙江汉族人群散发性大肠腺癌（SCRAC）易感性与谷胱甘肽转硫酶（GST）M1、T1基因型及烟酒嗜好的关系。方法　应用多重聚合酶链反应技术检测118例SCRAC患者和140例健康对照的GSTM1和GSTT1基因型，采用Logistic回归分析GSTM1-、GSTT1-基因型及烟酒嗜好与SCRAC的相关性。结果　GSTM1-和GSTT1-基因型能增加SCRAC的易感性（OR＝1.711，95 % CI：1.043～2.805；OR＝1.734，95 % CI：1.057～2.843），而烟酒嗜好对SCRAC的易感性无影响（OR＝0.584，95 % CI：0.356～0.958；OR＝0.378，95 % CI：0.217～0.657）；根据SCRAC临床特征进一步分层分析，发现GSTM1-和GSTT1-基因型均与年龄因素无关（P＞0.05）；GSTM1-基因型在远端SCRAC（P＝0.021）、Duke C期SCRAC（P＝0.003）及低分化SCRAC（P＝0.020）中的分布频率均明显增高；GSTT1-基因型则仅在Duke C期SCRAC中明显增高（P＝0.041），而与SCRAC的部位及组织分化程度无关（P＞0.05）。另发现GSTM1-／GSTT1-纯合子基因型在SCRAC患者中明显增高（P ＝0.023）。结论　GST基因型与中国浙江汉族人群SCRAC明显相关， GSTM1-和GSTT1-基因型能增加SCRAC的易感性，而烟酒嗜好对SCRAC的易感性无影响。     

Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with nonsmall cell lung cancer survival

The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79–0.94, p = 0.0007), 1.31 (1.16–1.47, p = 6.0 × 10⁻⁵) and 1.27 (1.12–1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (p_trend < 0.0001 for OS and p_trend < 0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes.     

Subsite-specific risk factors for colorectal cancer: a hospital-based case-control study in Japan

To investigate the subsite-specific risk factors for colorectal cancer, we conducted a case-control study, using a common questionnaire which inquired about general lifestyles over the past five years (1988–92), at the Aichi Cancer Center Hospital, Nagoya, Japan. This study compared 432 patients with histopathologically diagnosed colorectal cancer (94 proximal colon [cecum, ascending colon, transverse colon]; 137 distal colon [descending colon, sigmoid colon]; 201 rectum [rectosigmoid, rectum]); and 31,782 first-visit outpatient controls who were free from cancer. In both genders, habitual smoking selectively increased the risk for rectum cancer. Soft or loose feces increased the risk for all subsites of colorectal cancer, particularly in female cancer (odds ratio [OR]=4.5). Among female dietary habits, Japanese-style foods decreased the risk factors for distal colon cancer, but increased the risk for proximal colon cancer. These results suggested that the risk factors for colorectal cancer differ by subsite among such a low-risk population as the Japanese. It is suggested also that irritable bowel (soft or loose feces) might be associated with distal subsites of colorectal cancer, independently or combined with habitual smoking. Cancer Causes and Control 1995, 6, 14–22.Drs Inoue and Tajima, Ms Hirose, and Drs Hamajima and Takezaki are with the Division of Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. Authors are also affiliated with the Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan (Drs Hirai and Kato), and the Department of Preventive Medicine, Nagoya University School of Medicine, Nagoya, Japan (Drs Inoue and Ohno). Address correspondence to Dr Inoue, Division of Epidemiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Japan, 464. This study was funded in part by a Grant-in-Aid for Cancer Research (4-2) and the Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare, Japan.     

Effects of common genetic variants associated with colorectal cancer risk on survival outcomes after diagnosis: A large population-based cohort study

Genome-wide association studies have thus far identified 130 genetic variants linked to colorectal cancer (CRC) risk (r² < 0.2). Given their implication in disease causation, and thus plausible biologically effects on cancer-relevant biological pathways, we investigated whether these variants are associated with CRC prognosis and also whether they might provide predictive value for survival outcome. We conducted the analysis in a well-characterized population-based study of 5,675 patients after CRC diagnosis in Scotland. None of the genetic risk variants were associated with either overall survival (OS) or CRC-specific survival. Next, we combined the variants in a polygenic risk score, but again we observed no association between survival outcome and overall genetic susceptibility to CRC risk—as defined by common genetic variants (OS: hazard ratio = 1.00, 95% confidence interval = 0.96–1.05). Furthermore, we found no incremental increase in the discriminative performance when adding these genetic variants to the baseline CRC-survival predictive model of age, sex and stage at diagnosis. Given that our study is well-powered (>0.88) to detect effects on survival for 74% of the variants, we conclude that effects of common variants associated with CRC risk which have been identified to date are unlikely to have clinically relevant effect on survival outcomes for patients diagnosed with CRC.     

Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer

The ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome-wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09–1.36 and p = 0.0003], 0.82 (0.74–0.91 and p = 0.0002) and 1.21 (1.10–1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.     

细胞色素P450 2C19基因多态性与结直肠癌关系的对照研究

目的:研究细胞色素P4502C19(CYP2C19)基因多态性与结直肠癌发生的关系。方法:对117例结直肠癌患者和109名对照人群进行病例对照研究,采用PCR-RFLP方法检测CYP2C19基因型。结果:纯合子强代谢型(homEM)、杂合子强代谢型(hetEM)和弱代谢型(PM)分布频度在结肠癌组(38.7%、45.2%和16.1%)、直肠癌组(34.5%、52.7%和12.7%)和对照组(36.7%、44.0%和19.3%)间差异无统计学意义,P>0.05;在结肠癌和直肠癌组,PM型经性别和年龄调整后的OR值分别为0.693(95%CI:0.266～1.807,P=0.454)和0.757(95%CI:0.263～2.184,P=0.607),差异无统计学意义。结论:CYP2C19基因多态性与结直肠癌发生的危险性无直接关系。     

叶酸代谢酶基因多态与结直肠癌易感性的关系

目的 研究叶酸代谢酶基因多态MTHFRC677T、MTHFRA1298C、MTRA2756G和MTRRA66G及其联合作用与结直肠癌（CRC）易感性的关系。方法 采用聚合酶链-限制性片段长度多态性方法,检测140例CRC患者和343例正常对照者的叶酸代谢酶基因多态,采用非条件Logistic回归模型和似然比检验,分析各多态及其联合作用与CRC的关系。结果 MTR2756G等位基因携带者患CRC的风险是野生型纯合子（AA）的2倍（95％Cl为1．22～3．40）。与同时是MTHFR1298AA和MTR2756AA基因型者相比,同时是MTHFR1298AA和MTR2756AG／GG基因型者患CRC的风险显著升高（OR=2．57,95％C／为1．42～4．65）,两者之间存在联合作用（P=0．04）。结论 MTR2756G等位基因可能是CRC的危险因素,MTHFRA1298C和MTRA2756G之间存在联合作用。