Caspase 9 promoter polymorphisms and risk of primary lung cancer

Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the CASP-9 gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [-1263A>G, -905T>G, -712C>T and -293_-275delCGTGAGGTCAGTGCGGGGA (-293del)] in the CASP-9 promoter with the risk of lung cancer in a Korean population. The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The -1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the -1263 AA genotype or combined -1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42-0.98, P=0.04 and adjusted OR=0.67, 95% CI=0.46-0.97, P=0.01, respectively]. For the -712C>T polymorphism, individuals with at least one -712T allele were at a significantly increased risk of lung cancer compared with those harboring the -712 CC genotype (adjusted OR=1.42, 95% CI=1.06-1.89, P=0.02). Consistent with the results of genotype analyses, the -1263G/-712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47-0.75, P and Bonferroni corrected P (Pc)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45-0.81, P=0.0007 and Pc=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17-0.68, P=0.0023 and Pc=0.0046 for the G-C homozygotes; P(trend)<0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the -1263G/-712T and -1263A/-712C haplotypes. These results suggest that CASP-9 promoter polymorphisms affect CASP-9 expression and contribute to genetic susceptibility to lung cancer.     

Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk

The ataxia telangiectasia mutated (ATM) gene is known to be activated by DNA damage and involved in cell cycle arrest, apoptosis and DNA repair. Therefore, ATM gene polymorphisms may act as important factors predicting individual susceptibility to lung cancer. To evaluate the role of ATM gene polymorphisms in lung cancer development, genotypes of the ATM polymorphisms, -4518A>G, IVS21-77C>T, IVS61-55T>C, and IVS62+60G>A, were determined in 616 lung cancer patients and 616 cancer-free controls. When the effects of selected ATM genotypes were evaluated separately, only one ATM genotype (IVS62+60G>A) showed an association with lung cancer risk. Subjects with the A allele at the site (IVS62+60G>A) have significantly higher risk of lung cancer than those with the G allele [odds ratio (OR)=1.6, 95% confidence interval (CI) 1.1-2.1]. When the haplotypes of four ATM single nucleotide polymorphism sites (-4518A>G, IVS21-77C>T, IVS61-55T>C and IVS62+60G>A) were studied, the ATTA haplotype showed significantly increased risk of lung cancer compared with the GCCA haplotype, the most common haplotype (OR=7.6, 95% CI 1.7-33.5). Furthermore, subjects with the (NN)TA haplotype showed highly significant and increased risk of lung cancer when compared with those without the (NN)TA haplotype (OR=13.2, 95% CI 3.1-56.1). Therefore, our results suggest that polymorphisms or haplotypes of the ATM gene play an important role in the development of lung cancer.     

Correlation between survivin genetic polymorphisms and lung cancer susceptibility

Aims: The purpose of the study was to analyze the relationship of survivin polymorphisms including -31G/C, -625G/C, 9194A/G and 9809T/C with the susceptibility to lung cancer. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to test the polymorphisms of -31G/C, -625G/C, 9194A/G and 9809T/C in 104 patients with lung cancer and 104 healthy controls. Then, linkage disequilibrium and haplotypes were analyzed by HaploView software. The differences of genotype, allele and haplotype frequencies in case and control group were assessed via chi-square test. Odds ratio (OR) with 95% CI were used to evaluate the correlation of survivin polymorphisms with lung cancer. Results: Genotype distribution of each polymorphism site in control group was in agreement with Hardy-Weinberg equilibrium (HWE) (P>0.05). The frequency of -31G/C CC genotype and C allele in case group were much higher than that of controls, respectively (CC: 33.6% vs. 22.1%; C: 57.2% vs. 46.6%) and CC genotype as well as C allele were appeared to be risk factors for lung cancer. Meanwhile, 9194A/G GG genotype could increase the risk for lung cancer (OR=2.86, 95% CI=1.14-7.20). The risk of G allele carriers for lung caner was higher than that of A allele (OR=1.63, 95% CI=1.08-2.47). The haplotypes analysis indicated that CGGC and GCAT were associated with the susceptibility to lung cancer (OR=2.79, 95% CI=1.58-4.92; OR=2.36, 95% CI=1.29-4.30). Conclusions: Survivin -31G/C and 9194A/G polymorphisms were associated with the risk of lung cancer. The CGGC and GCAT haplotypes carriers were more likely to develop lung cancer.     

Comprehensive assessment of P21 polymorphisms and lung cancer risk

The purpose of this study is to comprehensively evaluate potential functional polymorphisms in the P21 gene in relation to the risk of lung cancer. We first determined the frequencies of P21 polymorphisms in 27 healthy Koreans, and then examined three polymorphisms (−2266G > A, S31R, and IVS2 + 16G > C), based on their frequencies and haplotype-tagging status, in a case–control study. Individuals with at least one −2266A allele were at a significantly decreased risk of lung cancer compared with those harboring the −2266 GG genotype [adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53–0.95, P = 0.02). The haplotypes (ht2–4) carrying 31R or IVS2 + 16C alleles were associated with a significantly decreased risk of lung cancer compared with the haplotype 31S/IVS2 + 16G, which carried wild-type alleles at both loci (adjusted OR = 0.65, 95% CI = 0.50–0.83, P = 0.007)]. When the −2266A allele and ht2–4 were considered to be protective alleles, the risk of lung cancer decreased in a dose-dependent manner as the number of protective alleles increased (P = 0.0002). These results suggest that a combined analysis of these three P21 polymorphisms might better predict the risk of lung cancer than the analysis of a single polymorphism.     

CD40 -1C>T polymorphism and the risk of lung cancer in a Chinese population

Background: The co-stimulatory molecule CD40 plays an important role in anti-tumor responses by promoting cytotoxic T lymphocyte (CTL) activity and differentiation of helper T cells. Growing evidence suggests that single nucleotide polymorphisms (SNPs) in CD40 are associated with the susceptibility to cancer. This study investigated the association between the CD40 -1C/T SNP (rs1883832) and lung cancer in a Chinese population. Methods: We conducted a hospital-based case-control study including 105 lung cancer patients and 109 healthy control subjects. The -1C/T SNP in CD40 was genotyped by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and its association with lung cancer susceptibility was evaluated. Results: The distribution of the genotypes of CD40-1C/T was significantly different between lung cancer patients and controls. The frequency of the TT genotype (adjusted P = 0.017; overall risk [OR] = 2.94; 95% confidence interval [CI] = 1.21-7.13) and TT/CT genotype (adjusted P = 0.020; OR = 1.95; 95% CI = 1.11-3.43) were significantly higher in lung cancer patients than that in controls. When the cases were categorized by tumor histology, the TT genotype was associated with a significantly increased risk of squamous cell carcinoma (adjusted OR = 6.53; 95% CI = 1.97-21.61; P = 0.002). Conclusion: Our findings suggest that the CD40 -1C/T SNP (rs1883832) is correlated with the susceptibility to lung cancer in Chinese, and the TT genotype may further increase the risk of lung cancer.     

DNA错配修复基因MSH2和MLH1单核苷酸多态性与食管癌发生风险相关性研究

目的:探讨DNA错配修复基因MSH2和MLH1单核苷酸多态性对于食管癌易感性的潜在作用。方法:采用医院为基础的病例-对照研究方法,应用PCR-RFLP检测包括正常对照132例,食管癌患者169例MSH2c.2063TG和MLH1IVS14-19AG两个基因多态性位点的基因型。通过Logistic回归分析计算出比值比(OR)和95%置信区间(95%CI),估计不同基因型频率分布与食管癌发生风险的关系。结果:MSH2c.2063TG携带突变等位基因个体发生食管癌的风险是非携带者的3.24倍。MLH1IVS14-19AG突变等位基因携带者发生食管癌风险是非携带者的1.58倍。对MSH2和MLH1基因交互作用分析发现两突变基因型携带者发生食管癌风险大大增加并具有显著的统计学意义。结论:DNA错配修复基因MSH2c.2063G突变等位基因和MLH1IVS14-19G突变等位基因可能在促成食管癌发生过程起到一定作用。     

Association between EGFR polymorphisms and the risk of lung cancer

Target: The study aimed to investigate the role of epidermal growth factor receptor (EGFR) rs6965469 and rs763317 polymorphisms in the occurrence and development of lung cancer. Methods: We used polymerase chain reaction-ligation detection reaction (PCR-LDR) method to detect the genotypes of EGFR rs6965469 and rs763317 polymorphisms and the data were analyzed by GeneMapper software. Odds ratios (ORs) with 95% confidence intervals (CIs) was calculated by χ² test to estimate the significance difference of genotype and allele frequencies in case and control groups. ORs and 95% CIs were adjusted by logistic regression analysis with age, gender, drinking and smoking. The genotypes distributions of control group were tested by Hardy-Weinberg equilibrium (HWE). Results: The genotypes frequencies of controls for rs6965469 and rs763317 polymorphims were consistent with HWE. The distribution of rs6965469 TT genotype in two groups was significantly different (P<0.05) and TT genotype was associated with an increased risk of lung cancer (OR=6.92, 95% CI=1.33-36.00). AA genotype and A allele of rs763317 were also the susceptible factors of lung cancer. Individuals with AA genotype or A allele were more likely to suffer lung cancer (AA vs. GG: OR=7.20, 95% CI=1.33-39.07; A vs. G: OR=2.61, 95% CI=1.04-6.59). Conclusions: The EGFR rs6965469 and rs763317 polymorphisms may be risk factors for lung cancer.     

Increase in interleukin-6 following arterial injury is related to insulin resistance, the -174G-->C polymorphism and complex plaque morphology

Interleukin-6 (IL-6) is associated with many disease states in humans. We prospectively sought to determine whether IL-6 levels increased following percutaneous coronary intervention (PCI) in the absence of myonecrosis. Additionally, we systematically assessed other clinical and anatomic factors associated with IL-6 levels in a population of patients with coronary atherosclerosis undergoing PCI. Blood samples were collected from 117 patients at baseline, 8 and 16 h following PCI. Samples were assayed for IL-6, creatine kinase-myocardial band (CK-MB), troponin-I (Tn-I), high sensitivity C-reactive protein, glucose, haemoglobin A1c, and a lipid profile. Genotyping of the -174G-->C polymorphism of the IL-6 gene was performed. IL-6 levels increased following PCI among the study group (slope = 0.4 pg/mL/h, P = 0.001). IL-6 levels increased to a similar degree in the absence of myonecrosis. Patients with the XC genotype (either having the GC or the CC allele) had higher IL-6-values at baseline compared to GG genotype patients (4.9 +/- 6.4 vs. 2.6 +/- 1.8 pg/mL, P = 0.02). Multivariable predictors of detectable baseline IL-6 levels included XC genotype (odds ratio [OR]: 4.14, 95% CI 1.58-10.82, P = 0.004), ACC/AHA type C lesion classification (OR: 4.08, 95% CI 1.54-10.84, P = 0.005), elevated baseline Tn-I (OR: 3.31, 95% CI 1.16-9.43, P = 0.025), diabetes (OR: 3.00, 95% CI 1.11-8.09, P = 0.030), and waist circumference (OR: 1.49, 95% CI 1.08-2.06, P = 0.015). Predictors of peak IL-6 following PCI included the XC genotype (estimate 1.4, 95% CI 1.06-1.87, P = 0.019), homeostasis model assessment (estimate 0.99, 95% 0.982-0.999, P = 0.042) and baseline Tn-I > upper limit of normal (estimate 0.7, 95% CI 0.50-0.96, P = 0.039). Lastly, IL-6 increased following PCI even in the absence of myonecrosis as measured by Tn-I elevation. IL-6 levels are also related to the -174G-->C polymorphism, arterial injury, lesion complexity, and insulin resistance.     

Glutathione S-transferase T1-null genotype interacts synergistically with heavy smoking on lung cancer risk

We studied the influence of genotype for glutathione S-transferase T1 (GSTT1) on susceptibility to lung cancer among 184 Swedish lung cancer patients (88 never-smokers and 96 ever-smokers) and 162 matched population controls (79 never-smokers and 83 ever-smokers), with special emphasis on gene-environment interactions. Cases had significantly lower frequency of the GSTT1-null genotype than that of controls among never-smokers (4.6 vs. 16.5%, P = 0.02), whereas the frequencies were very close to each other among smokers (7.4 vs. 7.2%). Cases with high packyears of smoking, however, had a significantly higher frequency of the GSTT1-null genotype compared to that of cases with low packyears (18.3 vs. 5.6%, P = 0.005). Adjusted for age and gender, the GSTT1-null genotype appeared to be protective against lung cancer among never-smokers (odds ratio [OR] = 0.2, 95% confidence interval [CI] = 0.07-0.7), although it was associated with an increased risk for lung cancer among smokers (OR = 2.1, 95% CI = 0.8-5.9), mainly attributed to the group of heavy smokers (>23 packyears; OR = 3.5, 95% CI = 0.7-17.3). Heavy smoking conferred a threefold increased risk for lung cancer (OR = 2.6, 95% CI = 1.3-5.0) among GSTT1-positive individuals, but a ninefold increased risk when combined with the GSTT1-null genotype (OR = 9.3, 95% CI = 1.9-46.3, relative to GSTT1-positive light smokers). This joint effect was further demonstrated by a positive interaction between the GSTT1-null genotype and packyears of smoking. The risk of lung cancer increased steeply with increasing packyears among GSTT1-null smokers, whereas no such effect was seen among GSTT1-positive smokers. We conclude that the GSTT1-null genotype may strengthen the effect of heavy smoking on lung cancer risk.     

CASP8 -652 6N del polymorphism and cancer risk: a meta-analysis of 30 case-control studies in 50 112 subjects

Disruptions of normal apoptotic pathways, which are mainly mediated by caspases, play an essential role in cancer development. Caspase-8 (CASP8) is encoded by the CASP8 gene and is centrally involved in the apoptosis of T lymphocytes. The association between a six-nucleotide deletion polymorphism (-652 6N del) of the CASP8 gene and the risk of cancer is widely reported; however, study results have been inconsistent and contradictory. To evaluate the association between the CASP8 -652 6N del polymorphism and the risk of cancer and to overcome the limitations of any individual study, a meta-analysis based on a total of 23?700 cases and 26?412 controls from 30 case-control studies was conducted. The results of the overall analysis suggested that the CASP8 -652 6N del polymorphism is associated with decreased risk of cancer for the allele contrast [del versus ins: odd ratio (OR) = 0.86, 95% confidence interval (CI) = 0.80-0.92], the additive genetic model (del/del versus ins/ins: OR = 0.78, 95% CI = 0.69-0.88), the dominant genetic model (del/del+del/ins versus ins/ins: OR = 0.83, 95% CI = 0.78-0.89) and the recessive genetic model (del/del versus ins/ins+del/ins: OR = 0.84, 95% CI = 0.75-0.93). In addition, after stratification for ethnicity and cancer type, significantly reduced risk was found for Asians and Caucasians as well as for individuals in the colorectal cancer group and the 'other cancers' group. Accordingly, there is an association between the CASP8 -652 6N del polymorphism and reduced cancer risk, especially among Asians, Caucasians and those with colorectal cancer. However, further research, such as studies focusing on additional ethnic groups and cancer types, is needed to provide a more exact and comprehensive synthesis conclusion.     

北京地区汉族人群DNA修复基因XPD单核苷酸多态性与肺癌及食管癌风险的研究

目的：研究核苷酸切除修复基因XPD单核苷酸多态性与北京地区汉族人群肺癌及食管癌风险的关系。方法：采用以医院患者为基础的病例－对照研究方法，包括正常对照383人，肺癌患者351例，食管癌患者325例。以聚合酶链反应－限制性片段长度多态性方法分析了XPD基因Asp312 Asn和Lys751Gln多态性，比较不同基因型与肺癌及食管癌风险的关系，并探讨吸烟与基因多态交互作用对患癌风险的影响。结果：与携带312 Asp/Asp基因型者比较，携带至少1个312Asn等位基因者（即Asp/Asn和Asn/Asn基因型）罹患肺鳞癌的风险增加1．8倍（95％CI1．10－2．93），而与肺腺癌无关（校正的比值比为1．07，95％CI0．55－2．08）。分层分析显示，风险型等位基因312Asn和751Gln与吸烟有明显的交互作用。吸烟剂量≥29包／年且携带312Asn或751Gln者罹患肺鳞癌的风险最高，校正的比值比分别为12．44（95％CI4．97－31．17）和10．74（95％CI4．51－25．57）。XPD基因Asp312Asn和Lys751Gln多态与食管鳞癌风险无关。结论：XPD基因Asp312Asn和Lys751Gln多态是地区汉族人群肺鳞癌遗传易感因素，而与肺腺癌以及食管鳞癌风险无关，可能反映了不同组织学类型肺癌以及肺癌和食管癌之间的病因学差异。     

Interactive Effect of Smoking and NQO1 Haplotypes on Lung Cancer Risk

The role of genetic polymorphisms of NAD(P)H:quinone oxidoreductase 1 (NQO1), which is known to be related to carcinogen metabolism and oxidative status, was evaluated for lung cancer development. The genotypes of two NQO1 polymorphisms, namely, IVS1-27C>G and Ex6+40C>T, were determined in 616 lung cancer cases and 616 lung cancer-free controls and haplotypes composed of the two polymorphisms were estimated. In the evaluation of the effect of the NQO1 genotypes or diplotypes, we did not find any significant association with lung cancer risk after adjusting for body mass index and smoking status. However, when we evaluated the effect of the NQO1 diplotypes for lung cancer risk in combination with smoking, smokers without the C-T/C-T diplotype showed a significantly increased risk of lung cancer compared with nonsmokers without the C-T/C-T diplotype (adjusted OR, 2.2; 95% CI, 1.67-3.02), and smokers with the C-T/C-T diplotype showed the highest OR of lung cancer (adjusted OR, 2.7; 95% CI, 1.78-4.21). Moreover, a trend test showed an additive interaction between smoking and the NQO1 C-T/C-T diplotype (P_trend < 0.01). The additive effect of smoking and the NQO1 C-T/C-T diplotype was more apparent in squamous cell carcinoma, although this effect was statistically significant in all lung cancer cell types (all cell types, P_trend < 0.05). This result suggests that haplotypes of the NQO1 gene play an important role in the development of lung cancer by interaction with smoking.

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Correlation between LSP1 polymorphisms and the susceptibility to breast cancer

Objective: The present study aimed at assessing the relationship between Leukocyte-specific protein 1 gene (LSP1) polymorphisms (rs569550 and rs592373) and the pathogenesis of breast cancer (BC). Methods: 70 BC patients and 72 healthy subjects were enrolled in the study. Rs569550 and rs592373 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratio (OR) with 95% confidence interval (CI) were calculated by the chi-squared test to assess the relationship between LSP1 polymorphisms and BC risk. Linkage disequilibrium (LD) and haplotypes were also analyzed by HaploView software. Results: Genotype distribution of the control was in accordance with Hardy-Weinberg equilibrium (HWE). The homozygous genotype TT and T allele of rs569550 could significantly increase the risk of BC (TT vs. GG: OR=3.17, 95% CI=1.23-8.91; T vs. G: OR=1.63, 95% CI=1.01-2.64). For rs592373, mutation homozygous genotype CC and C allele were significantly associated with BC susceptibility (CC vs. TT: OR=4.45, 95% CI=1.38-14.8; C vs. T: OR=1.70, 95% CI=1.03-2.81). LD and haplotypes analysis of rs569550 and rs592373 polymorphisms showed that T-C haplotype was a risk factor for BC (T-C vs. G-T: OR=1.74, 95% CI=1.04-2.92). Conclusion: LSP1 rs569550 and rs592373 polymorphisms are both risk factors for BC.     

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility

Aim: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. Methods: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. Results: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). Conclusion: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.     

Variants in DNA double-strand break repair genes and breast cancer susceptibility

We performed genetic association studies in a population-based breast cancer case-control study analysing polymorphisms in genes involved in homologous recombination (NBS1, RAD52, RAD51, XRCC2 and XRCC3) and non-homologous end-joining (KU70/80 and LIG4). These DNA double-strand break repair genes are candidates for breast cancer susceptibility. Genotype results were available for up to 2205 cases and 1826 controls. In the homologous recombination (HR) pathway, genotype frequencies differed between cases and controls for two polymorphisms in XRCC3; T241M (P=0.015) and IVS5 A>G at nt 17893 (P=0.008). Homozygous carriers of M241 were associated with an increased risk [odds ratio (OR) MM versus TT=1.3 (95% confidence interval (CI) 1.1-1.6)], while the rare allele of IVS5A>G was associated with a dominant protective effect [OR AG versus AA=0.8 (0.7-0.9)]. The association of a rare variant in XRCC2 (R188H) was marginally significant [P=0.07; OR HH versus RR=2.6 (1.0-6.7)]. In the non-homologous end-joining (NHEJ) pathway, a polymorphism in LIG4 (T>C at nt 1977) was associated with a decrease in breast cancer risk [P=0.09; OR CC versus TT=0.7 (0.4-1.0)]. No significant association was found for 12 other polymorphisms in the other genes studied. For XRCC3, we found evidence for four common haplotypes and four rarer ones that appear to have arisen by recombination. Two haplotypes, AGC and GGC, were associated with non-significant reductions in breast cancer risk, and the rare GAT haplotype was associated with a significantly increased risk. These data provide some evidence that variants in XRCC2 and LIG4 alter breast cancer risk, together with stronger evidence that variants of XRCC3 are associated with risk. If these results can be confirmed, understanding the functional basis should improve our understanding of the role of DNA repair in breast carcinogenesis.     

A comprehensive haplotype analysis of CYP19 and breast cancer risk: the Multiethnic Cohort

The CYP19 gene encodes for aromatase (P450arom), a key steroidogenic enzyme that catalyzes the final step of estrogen biosynthesis. Apart from rare mutations in CYP19 which result in severe phenotypes associated with estrogen insufficiency, little is known about whether common variation in CYP19 is associated with risk of hormone-related diseases. In this study, we employed a haplotype-based approach to search for common disease-associated variants in this candidate breast cancer susceptibility gene among African-American, Hawaiian, Japanese, Latina and White women in the Multiethnic Cohort Study (MEC). We utilized 74 densely spaced single-nucleotide polymorphisms (SNPs) (one every approximately 2.6 kb) spanning 189.4 kb of the CYP19 locus to characterize linkage disequilibrium (LD) and haplotype patterns among 69-70 individuals from each ethnic population. We detected four regions of strong LD (blocks 1-4) that were quite closely conserved across populations. Within each block there was a limited diversity of common haplotypes (5 to 10 with a frequency >/=5%) and most haplotypes were observed to be shared across populations. Twenty-five haplotype-tagging SNPs (htSNPs) were selected to predict the common haplotypes with high probability (average Rh2=0.92) and genotyped in a breast cancer case-control study in the MEC (cases, n=1355; controls, n=2580). We first performed global tests for differences in risk according to the common haplotypes and observed significant haplotype-effects in block 2 [P=0.01; haplotypes 2b (OR=1.23; 95% CI, 1.07-1.40), 2d (OR=1.28; 95% CI, 1.01-1.62)]. We also found a common long-range haplotype comprised of block-specific haplotypes 2b and 3c to be associated with increased risk of breast cancer (haplotype 2b-3c: OR=1.31; 95% CI, 1.11-1.54). Our findings suggest the hypothesis that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele.     

Genetic variants and haplotypes of the caspase-8 and caspase-10 genes contribute to susceptibility to cutaneous melanoma

Caspase-8 (CASP8) and caspase-10 (CASP10) play key roles in regulating apoptosis, and their functional polymorphisms may alter apoptosis and cancer risk. However, no reported studies have investigated the association between such polymorphisms and the risk of cutaneous melanoma (CM). In a hospital-based study of 805 non-Hispanic white patients with CM and 835 cancer-free age-, sex-, and ethnicity-matched controls, we genotyped three reported putatively functional polymorphisms of CASP8 and CASP10-CASP8 D302 H (rs1045485:G>C), CASP8 -652 6N del (rs3834129:-/CTTACT), and CASP10 I522L (rs13006529:A>T)-and assessed their associations with risk of CM and interactions with known risk factors for CM. We also calculated the false-positive report probability (FPRP) for significant findings. CASP8 302 H variant genotypes (DH: adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.50-0.98; DH+HH: unadjusted OR, 0.78; 95% CI, 0.62-0.98; FPRP, 0.79) and CASP8 -652 6N del variant genotypes (ins/del: OR, 0.74; 95% CI, 0.57-0.97; ins/del+del/del: OR, 0.76; 95% CI, 0.61-0.95; FPRP, 0.61) were associated with significantly lower CM risk than were the DD and ins/ins genotypes, respectively. However, the CASP10 522L variant genotypes were not associated with significantly altered CM risk. Also, the D-del-I haplotype was associated with a significantly lower CM risk (OR, 0.52; 95% CI, 0.37-0.74; FPRP, 0.04) than was the most common haplotype, D-ins-I. Furthermore, multivariate logistic regression analysis revealed that CASP8 D302 H, CASP8 -652 6N del, and CASP10 I522L were independent risk factors for CM. Therefore, these CASP8 and CASP10 polymorphisms may be biomarkers for susceptibility to CM.