Lack of association between the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and the risk of benign prostatic hyperplasia in Caucasian men

Glucuronidation, mediated by the UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme, is an important metabolic process during which steroids are converted to more easily excreted compounds in steroid target tissues, such as the prostate. The aim of our study was to investigate the possible correlation between UGT1A1 promoter gene polymorphism and benign prostatic hyperplasia. 421 blood samples were obtained from 138 consecutive patients diagnosed with benign prostatic hypeplasia (BPH group) and 283 healthy volunteers (control group). A(TA)6TAA promoter polymorphism of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/7, heterozygous 6/7 and normal homozygous 6/6) were identified. No significant differences were observed between the BPH group and controls regarding the genotyping distribution of the three UGT1A1 promoter genotypes (P = 0.39). Also, no association was found between overall disease risk and the presence of the polymorphic homozygous genotype (TA(7)/TA)7) vs. TA(6)/TA(7) + TA(6)/TA(6)) (P = 0.31). Our data suggest that the TA repeat polymorphism of UGT1A1 is not associated with increased BPH risk susceptibility in Caucasian men.     

A higher prediagnostic insulin level is a prospective risk factor for incident prostate cancer

A higher insulin level has been linked to the risk of prostate cancer promotion. However, several reports claim that there is no association between a higher insulin level and the risk of incident prostate cancer. In the present report, the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder. Three hundred and eighty-nine consecutive patients referred with lower urinary tract symptoms without clinical prostate cancer were included during 1994–2002. Follow-up was performed in 2006. Data were obtained from the Swedish National Cancer Register and the Regional Cancer Register, Oncological Centre, Göteborg, Sweden. At this follow-up, 44 of the patients included had developed prostate cancer. Men with prostate cancer diagnosis had a higher systolic (P < 0.001) and diastolic blood pressure (P < 0.000), were more obese as measured by BMI (P = 0.010), waist (P = 0.007) and hip measurements (P = 0.041) than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level (P = 0.040), and a higher fasting serum insulin level (P = 0.023) than men who did not have prostate cancer diagnosis at follow-up. Following exclusion of T1a/b prostate cancer cases, the difference of the fasting serum insulin level between the groups was still significant (P = 0.038). Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer.     

The association between UGT1A7 polymorphism and cancer risk: a meta-analysis

Background: studies investigating the associations between UDP-glucuronosyltransferase 1A7 (UGT1A7) gene polymorphisms and various carcinomas risk reported conflicting results. To derive a more precise estimation of the association, we have conducted a meta-analysis. Methods: data were collected from the following electronic databases: PubMed, Medline and Chinese Biomedical Literature Database, with the last report up to September 2011. Case–control studies containing available genotype frequencies of UGT1A7 were chose. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of association. Results: a total of 22 separate case–control studies including 3852 cases and 5604 controls based on the search criteria were involved in this meta-analysis. The combined results based on all studies showed that there was a statistically significant link between UGT1A7*3 allele and cancer risk (OR = 1.31, 95%CI = 1.14–1.50, P = 0.0001). In the stratified analysis by racial descent, significant increased risk was found in Asian population for UGT1A7*3 allele (OR = 1.41, 95%CI = 1.22–1.63, P < 0.00001). No significant associations were found between the UGT1A7 polymorphism and cancer susceptibility among Caucasians and African-Americans. In the subgroup analysis by cancer types, significant associations were found in UGT1A7*2 allele (OR = 1.23, 95%CI = 1.06–1.43, P = 0.006) and *3 allele (OR = 1.51, 95%CI = 1.11–2.06, P = 0.009) for hepatocellular carcinoma, *3 allele for lung cancer (OR = 1.36, 95%CI = 1.11–1.68, P = 0.004) and for bladder cancer (OR = 1.50, 95%CI = 1.09–2.07, P = 0.01). Conclusions: This meta-analysis suggests that the UGT1A7*3 allele is a risk factor for cancer among Asians, especially for hepatocellular carcinoma.     

Polymorphisms of glutathione-S-transferase M1 and T1 and prostate cancer risk in a Tunisian population

Several genes involved in the metabolism of carcinogenesis have been found to be polymorphic in the human population, and specific alleles are associated with increase risk of cancer of various sites. This study is focused on the polymorphic enzymes glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) that involved in the detoxification of many xenobiotics involved in the etiology of prostate cancer. Objective. To evaluate whether GSTM1 and/or GSTT1 contribute to prostate cancer (CaP) etiology, we studied 110 incident CaP cases and 122 controls. Results. The probability of having CaP was increased in men who had homozygous deleted (non-functional) genotypes at GSTT1 (OR = 2.17; 95% CI = 1–3.79) but not GSTM1 (OR = 0.89; 95% CI = 0.66–1.88). Hence, individuals lacking the GSTT1 gene are at approximately twofold higher risk of developing prostate cancer in comparison with individuals with at least one active allele in the GSTT1 locus. Conclusion. These results suggest that GSTT1 is associated with CaP risk. The effect of smoking associated with the GSTT10/0 genotype was not found to affect the risk of prostate cancer.     

STK15 rs2273535 polymorphism and cancer risk: A meta-analysis of 74,896 subjects

Background: It has been suggested that the serine/threonine kinase 15 (STK15) T91A rs2273535 polymorphism is associated with susceptibility to cancer. However, the results are conflicting. We performed this meta-analysis to derive a more precise estimation of the relationship. Methods: PubMed was searched to select studies. Case–control studies containing available genotype frequencies of the STK15 rs2273535 polymorphism were chosen, and the odds ratio (OR) with its 95% confidence interval (CI) was utilized to assess the strength of association. Results: 52 studies – including 34,057 cases and 40,839 controls – were identified. A significant effect of the STK15 rs2273535 polymorphism on cancer risk was found (AA vs. TT: OR = 1.13, 95%CI = 1.01–1.26, P_{heterogeneity} < 0.001; AA vs. TA/TT: OR = 1.12, 95%CI = 1.02–1.22, P_{heterogeneity} < 0.001; TA/AA vs. TT: OR = 1.06, 95%CI = 1.01–1.12, P_{heterogeneity} < 0.001). Stratified analysis by cancer type revealed that the STK rs2273535 polymorphism may contribute to the risk of breast cancer (AA vs. TT: OR = 1.21, 95%CI = 1.01–1.44, P_{heterogeneity} = 0.002), colorectal cancer (AA vs. TA/TT: OR = 1.24, 95%CI = 1.05–1.47, P_{heterogeneity} = 0.124), and esophageal cancer (AA vs. TA/TT: OR = 1.19, 95%CI = 1.02–1.39, P_{heterogeneity} = 0.148). Further subgroup analysis by ethnicity indicated that there was a statistically increased cancer risk in Asians (AA vs. TA/TT: OR = 1.20, 95%CI = 1.05–1.37, P_{heterogeneity} = 0.004). Conclusion: This meta-analysis suggests that the STK15 rs2273535 polymorphism is a candidate gene polymorphism for cancer susceptibility, especially in Asian populations.     

Genetic polymorphisms in AURKA,BRCA1, CCNE1 and CDK2 are associated with ovarian cancer susceptibility among Chinese Han women

IntroductionCentrosome aberrations and cell-cycle deregulation have important implications for ovarian cancer development. The AURKA, BRCA1, CCNE1 and CDK2 genes play pivotal roles in centrosome duplication and cell-cycle regulation.MethodsUsing a haplotype-based analysis, this study aimed to investigate whether genetic polymorphisms in these four genes may contribute to ovarian cancer susceptibility. A total of 22 single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 287 cases of ovarian serous cystadenocarcinomas and 618 age-matched cancer-free controls from the Chinese Han population, and then haplotype blocks were reconstructed according to our genotyping data and linkage disequilibrium (LD) status of these SNPs.ResultsFor AURKA, we found that haplotype GA [rs6064391 (T→G) + rs911162 (G→A)] was strongly associated with decreased ovarian cancer risk (adjusted OR = 0.31, 95% CI = 0.15–0.63, P = 0.0012). For BRCA1, we found that haplotype CGTAG was associated with decreased ovarian cancer risk (adjusted OR = 0.64, 95% CI = 0.41–0.98, P = 0.0417). Moreover, women harboring homozygous GA/CGTAG haplotypes showed the lowest risk (OR = 0.12, 95% CI = 0.02–0.94, P = 0.0438). In CCNE1, the SNPs rs3218035 and rs3218042 were significantly associated with increased ovarian cancer risk (rs3218035: adjusted OR = 5.20, 95% CI = 1.85–14.52, P = 0.0017; rs3218042: adjusted OR = 4.98, 95% CI = 1.75–14.19, P = 0.0027). For CDK2, no significant association was found.ConclusionsThis study indicates that genetic polymorphisms of AURKA, BRCA1 and CCNE1 may affect ovarian cancer susceptibility in Chinese Han women.     

MGMT Ile143Val polymorphism,dietary factors and the risk of breast,colorectal and prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study

O⁶-Methylguanine-DNA methyltransferase (MGMT) repairs DNA damage caused by alkylating agents including N-nitroso compounds from diet. MGMT Ile143Val polymorphism may lead to less DNA damage repair and increased cancer risk depending on the environmental exposures. We investigated interactions between dietary factors and the MGMT Ile143Val polymorphism in relation to breast, colorectal and prostate cancer risk. There were 276/1498, 273/2984 and 312/1486 cases/controls for the breast, colorectal and prostate cancer studies respectively; all nested within the EPIC-Norfolk study, a prospective cohort of approximately 25,000 men and women aged 40–79. Baseline 7-day food diary data were collected for dietary assessment. MGMT Ile143Val polymorphism was not overall associated with breast, colorectal and prostate cancer risk. There was a significant interaction between this polymorphism and intake of red and processed meat on colorectal cancer risk (P_interaction = 0.04) suggesting an increased risk among carriers of the variant genotype compared to the MGMT Ile143Ile common genotype. A lower colorectal cancer risk was seen with higher intake of vitamin E and carotene among the variant genotype group but not in the common genotype group (P_interaction = 0.009 and P_interaction = 0.005 for vitamin E and carotene, respectively). A higher prostate cancer risk was seen with higher alcohol intake among the variant genotype (OR = 2.08, 95% CI = 1.21–3.57, P_interaction = 0.0009) compared to the common genotype with lower alcohol intake. In this UK population, the MGMT Ile143Val polymorphism was not overall associated with breast, colorectal and prostate cancer risk. There was evidence for this polymorphism playing a role in modulating the risk of prostate cancer in presence of alcohol. For colorectal cancer, the MGMT Ile143Val polymorphism may confer increased or decreased risk depending on the dietary exposure.     

The impact of PSA and digital rectal examination on the risk of prostate cancer specific mortality in men with a PSA level <2.5 ng/ml

IntroductionIt is unknown whether a normal range, diagnostic serum prostate specific antigen (PSA) level's influence on prostate cancer specific mortality (PCSM) is dependent upon digital rectal examination (DRE) findings.MethodsBetween 2004 and 2007, 9081 men diagnosed with non-palpable (T1c, N = 1710) or palpable (T2–T4, N = 7371) and non-metastatic prostate cancer (PC) were identified from surveillance, epidemiology, and end results data, selected based on pre-treatment PSA < 2.5 ng/ml. A multivariable competing risks regression model evaluated whether DRE findings interacted with PSA level in predicting risk of PCSM.ResultsAfter median follow-up of 2.83 years, 118 of 548 deaths (21.5%) were due to PC. Increasing diagnostic PSA was associated with increased risk of PCSM (AHR = 3.52; 95% CI: 1.25–9.89; P = .017) in men with T1c, Gleason score 7–10 PC, but decreased PCSM risk (AHR = 0.66; 95% CI: 0.52–0.83; P < .001) for men with T2–T4 PC and any Gleason score.DiscussionFor men with diagnostic PSA level <2.5 ng/ml and palpable PC, risk of early PCSM increases by 34% for a 1 point decrease in PSA from 2. This suggests the existence of clinically detectable, low PSA secreting disease with an elevated risk of early PCSM, highlighting the importance of the DRE in men with PC and normal range, diagnostic PSA.     

UDP-glucuronosyltransferase 2B17 genotype and the risk of lung cancer among Austrian Caucasians

Background: The enzyme uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) glucuronidates several endogenous and exogenous compounds, including carcinogens from tobacco smoke like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanl (NNAL). UGT2B17 shows a remarkable copy number variation (CNV) and an association between deletion genotype and increased risk of lung adenocarcinoma in women has been previously reported. Methods: We investigated the UGT2B17 CNV by PCR in 453 Austrian lung cancer patients and in 449 healthy donors and analyzed the impact on lung cancer susceptibility and outcome. Results: Copy numbers of UGT2B17 were 44.4% (+/+), 42.2% (+/?) and 13.5% (?/?) in lung cancer patients and 43.0% (+/+), 46.3% (+/?) and 10.7% (?/?) among healthy donors. The null genotype was not significantly more frequent among women with adenocarcinoma compared to healthy women (p = 0.59). There was no association with overall survival (p = 0.622) and no significant sex-associated (p = 0.423) or histology-related impact on development of lung cancer. Conclusion: UGT2B17 deletion genotype was not associated with a significant risk for lung cancer development or outcome in our Central European patient cohort. Our study indicates that UGT2B17 is not a crucial factor in lung carcinogenesis among Caucasians and shows the importance of investigating such markers in large cohorts from different populations.     

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population

Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C<A) genes has been reported on Bangladeshi population relating those with colorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR = 2.58, 95% CI = 1.77–3.77, p < 0.05) and Pro/Pro mutant homozygosity (adjusted OR = 2.92, 95% CI = 1.78–4.78, p < 0.05) along with the combined genotype (Arg/Pro + Pro/Pro) (adjusted OR = 2.70, 95% CI = 1.90–3.82, p < 0.05) and colorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (p < 0.05) found to be associated with colorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR = 2.02, 95% CI = 1.42–2.87, p < 0.05). In conclusion, heterozygosity and mutant homozygosity as well as the combination of both TP53 Arg72Pro and CDH1 rs16260 polymorphisms are responsible to increase the risk of colorectal cancer development in Bangladeshi population.     

Cancer with Diabetes: Prevalence,Metabolic Control,and Survival in an Academic Oncology Practice

ObjectiveTo determine the prevalence of diabetes mellitus, glycemic control, and impact of diabetes on over all survival in an academic oncology practice.MethodsData on cancer patients (1999 to 2008) were retrieved from the institutional cancer registry and linked to electronic files to obtain diabetes status and hemoglobin A1c (A1C) values within the first 6 months of cancer diagnosis. Overall survival by cancer type with and without diabetes was compared using Cox regression.ResultsExcluding skin and hematologic malignancies, 15,951 cancer cases were identified. Overall diabe tes prevalence was 6.8% (n = 1,090), declining over time (P < 0.001). Diabetes was common among patients with pancreatic (9.8% [61 of 624]), colorectal (7.7% [89 of 1,151]), or bladder cancers (7.6% [68 of 899]). Patients with diabetes were older (mean age, 70 versus 66 years; P < 0.001) and more likely to be male (66.3% [723 of 1,090] versus 60.2% [8,949 of 14,858]; P < 0.001). The mean A1C among diabetic cancer patients was 6.8% and did not dif fer across cancer types (P = 0.80). Only 58.6% (331 of 565) of diabetic cancer patients had all A1C < 7.0% during the first 6 months following cancer diagnosis. Pancreatic cancer patients with coexisting diabetes had better overall survival than pancreatic cancer patients without diabetes (hazard ratio, 0.60; 95% confidence interval 0.44 to 0.80; P < 0.001). Conversely, diabetic prostate cancer patients had worse overall survival than prostate cancer patients without diabetes (hazard ratio, 1.36; 95% confidence interval 1.05 to 1.76; P = 0.02).ConclusionIn this academic oncology practice, diabetes was common, glycemic control often was subopti mal, and survival varied by cancer type. Additional study is needed to optimize glucose management and investigate mechanisms underlying age, sex, and survival differences. (Endocr Pract. 2012;18:898-905)     

A potentially functional polymorphism in the promoter region of let-7 family is associated with survival of hepatocellular carcinoma

Background: The let-7 family plays a vital role in the normal cellular activity of liver cells and the carcinogenesis of hepatocellular carcinoma (HCC). In the previous study, we have detected the association between single nucleotide polymorphisms (SNPs) in the promoter region of let-7 and susceptibility to HCC. However, it is still unknown whether these polymorphisms are associated with HCC prognosis. Methods: We investigated the effect of two potentially functional SNPs in the promoter region of let-7 family, rs10877887 (T > C) and rs13293512 (T > C), on the overall survival of 331 HCC patients. Log-rank test and Cox proportional hazard models were used for the survival analyses. Results: We found that HCC patients carrying the C allele of rs10877887 had a significantly increased death risk (adjusted HR = 1.22, 95%CI = 1.02–1.47, P = 0.03 in the additive model), compared to those with T allele. In the stratified analysis, the risk effect was evident in HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B (adjusted HR = 1.24, 95%CI = 1.02–1.51, P = 0.03) and in those who received chemotherapy or intervention (adjusted HR = 1.25, 95%CI = 1.02–1.53, P = 0.04). Conclusions: Our results suggest that rs10877887 in the promoter region of let-7 may be a prognostic biomarker for HCC patients, which need the validation from other larger studies in different populations.     

Folate deprivation induces cell cycle arrest at G0/G1 phase and apoptosis in hippocampal neuron cells through down-regulation of IGF-1 signaling pathway

Folate deficiency contributes to impaired adult hippocampal neurogenesis, yet the mechanisms remain unclear. Here we use HT-22 hippocampal neuron cells as model to investigate the effect of folate deprivation (FD) on cell proliferation and apoptosis, and to elucidate the underlying mechanism. FD caused cell cycle arrest at G0/G1 phase and increased the rate of apoptosis, which was associated with disrupted expression of folate transport and methyl transfer genes. FOLR1 and SLC46A1 were (P < 0.01) down-regulated, while SLC19A1 was up-regulated (P < 0.01) in FD group. FD cells exhibited significantly (P < 0.05) higher protein content of BHMT, MAT2b and DNMT3a, as well as increased SAM/SAH concentrations and global DNA hypermethylation. The expression of the total and all the 3 classes of IGF-1 mRNA variants was significantly (P < 0.01) down-regulated and IGF-1 concentration was decreased (P < 0.05) in the culture media. IGF-1 signaling pathway was also compromised with diminished activation (P < 0.05) of STAT3, AKT and mTOR. CpG hypermethylation was detected in the promoter regions of IGF-1 and FOLR1 genes, while higher SLC19A1 mRNA corresponded to hypomethylation of its promoter. IGF-1 supplementation in FD media significantly abolished FD-induced decrease in cell viability. However, IGF-1 had limited effect in rescuing the cell phenotype when added 24 h after FD. Taken together, down-regulation of IGF-1 expression and signaling is involved in FD-induced cell cycle arrest and apoptosis in HT-22 hippocampal neuron cells, which is associated with an abnormal activation of methyl transfer pathway and hypermethylation of IGF-1 gene promoter.     

Sex steroid-induced DNA methylation changes and inflammation response in prostate cancer

BackgroundSex steroid hormones have been reported to induce inflammation causing dysregulation of cytokines in prostate cancer cells. However, the underlying epigenetic mechanism has not well been studied. The objective of this study was to evaluate the effect of sex steroid hormones on epigenetic DNA methylation changes in prostate cancer cells using a signature PCR methylation array panel that correspond to 96 genes with biological function in the human inflammatory and autoimmune signals in prostate cancer. Of the 96-gene panel, 32 genes showed at least 10% differentially methylation level in response to hormonal treatment when compared to untreated cells. Genes that were hypomethylated included CXCL12, CXCL5, CCL25, IL1F8, IL13RAI, STAT5A, CXCR4 and TLR5; and genes that were hypermethylated included ELA2, TOLLIP, LAG3, CD276 and MALT1. Quantitative RT-PCR analysis of select genes represented in a cytokine expression array panel showed inverse association between DNA methylation and gene expression for TOLLIP, CXCL5, CCL18 and IL5 genes and treatment of prostate cancer cells with 5′-aza-2′-deoxycytidine with or without trichostatin A induced up-regulation of TOLLIP expression. Further analysis of relative gene expression of matched prostate cancer tissues when compared to benign tissues from individual patients with prostate cancer showed increased and significant expression for CCL18 (2.6-fold; p < 0.001), a modest yet significant increase in IL5 expression (1.17-fold; p = 0.015), and a modest increase in CXCL5 expression (1.4-fold; p = 0.25). In conclusion, our studies demonstrate that sex steroid hormones can induce aberrant gene expression via differential methylation changes in prostate carcinogenesis.     

Glutathione S-transferase M1, T1, and P1 polymorphisms and thyroid cancer risk: A meta-analysis

Glutathione S-transferases (GSTs) genetic variants have been explored extensively as a predictive factor for cancer etiology. This meta-analysis aimed to examine the associations GSTM1, GSTT1, and GSTP1 genetic polymorphisms with thyroid cancer risk. PubMed, EMBASE, Cochrane Library, and HuGNet database were searched up to November 2011 using the appropriate terms. Twelve studies regarding GSTM1 null polymorphism (1569 cases and 2907 controls), 11 studies concerning GSTT1 null polymorphism (1515 cases and 2863 controls), and 8 studies on GSTP1 Ile105Val (965 cases and 1604 controls) were included in the meta-analysis. The random effects odds ratio was 1.07 (95% CI: 0.88–1.31; I² = 54.1%, P for heterogeneity = 0.013) for the GSTM1 null vs. present genotype and 1.08 (95% CI: 0.75–1.57; I² = 81.4%, P for heterogeneity < 0.001) for the GSTT1 null vs. present genotype, and 1.02 (95% CI: 0.70–1.49; I² = 74.6%, P for heterogeneity < 0.001) for the GSTP1 Val/Val + Val/Ile vs. Ile/Ile genotype. Similarly, no significant associations were demonstrated for subgroup analyses performed by ethnicity and histological type. In conclusion, these three polymorphisms are unlikely to be major determinants of susceptibility to thyroid cancer. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation. The relationship between these three genes and thyroid carcinoma must be evaluated further with gene–gene and gene–environment interactions.     

CYP1A2 genetic polymorphisms and adenocarcinoma lung cancer risk in the Tunisian population

AimsIn this study, the effects of four single nucleotide polymorphisms (SNPs), ? 3860G > A, ? 2467delT, ? 739T > G and ? 163C > A, of CYP1A2 gene on lung cancer were evaluated in Tunisian population.Main methodsFour polymorphisms of CYP1A2 gene were analysed in 109 healthy smokers and in 101 lung cancer cases, including 63 with squamous cell carcinoma (SCC) and 41 with adenocarcinoma (AD). The genotyping for the SNPs ? 3860 G > A, ? 2467delT, ? 739T > G and ? 163C > A was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis.Key findingsThe results showed that smokers with CYP1A2 gene polymorphisms were associated with an increased risk for the development of lung AD. There was however no significant increased risk of developing lung SCC in smokers having CYP1A2 gene polymorphisms. An increased risk of developing AD was observed in smokers who are carriers of at least one copy of ? 3680A or ? 739G giving a significant odds ratio (OR) of 6.02 (CI = 2.91–12.9) and 3.01 (CI = 1.54–5.98), respectively.SignificanceThese genotyping data are consistent with the hypothesis that tobacco-specific-N-nitrosamines (TSN) such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are major contributors to the development of lung AD and that CYP1A2 gene product plays an important role in the metabolic activation of NNK. This study suggests that SNPs of CYP1A2 could be considered as promising biomarkers in the aetiology of lung AD in smokers.     

Genetic polymorphisms involved in the inflammatory response and lung cancer risk: A case-control study in Japan

Evidence is accumulating that chronic inflammation may have an important mechanism for the development and progression of lung cancer. Therefore, genetic polymorphisms in genes that involved in the inflammatory response may be associated with lung cancer risk. We evaluated the role of tumor necrosis factor α (TNFA) rs1799724, interleukin 1β (IL1B) rs16944, IL6 rs1800796, myeloperoxidase (MPO) rs2333227 and C-reactive protein (CRP) rs2794520 in a case-control study comprised of 462 lung cancer cases and 379 controls in a Japanese population. Unconditional logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). CRP rs2794520 (OR = 1.64, 95% CI = 1.19–2.26) and IL6 rs1800796 (OR = 1.41, 95% CI = 1.02–1.96) were associated with lung cancer risk. In addition, we assessed interactions between the polymorphisms and smoking. The polymorphisms did not significantly modify the association between smoking and lung cancer. As TNFA triggers a cytokine cascade, the modifying effect of the TNFA rs1799724 genotypes on the association of any of the remaining polymorphisms with lung cancer risk was also examined. There was a significant interaction between TNFA rs1799724 and MPO rs2333227 (P_interaction = 0.058). Future studies involving larger control and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the inflammation pathway in lung cancer.     

Birth weight and subsequent risk of cancer

Background: We aimed to determine the association between self-reported birth weight and incident cancer in the Women's Health Initiative Observational Study cohort, a large multiethnic cohort of postmenopausal women. Methods: 65,850 women reported their birth weight by category (<6 lbs, 6–7 lbs 15 oz, 8–9 lbs 15 oz, and ≥10 lbs). All self-reported, incident cancers were adjudicated by study staff. We used Cox proportional hazards regression to estimate crude and adjusted hazard ratios (aHR) for associations between birth weight and: (1) all cancer sites combined, (2) gynecologic cancers, and (3) several site-specific cancer sites. Results: After adjustments, birth weight was positively associated with the risk of lung cancer (p = 0.01), and colon cancer (p = 0.04). An inverse trend was observed between birth weight and risk for leukemia (p = 0.04). A significant trend was not observed with breast cancer risk (p = 0.67); however, women born weighing ≥10 lbs were less likely to develop breast cancer compared to women born between 6 lbs-7 lbs 15 oz (aHR 0.77, 95% CI 0.63, 0.94). Conclusion: Birth weight category appears to be significantly associated with the risk of any postmenopausal incident cancer, though the direction of the association varies by cancer type.     

Influence of ABCB1 genetic variants in breast cancer treatment outcomes

BackgroundTransportation of anticancer drugs such as anthracyclines across the membrane is regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 (ABCB1). Polymorphisms in the ABCB1 gene (1236C > T, 2677G > T/A, 3435C > T) have been found to be associated with intrinsic and acquired cross resistance to these anticancer drugs. Therefore, the aim of this study is to evaluate the influence of ABCB1 gene polymorphisms in breast cancer treatment outcomes in terms of response and toxicity.MethodResponse to neo-adjuvant chemotherapy was evaluated in 100 patients while grade 2–4 toxicity was followed in 207 patients, who had undergone FEC/FAC chemotherapy. Genotyping for ABCB1 polymorphisms was done by PCR-RFLP. Chi square and logistic regression analyses were used to calculate Odd's ratio using SPSS ver 17.0. A meta analysis was also performed using Comprehensive Meta Analysis Ver 2.ResultsIn response evaluation, 1236C > T polymorphism was significantly associated with treatment response for CT genotype [OR = 5.17(1.3–20.2), P = 0.018] and in dominant model (CC vs CT + TT) [OR = 4.63(1.25–17.0), P = 0.021]. In the toxicity group, the T allele of 1236C>T was associated with grade 2–4 tocxicity [OR 1.48(1.00–2.20), P = 0.049] and the association was also significant in the recessive model [OR 1.88(1.05–3.39), P = 0.033]. For other two SNPs 2677G>T/A and 3435C>T no association was seen with either treatment response or grade 2–4 toxicity. In meta analysis, no overall association was found.ConclusionIn our study, significant association was seen for ABCB1 1236C>T polymorphism with treatment response. The meta analysis did not show overall association with treatment outcomes.