转化生长因子β1基因多态性与结直肠癌的相关性分析

目的分析转化生长因子β1(TGF-β1)基因多态性与结直肠癌的相关性。方法选取2008年1月至2013年1月间诊治的109例结直肠癌患者为观察组,120例健康体检者作为对照组。分析对比两组TGF-β1基因多态性及其与结直肠癌的相关性。结果两组TGF-β1 869C及869T等位基因频率差异无统计学意义(P>0.05)。观察组患者TGF-β1的509T等位基因频率显著高于对照组(χ~2=6.109,P=0.013)。Logistic回归分析显示,携带TGF-β1(509T)基因是发生结直肠癌的独立危险因素(OR=3.512,95%CI为2.136~5.641)。结论 TGF-β1 509基因与结直肠癌发病相关,其T等位基因可能是结直肠癌发病的危险因素。     

Meta-analysis of the association between GSTM1 and GSTT1 gene polymorphisms and cervical cancer

Aim: We conducted a meta-analysis to analyze the influence of GSTM1 and GSTT1 gene polymorphisms on cervical cancer risk, and explore gene-environment interactions. Methods: Identification of relevant studies was carried out through a search of Medline and the EMbase up to Oct. 2011. All case-control studies that investigated the association between GSTM1 and GSTT1 gene polymorphisms and risk of cervical cancer were included. The pooled odds ratio (OR) was used for analyses of results and the corresponding 95% confidence intervals (CI) were estimated. Results: A total of 21 case-control studies were included in the meta-analysis of GSTM1 (2,378 cases and 2,639 controls) and GSTT1 (1,229 cases and 1,223 controls) genotypes. The overall results showed that the GSTM1 null was related to an increased risk of cervical cancer (OR=1.50, 95% CI=1.21-1.85). Subgroup analysis were performed based on smoking and ethnicity. Our results showed that smokers with null GSTM1 genotype had a moderate increased risk of cervical cancer (OR=1.85, 95% CI=1.07-3.20). For the ethnicity stratification, moderate significantly increased risk of null GSTM1 genotype was found in Chinese (OR=2.12, 95% CI=1.43-3.15) and Indian populations (OR=2.07, 95% CI=1.49-2.88), but no increased risk was noted in others. Conclusion: This meta-analysis provided strong evidence that the GSTM1 genotype is associated with the development of cervical cancer, especially in smokers, and Chinese and Indian populations. However, no association was found for GSTT1 null genotype carriers.     

GSTM1 null polymorphisms and oral cancer risk: a meta-analysis

Many studies have examined the association between the GSTM1 null gene polymorphism and oral cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The PubMed and Embase databases were searched for case–control studies published up to May 2013. Data were extracted and pooled odds ratio (OR) with 95 % confidence intervals (CI) were calculated. Ultimately, 39 studies, comprising of 4,704 oral cancer cases and 7,090 controls, were included. Overall, for null versus present, the pooled OR was 1.29 (95 % CI?=?1.20–1.40), and the heterogeneity was found in all studies. In the stratified analysis by ethnicity, significant risks were found among Asians (OR?=?1.39, 95 % CI?=?1.27–1.53; P?=?0.000 for heterogeneity), but not in Caucasians (OR?=?0.99, 95 % CI?=?0.83–1.18; P?=?0.677 for heterogeneity). In conclusion, this meta-analysis demonstrates that the GSTM1 null gene polymorphism may be an increased risk of oral cancer in Asians but not in Caucasians.     

Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking.

We investigated CYP1A1*2A, CYP1A1*2C, CYP1A2*1C, CYP1A2*1F, GSTM1 and NAT2 gene polymorphisms, involving enzymes which metabolize many carcinogens, with reference to colorectal cancer risk. The distribution of these genotypes was not associated with risk overall. However, the CYP1A1*2A T/C genotype showed a significant association with colorectal cancer risk in never-smokers (odds ratio [OR], 3.06; 95% confidence interval [95% CI], 1.11-8.40; p = 0.030). The risk of the NAT2 rapid genotype in never-smokers was also statistically significantly increased (OR, 5.38; 95%CI, 1.80-16.1; p = 0.003). Furthermore, the joint effects of NAT2 rapid plus other genotypes were associated with colorectal cancer overall (OR, 3.12; 95%CI, 1.15-8.51; p = 0.026, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, OR, 3.25; 95%CI, 1.09-9.74; p = 0.035, for NAT2 rapid plus CYP1A2*1C G/G, and OR, 4.20; 95%CI, 1.09-16.1; p = 0.037, for NAT2 rapid plus GSTM1 null, respectively). In never-smokers, the joint effects of NAT2 rapid plus other genotypes were remarkable (OR, 15.9; 95%CI, 1.87-135.8; p = 0.011, for NAT2 rapid plus combined CYP1A1*2A T/C and C/C, OR, 5.71; 95%CI, 1.49-21.9; p = 0.011, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, and OR, 9.14; 95%CI, 2.05-40.7; p = 0.004, for NAT2 rapid plus CYP1A2*1F A/A, respectively). The joint effect of CYP1A2*1F A/A plus CYP1A2*1C G/G genotypes was also increased in never-smokers (OR, 6.16; 95%CI, 1.26-30.1; p = 0.025). Our findings suggest that the CYP1A1*2A T/C and NAT2 rapid genotypes is associated with colorectal cancer susceptibility without smoking exposure. These results also indicate that the NAT2 in combination with CYP1A1*2C, CYP1A2*1C, or GSTM1 genotypes may strongly confer susceptibility to colorectal cancer. In particular, the combination of NAT2 plus CYP1A1*2A, CYP1A1*2C, or CYP1A2*1F genotypes, and that of CYP1A2*1F plus CYP1A2*1C genotype may define a group of persons who are genetically susceptible to colorectal cancer in never smokers.     

Significant associations between GSTM1/GSTT1 polymorphisms and nasopharyngeal cancer risk

Glutathione S-transferases play a critical role in the detoxification and elimination of electrophilic carcinogens by conjugating them to glutathione. Homozygous deletions of GSTM1 and GSTT1 have been suggested as risk factors for some cancers, including colorectal, pancreatic, and esophageal cancers. Results of previous individual studies published to estimate the associations between GSTM1/GSTT1 polymorphisms and nasopharyngeal cancer (NPC) risk remained controversial. Thus, we carried out a meta-analysis by pooling the odds ratios (ORs) with corresponding 95 % confidence intervals (95 % CIs) of all currently available case–control studies to shed some light on the contradictory finding. A comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases up to October 20, 2012 was performed to identify eligible studies. A total of 15 separate publications involving 2,226 NPC cases and 3,339 controls were finally included into this meta-analysis. The meta-analysis of total studies showed that the null genotypes of GSTM1 and GSTT1 were both significantly associated with increased risk of NPC (for GSTM1: OR?=?1.54, 95 % CI 1.28–1.86, P _OR?<?0.001; for GSTT1: OR?=?2.25, 95 % CI 1.50–3.36, P _OR?<?0.001). Subgroup analysis by ethnicity suggested that carriers of both GSTM1 and GSTT1 null genotypes in Asians were more susceptible to NPC. Additionally, in the subgroup analysis based on the sample size, significant associations of the GSTM1 and GSTT1 polymorphisms with NPC susceptibility were identified among studies both with larger case sample size (number of cases ≥100) and smaller case sample size (number of cases <100). Sensitivity analysis confirmed the stability of our results. These results indicate that the GSTM1 and GSTT1 polymorphisms may play crucial roles in the development of NPC, especially in Asians.     

Prognostic significance of vascular endothelial growth factor gene polymorphisms in patients with colorectal cancer

Background

Angiogenesis plays an important role in tumor development, progression, and metastasis. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis. However, the contribution of common VEGF polymorphisms to colorectal cancer (CRC) prognosis remains unclear.

Methods

We have genotyped four polymorphisms of VEGF (?2578C>A, ?1154G>A, ?634G>C, and 936C>T) in 350 CRC cases from the Korean population. The genotyping of VEGF polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism assay.

Results

Although not every VEGF polymorphism was significantly correlated with patient prognosis in overall 350 CRC patients, we found that the VEGF ?2578CA genotype was associated with a significantly poor prognosis for rectal cancers compared to the CC genotype (HR = 2.156; 95 % CI 1.090–4.267; P = 0.028). In addition, we found that the ?2578A/?1154G/?634G/+936C haplotype was significantly associated with a decreased overall survival (OS) rate in all 350 CRC patients (HR = 2.530; 95 % CI 1.340–4.780; P = 0.004). In combination analysis, we found that the combined VEGF ?2578CA+AA/?1154GG genotype was associated with a poor OS rate in all 350 CRC patients (HR = 2.068; 95 % CI 1.159–3.693; P = 0.015).

Conclusions

The VEGF gene polymorphisms investigated in this study were not found to be independent prognostic markers in Korean CRC populations. However, our results suggest that the VEGF ?2578C>A variant may be a potential genetic marker for rectal cancer prognosis. Further large population studies are warranted to define whether the ?2578C>A polymorphism is a prognostic marker of rectal cancer.     

GSTM1 and NAT2 polymorphisms in operable and non-operable lung cancer patients

We have genotyped 657 Norwegian men, including 282 lung cancer patients (147 non-operable and 135 operable) and 375 healthy referents (210 smokers and 165 non-smokers), to study the possibility that glutathione S-transferase M1 (GSTM1)-null and/or N-acetyl transferase 2 (NAT2)-slow genotypes confer susceptibility towards lung cancer in smokers. Compared with smoking referents, there was a significant over-representation of the GSTM1-null genotype among patients with squamous cell carcinoma (SQ) [odds ratio (OR) = 1.7, 95% confidence interval (95%CI) = 1.1-2.7], and the NAT2-slow genotype among patients with large cell carcinoma or mixed histological diagnosis (LM) (OR = 2.5, 95%CI = 1.0-6.1). In contrast to operable patients, non-operable patients showed a clear over-representation of slow genotypes if they were younger (相似文献   

Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis.

The glutathione S-transferase (GST) gene superfamily encodes for enzymes involved in conjugation of electrophilic compounds to glutathione. Several polymorphisms in the GST genes have been implicated as risk factors for prostate cancer. We did a meta-analysis of 11 studies with GSTM1 genotyping (2,063 prostate cancer cases and 2,625 controls), 10 studies with GSTT1 genotyping (1,965 cases and 2,554 controls), and 12 studies with GSTP1 genotyping (2,528 cases and 3,076 controls). The random effects odds ratio was 1.08 [95% confidence interval (95% CI), 0.93-1.25, no significant between-study heterogeneity] for the GSTM1 null versus nondeleted genotype and 0.90 (95% CI, 0.73-1.12; P = 0.03 for heterogeneity) for the GSTT1 null versus nondeleted genotype. Overall, the random effects odds ratio was 1.05 (95% CI, 0.90-1.21; P < 0.01 for heterogeneity) for the GSTP1-Val versus GSTP1-Ile allele. For all three polymorphisms, there was a trend for the presence of an association in the earliest published studies, but this did not seem to be validated in subsequent research. For GSTT1, larger studies gave different results than smaller ones. The meta-analysis shows that these three polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.     

UGT1A1基因多态性与伊立替康治疗结直肠癌不良反应的关系

背景与目的：尿苷二磷酸葡萄糖醛酸转移酶1A1(uridine diphosphoglucu-ronosyltransferase 1A1,UGTlA1)是伊立替康代谢关键酶,其活性受基因多态性影响显著。本研究探讨结直肠癌患者中,UGT1A1*28和UGT1A1*6基因多态性与伊立替康治疗相关不良反应之间的关系。方法：入组2013年4月—2013年12月于复旦大学附属中山医院肿瘤内科接受治疗的消化道恶性肿瘤患者160例。抽提外周血中基因组DNA,分别采用STR方法和Sanger测序法,检测UGT1A1*28和UGT1A1*6基因型,分析UGT1A1基因多态性分布情况。对其中82例化疗方案中含伊立替康的结直肠癌患者进行随访,记录不良反应发生情况和严重程度,比较不同基因型患者之间的差异。结果：160例消化道肿瘤患者中,UTG1A1*28(启动子TATA盒区域TA重复次数)野生型TA6/6124例(77.5%);杂合子TA6/7 33例(20.5%);纯合子TA7/7 3例(2.0%)。UGT1A1*6位点(211G>A)野生型GG 105例(65.6%),杂合子GA 48例(30.0%);纯合子AA 7例(4.4%)。82例化疗方案中含伊立替康的结直肠癌患者中,*28基因型(TA6/7和TA7/7)显著增加发生3级以上中性粒细胞减少的风险(58.3% vs 0.0%,P<0.001),并增加整体不良反应发生率(76.0% vs 45.6%,P<0.001);*6基因型(GA和AA)、年龄、性别、化疗方案和伊立替康相关不良反应发生无显著相关性。结论：接受伊立替康化疗的结直肠癌患者,UGT1A1*28位点多态性显著增加中性粒细胞减少发生的风险,可预测伊立替康引起的骨髓抑制性不良反应,辅助临床选择合适的化疗方案。     

Insulin-like growth factor polymorphisms and colorectal cancer risk.

Several modifiable lifestyle factors, such as physical activity, obesity, and postmenopausal hormone use, have been associated with colorectal cancer risk. It has been hypothesized that some or all of these factors may mediate their effects through alterations in insulin-like growth factor-1 (IGF-1) and its binding proteins (IGFBP). To evaluate the role of IGFs in colorectal cancer, we examined the relationship of two common genetic polymorphisms in IGF-1 (a cytosine-adenosine dinucleotide repeat) and IGFBP-3 (a G --> C single nucleotide polymorphism) with colorectal cancer risk, as well as their potential modification by physical activity, body mass index (BMI), and postmenopausal hormone use. Subjects included 782 male and female colorectal cancer cases diagnosed between 1998 and 2002 and reported to the statewide registry in the metropolitan Seattle area, and 503 age- and sex-matched cancer-free population controls. Colorectal cancer was modestly associated with having an IGF-1 genotype other than homozygous for 19 repeats (odds ratio, 1.3; 95% confidence interval, 1.0-1.6) and having the GG IGFBP-3 genotype (odds ratio, 1.3; 95% confidence interval, 1.0-1.8). There was evidence that IGF-1 genotype modified the relationship between BMI and colorectal cancer among women, such that high BMI increased risk of colorectal cancer only among those with the 19/19 genotype (P(interaction) = 0.02). IGFBP-3 genotype was also a significant effect modifier of the relationship between risk factors and colorectal cancer: The positive association between BMI and colorectal cancer was observed only among men (P(interaction) < 0.01) and women (P(interaction) = 0.06) with the GG genotype; the inverse association between postmenopausal hormone use and colorectal cancer was observed only among women with the GG genotype (P = 0.01) and the inverse association between physical activity and colorectal cancer was observed only among men who carried the C allele (P < 0.01). The current study provides some support for a role of IGFs in colorectal cancer etiology, particularly in mediating the relationship of common risk factors (physical activity, BMI, and postmenopausal hormone use).     

Vascular endothelial growth factor gene polymorphisms associated with prognosis for patients with colorectal cancer

PURPOSE: Vascular endothelial growth factor (VEGF) or its family may be considered to play an important role in lymphangiogenesis and lymphatic tumor spread, thereby affecting prognosis of colorectal cancer. Accordingly, the present study analyzed VEGF gene polymorphisms and their effect on the prognosis for patients with colorectal cancer. EXPERIMENTAL DESIGN: Four hundred and forty-five consecutive patients with surgically treated colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and three VEGF (-2578C>A, -634G>C, and +936C>T) gene polymorphisms were determined using a PCR/denaturing high-performance liquid chromatography assay. RESULTS: Multivariate survival analysis showed that the survival for the patients with the -634 G/C genotype [overall survival (OS): hazard ratio (HR), 0.158; P < 0.001] or C/C genotype (OS: HR, 0.188; P < 0.001) were better than for the patients with the -634G/G genotype, whereas the +936 C/T genotype (OS: HR, 12.809; P < 0.001) or T/T genotype (OS: HR, 37.260; P < 0.001) was associated with a worse survival compared with the +936 C/C genotype. In haplotype analysis, the -2578A/-634G/+936T haplotype exhibited a significantly worse survival when compared with the wild -2578C/-634G/+936C haplotype (OS: HR, 3.866; P < 0.001). CONCLUSIONS: VEGF gene polymorphisms were found to be an independent prognostic marker for patients with colorectal cancer. Accordingly, the analysis of VEGF gene polymorphisms can help identify patient subgroups at high risk of a poor disease outcome.     

GSTM1、GSTT1基因多态性对宫颈癌患者新辅助化疗疗效及预后的影响

目的:研究谷胱苷肽硫转移酶M1（GSTM1）、谷胱苷肽硫转移酶T1（GSTT1）基因多态性对新辅助化疗（NACT）宫颈癌患者疗效的影响及与患者预后的关系。方法:选取2011年5月至2013年5月本院诊治的宫颈癌患者78例为研究对象,NACT采用铂类和紫杉醇类药物,GSTM1、GSTT1基因多态性检测采用多重PCR技术。结果:GSTM1和GSTT1基因在宫颈癌患者中呈多态性分布,GSTM1、GSTT1非缺失组患者总有效率显著高于GSTM1、GSTT1缺失组（P＜0.05）。GSTM1、GSTT1缺失组患者5年生存率显著低于GSTM1、GSTT1非缺失组患者（P＜0.05）。GSTM1、GSTT1基因缺失是影响NACT宫颈癌患者不良预后发生的独立危险因素（P＜0.05）。结论:不同GSTM1、GSTT1基因分型下,NACT对宫颈癌患者的疗效有显著差异,GSTM1、GSTT1基因缺失是影响NACT宫颈癌患者不良预后发生的独立危险因素。     

GSTM1, GSTT1, and GSTP1 polymorphisms and risk of advanced colorectal adenoma.

Cigarette smoking is a risk factor for colon adenoma. The glutathione S-transferase enzymes are involved in the detoxification of carcinogenic compounds including those found in tobacco smoke, and thus, may be important modifiers of individual risk of developing this disease. We examined the prevalence of GSTM1 and GSTT1 gene deletions, and two GSTP1 polymorphisms in 772 cases with advanced colorectal adenomas (>1 cm, villous elements or high-grade dysplasia) of the distal colon (descending or sigmoid colon or rectum) and 777 sigmoidoscopy negative controls enrolled in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Epidemiologic data on smoking was collected by self-administered questionnaire and DNA was extracted from whole blood or buffy coat. For GSTM1 and GSTT1, we used a newly developed TaqMan-based assay capable of discriminating heterozygous (+/-) individuals from those with two active alleles (+/+) and homozygous deletions (-/-). For GSTP1, the I105V and the A114V substitutions were identified using end point 5' nuclease assays (TaqMan). Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were determined using unconditional logistic regression, controlling for age, race, and gender. Advanced adenoma risk was increased in current/former smokers (OR, 1.4; 95% CI, 1.2-1.8). Risks were decreased in subjects with > or =1 inactive GSTM1 alleles (OR, 0.6; 95% CI, 0.4-0.9); and the association was independent of smoking status (P interaction = 0.59). Having > or =1 inactive GSTT1 allele was associated with increased risk among smokers (OR, 1.4; 95% CI, 1.1-1.9; P trend = 0.02) but not among never smokers (OR, 0.9; 95% CI, 0.6-1.3) and a significant interaction between smoking and genotype was observed (P interaction = 0.05). In summary, this is the first study to report associations between colorectal adenomas and GSTM1 wild-type and GSTT1 null allele among smokers. These findings only became apparent using a newly developed assay able to distinguish heterozygous from wild-type individuals. Our data provide evidence that phenotypic differences between these two groups exist.     

MDR1 gene polymorphisms: possible association with its expression and clinicopathology characteristics in colorectal cancer patients

Aim: Over-expression of some genes, such as MDR1, can increase the level of chemotherapy drug afflux and limit the effectiveness of treatment. We aimed to investigate the effect of MDR1 polymorphisms on its expression level and related characteristics in Iranian colorectal cancer patients. Methods: Tumor, normal mucosal tissue and blood samples from CRC patients and blood samples from healthy controls (n=60) were obtained for genotyping and measuring the expression level of MDR1. Results: The expression of the MDR1 gene showed a significant increase in cancerous regions compared to adjacent normal tissue. Furthermore, the GG2677 genotype was correlated with highest while the AT 2677genotype was associated with the lowest levels of expression. In addition only the G2677T/A polymorphism showed association with histological grade of colorectal tumors. Conclusion: Our study once more emphasizes effects of MDR1 SNPs which may indirectly impact on response to drugs.     

Association between bevacizumab-related hypertension and vascular endothelial growth factor (VEGF) gene polymorphisms in Japanese patients with metastatic colorectal cancer

Purpose

Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known toxic effect of hypertension. We studied possible associations between bevacizumab-related hypertension and gene polymorphisms to assure safer cancer therapy.

Methods

We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab-based chemotherapy. Genotypes were determined for five well-known functional single-nucleotide polymorphism of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C, and C936T. Hypertension was graded according to CTCAE v4.0 on the basis of home blood pressure.

Results

The VEGF-2578 C/C and -1498 T/T genotypes were associated with significantly less hypertension during the first 2 months of bevacizumab-based chemotherapy (p = 0.004, p = 0.025, respectively). During the treatment period as a whole, the VEGF-2578 C/C and 936 C/C genotypes were associated with less hypertension (p = 0.031, p = 0.043, respectively). Preexisting hypertension was not associated with bevacizumab-related hypertension.

Conclusions

This study demonstrated a significant relation between a lower incidence of grade 2 or higher bevacizumab-related hypertension and the VEGF-2578 C/C genotype for the entire treatment period in Japanese patients with metastatic colorectal cancer. This genotype might be useful for ensuring safer treatment of patients who receive bevacizumab-based chemotherapy.     

CYP1A1 and GSTM1 polymorphisms and lung cancer risk in Chinese populations: a meta-analysis

Genetic polymorphisms of cytochrome p450 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genes are thought to have significant effects on the metabolism of environmental carcinogens and thus on cancer risk, but the reported results are not always consistent. In this meta-analysis, we assessed reported studies of associations between polymorphisms of these two genes and risk of lung cancer in Chinese populations. Through a systematic literature search for publications between 1989 and 2006, we summarized the data from 46 studies on polymorphisms of MspI and exon7-Val of CYP1A1 and GSTM1 and lung cancer risk in Chinese populations, and found that compared with the wild-type homozygous genotype (type A), lung cancer risk for the combined variant genotypes (types B and C) was 1.34-fold (95% confidence interval [CI]=1.08-1.67) (Z=2.64, P=0.008); the risk for the combined variant genotypes (Ile/Val and Val/Val) of CYP1A1 exon7 was 1.61-fold (95% CI=1.24-2.08) (Z=3.62, P<0.001), compared with the Ile/Ile genotype; and that the risk for the GSTM1 null genotype was 1.54-fold (95% CI=1.31-1.80) (Z=5.32, P<0.001), compared with the GSTM1 present genotype. Therefore, in 46 published studies in Chinese populations, we found evidence of an association between the CYP1A1 variant and GSTM1 null genotypes and increased risk of lung cancer.     

Association between ulcerative growth and hypoxia inducible factor-1alpha polymorphisms in colorectal cancer patients

The hypoxia inducible factor-1alpha (HIF-1alpha) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1alpha is hydroxylated at normoxia and rapidly degraded via the von Hippel-Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1alpha gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26-21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58-26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1alpha C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33-13.08; P = 0.004). These results suggest that the HIF-1alpha polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1alpha allele may therefore be of importance in the selection of treatment strategies of CRC.     

淋巴瘤患者多环芳烃-DNA加合物及代谢酶基因细胞色素氧化酶P4501A1与谷胱苷肽硫转移酶M1基因多态性的研究

目的 探讨多环芳烃（PAH）-DNA加合物和代谢酶基因细胞色素氧化酶P4501A1（CYP1A1）与谷胱苷肽硫转移酶M1（GSTM1）基因多态性与淋巴瘤发病的关系.方法 通过竞争性酶联免疫吸附法测定54例淋巴瘤患者及34例对照组骨髓液中PAH-DNA加合物含量,采用限制性片段长度多态性PCR法（PCR-RFLP）测定上述标本CYP1A1、GSTM1基因多态性.结果 淋巴瘤患者骨髓液中PAH-DNA加合物含量为（2498±1 250） pg/ml,较对照组的（1 882±797） pg/ml增加,差异有统计学意义（t=0.006,P＜0.05）;淋巴瘤患者GSTM1基因型缺失占85.2％,对照组占58.8％,差异有统计学意义（x2=7.73,P＜0.05）,GSTM1基因型缺失者患淋巴瘤风险是GSTM1表达者的4.03倍（95％ CI1.51～10.76,P＜ 0.05）;CYP1A1变异型是野生型患淋巴瘤风险的1.36倍（95％CI 0.56～ 3.31,P＞ 0.05）,GSTM1缺失者PAH-DNA加合物水平≥2 200 pg/ml时患淋巴瘤的危险性增加（OR=9.53,95％CI 2.397～ 37.990,P＜ 0.05）.结论 PAH-DNA加合物可能参与淋巴瘤的发病,GSTM1缺失与淋巴瘤发生有关,并且增加患淋巴瘤的风险.     

N-acetyl transferase 1: two polymorphisms in coding sequence identified in colorectal cancer patients.

Increased cancer risk has been associated with functional polymorphisms that occur within the genes coding for the N-acetyltransferase enzymes NAT1 and NAT2. We detected two NAT1 polymorphisms in colorectal cancer patients by heteroduplex analysis. DNA sequencing revealed the wild-type sequence (NAT1*4) and two single base substitutions at adjacent positions 999 bp (C to T, NAT1*14) and 1000 bp (G to A, NAT1*15) of the gene, changing Arg187 to a stop codon and Arg187 to Gln respectively. NAT1 alleles NAT1*4 (0.98) and NAT1*15 (0.02) were present at a similar frequency in patients with colorectal cancer (n=260) and in a Scottish control group (n=323). The third allele, NAT1*14, was present only in the colorectal cancer group at a frequency of 0.006. NAT1 genotype NAT1*4/ NAT1*15 was significantly less frequent in individuals that had a slow NAT2 genotype. This was observed in both cancer and control groups and suggests that this association was unrelated to cancer risk. We conclude that polymorphisms within the coding region of the NAT1 gene are infrequent and do not appear to have an independent association with colorectal cancer risk. However, the relationship between NAT1 and NAT2 polymorphisms appears non-random, suggesting a linkage between these enzymes.