Finasteride Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial

ObjectiveIn the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%, even though high-grade prostate cancer was more common in the finasteride group. However, it remains to be determined whether finasteride concentrations may affect prostate cancer risk. In this study, we examined the association between serum finasteride concentrations and the risk of prostate cancer in the treatment arm of the PCPT and determined factors involved in modifying drug concentrations.MethodsData for this nested case-control study are from the PCPT. Cases were drawn from men with biopsy-proven prostate cancer and matched controls. Finasteride concentrations were measured using a liquid chromatography-mass spectrometry validated assay. The association of serum finasteride concentrations with prostate cancer risk was determined by logistic regression. We also examine whether polymorphisms in the enzyme target and metabolism genes of finasteride are related to drug concentrations using linear regression.

Results and Conclusions

Among men with detectable finasteride concentrations, there was no association between finasteride concentrations and prostate cancer risk, low-grade or high-grade, when finasteride concentration was analyzed as a continuous variable or categorized by cutoff points. Since there was no concentration-dependent effect on prostate cancer, any exposure to finasteride intake may reduce prostate cancer risk. Of the twenty-seven SNPs assessed in the enzyme target and metabolism pathway, five SNPs in two genes, CYP3A4 (rs2242480; rs4646437; rs4986910), and CYP3A5 (rs15524; rs776746) were significantly associated with modifying finasteride concentrations. These results suggest that finasteride exposure may reduce prostate cancer risk and finasteride concentrations are affected by genetic variations in genes responsible for altering its metabolism pathway.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00288106","term_id":"NCT00288106"}}NCT00288106     

Oxidative DNA Damage in the Prostate May Predispose Men to a Higher Risk of Prostate Cancer

DNA damage has been associated with prostate cancer risk. Men who were referred for initial prostate biopsy for elevated prostate-specific antigen or abnormal digital rectal examination are often found with no cancer but have a higher risk of developing prostate cancer than the general population of men in their lifetime. In this study, we investigated whether DNA damage is one of the factors that predispose these men referred for prostate biopsies to a higher risk of prostate cancer. We found significantly elevated levels of 8-oxo-2-deoxyguanosine immunoreactivity in the prostates of the referred men (n = 50) in comparison to the control prostates of men (n = 32) with no indication for referral for prostate biopsy. Twelve of these control men were healthy middle-aged men and 20 of them were older men whose conditions were diagnosed with bladder cancer but with normal serum prostate-specific antigen and digital rectal examination and no evidence of prostate disease. In all the 8-oxo-2-deoxyguanosine-positive prostates, we detected phosphorylation of the ataxia telangiectasia mutated kinase and expression of the immune-stimulatory molecule MIC in the prostate epithelium. These data suggest that: 1) oxidative DNA damage has occurred in the “referred” but pathologically normal prostates, indicating that these prostates may be subjected to genomic instability and eventually neoplastic transformation; 2) in response to DNA damage, two surveillance pathways, represented by ataxia telangiectasia mutated phosphorylation and induction of the NKG2D ligand MIC, were activated to prevent tumorigenesis.     

Genetic Variations in SMAD7 Are Associated with Colorectal Cancer Risk in the Colon Cancer Family Registry

Background

Recent genome-wide studies identified a risk locus for colorectal cancer at 18q21, which maps to the SMAD7 gene. Our objective was to confirm the association between SMAD7 SNPs and colorectal cancer risk in the multi-center Colon Cancer Family Registry.

Materials and Methods

23 tagging SNPs in the SMAD7 gene were genotyped among 1,592 population-based and 253 clinic-based families. The SNP-colorectal cancer associations were assessed in multivariable conditional logistic regression.

Results

Among the population-based families, both SNPs rs12953717 (odds ratio, 1.29; 95% confidence interval, 1.12–1.49), and rs11874392 (odds ratio, 0.80; 95% confidence interval, 0.70–0.92) were associated with risk of colorectal cancer. These associations were similar among the population- and the clinic-based families, though they were significant only among the former. Marginally significant differences in the SNP-colorectal cancer associations were observed by use of nonsteroidal anti-inflammatory drugs, cigarette smoking, body mass index, and history of polyps.

Conclusions

SMAD7 SNPs were associated with colorectal cancer risk in the Colon Cancer Family Registry. There was evidence suggesting that the association between rs12953717 and colorectal cancer risk may be modified by factors such as smoking and use of nonsteroidal anti-inflammatory drugs.     

Outcomes and Trends of Prostate Biopsy for Prostate Cancer in Chinese Men from 2003 to 2011

Background

Prostate-specific antigen (PSA) screening is growing in popularity in China, but its impact on biopsy characteristics and outcomes are poorly understood.

Objective

Our objective was to characterize prostate biopsy outcomes and trends in Chinese men over a 10-year period, since the increasing use of PSA tests.

Methods

All men (n = 1,650) who underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China from 2003–2011 were evaluated. Demographic and clinical information was collected for each patient, including age, digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total prostate-specific antigen (tPSA) levels and free PSA ratio (fPSA/tPSA) prior to biopsy. Prostate biopsy was performed using six cores before October 2007 or ten cores thereafter. Logistic regression and multivariate analysis were used to evaluate our data.

Results

The overall positive rate of prostate biopsy for PCa was 47% and the rate decreased significantly over the years from 74% in 2003 to 33% in 2011 (P-trend = 0.004) . Age at diagnosis was slightly increased (P-trend = 0.04) while fPSA/tPSA was significantly decreased (P-trend = 1.11×10-5). A statistically significant trend was not observed for tPSA levels, prostate volume, or proportion of positive nodule. The model including multiple demographic and clinical variables (i.e., age, DRE, tPSA, fPSA/tPSA and transrectal ultrasound results) (AUC = 0.93) statistically outperformed models that included only PSA (AUC = 0.85) or fPSA/tPSA (AUC = 0.66) to predict PCa risks (P<0.05). Similar results were observed in a subgroup of men whose tPSA levels were lower than 20 ng/mL (AUC = 0.87, vs. AUC of tPSA  = 0.62, P<0.05).

Conclusions

Detection rates of PCa and high-grade PCa among men that underwent prostate biopsy at the institution has decreased significantly in the past 10 years, likely due to increasing use of PSA tests. Predictive performance of demographic and clinical variables of PCa was excellent. These variables should be used in clinics to determine the need for prostate biopsy.     

Higher Body Mass Index Increases the Risk for Biopsy-Mediated Detection of Prostate Cancer in Chinese Men

Objective

To investigate the relationship between body mass index (BMI) and prostate cancer (PCa) risk at biopsy in Chinese men.

Patients and Methods

We retrospectively reviewed the records of 1,807 consecutive men who underwent initial multicore (≥10) prostate biopsy under transrectal ultrasound guidance between Dec 2004 and Feb 2014. BMI was categorised based on the Asian classification of obesity as follows: <18.5 (underweight), 18.5–22.9 (normal weight), 23–24.9 (overweight), 25–29.9 (moderately obese), and ≥30 kg/m2 (severely obese). The odds ratios (OR) of each BMI category for risk of PCa and high-grade prostate cancer (HGPCa, Gleason score ≥4+3) detection were estimated in crude, age-adjusted and multivariate-adjusted models. Prevalence ratios and accuracies of PSA predicted PCa were also estimated across BMI groups.

Results

In total, PCa was detected by biopsy in 750 (45.4%) men, and HGPCa was detected in 419 (25.4%) men. Compared with men of normal weight, underweight men and obese men were older and had higher prostate specific antigen levels. The risk of overall PCa detection via biopsy presented an obvious U-shaped relationship with BMI in crude analysis. Overall, 50.0%, 37.4%, 45.6% 54.4% and 74.1% of the men in the underweight, normal weight, overweight, moderately obese and severely obese groups, respectively, were diagnosed with PCa via biopsy. In multivariate analysis, obesity was significantly correlated with a higher risk of PCa detection (OR = 1.17, 95%CI 1.10–1.25, P<0.001). However, higher BMI was not correlated with HGPCa detection (OR = 1.03, 95%CI 0.97–1.09, P = 0.29). There were no significant differences in the accuracy of using PSA to predict PCa or HGPCa detection across different BMI categories.

Conclusion

Obesity was associated with higher risk of PCa detection in the present Chinese biopsy population. No significant association was detected between obesity and HGPCa.     

Pleiotropic and Sex-Specific Effects of Cancer GWAS SNPs on Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study

Background

Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.

Methods

We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.

Results

We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10^-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10^-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e^-4).

Conclusions

We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.     

Family History of Diabetes is Associated with Increased Risk of Recurrent Diabetic Ketoacidosis in Pediatric Patients

Objective: To determine the relationship between family history of diabetes mellitus (DM) and diabetic ketoacidosis (DKA) recurrence in youth with established type 1 diabetes mellitus (T1DM).Methods: We performed a retrospective chart review of patients with DKA admitted to a pediatric hospital between January, 2009, and December, 2014. We compared patients with recurrent (≥2 admissions) and nonrecurrent DKA (1 admission) and investigated patient level factors, including family history, that may be associated with DKA recurrence in pediatric patients with established T1DM.Results: Of the 131 subjects in the study, 51 (39%) subjects were in the recurrence group. Age ≥15 years old, public health insurance, and family history of T1DM or type 2 diabetes mellitus were associated with recurrent DKA admissions in both univariable and multivariable analyses. Family history was associated with DKA recurrence, with an incidence rate ratio of 1.5 (95% confidence interval = 1.0 to 2.3; P = .03). The association was not explained by type of familial diabetes, first degree relative status, or whether the family member lived in the household.Conclusion: Recognition that a positive family history of DM may be associated with a higher risk for DKA recurrence in patients with established T1DM may allow for targeted education and focus on a previously unidentified population at increased risk for DKA. Understanding the mechanism underlying the effect of family history of diabetes on the rates of DKA in patients with established T1DM may allow for improved identification and education of patients who may be at risk for DKA recurrence.Abbreviations: CI = confidence interval; DKA = diabetic ketoacidosis; EHR = electronic health record; IBD = inflammatory bowel disease; IRR = incidence rate ratio; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus     

The Leptin Gene Family and Colorectal Cancer: Interaction with Smoking Behavior and Family History of Cancer

Background

Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin.

Methodology/Principal Findings

A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13–1.76) and 1.74 (95%CI 1.08–2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82×10⁻¹⁰).

Conclusions/Significance

Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.     

The SNP rs931794 in 15q25.1 Is Associated with Lung Cancer Risk: A Hospital-Based Case-Control Study and Meta-Analysis

Background

Lung cancer is one of the most common human malignant diseases and the leading cause of cancer death worldwide. The rs931794, a SNP located in 15q25.1, has been suggested to be associated with lung cancer risk. Nevertheless, several genetic association studies yielded controversial results.

Methods and Findings

A hospital-based case-control study involving 611 cases and 1062 controls revealed the variant of rs931794 was related to increased lung cancer risk. Stratified analyses revealed the G allele was significantly associated with lung cancer risk among smokers. Following meta-analysis including 6616 cases and 7697 controls confirmed the relevance of rs931794 variant with increased lung cancer risk once again. Heterogeneity should be taken into account when interpreting the consequences. Stratified analysis found ethnicity, histological type and genotyping method were not the sources of between-study heterogeneity. Further sensitivity analysis revealed that the study “Hsiung et al (2010)” might be the major contributor to heterogeneity. Cumulative meta-analysis showed the trend was increasingly obvious with adding studies, confirming the significant association.

Conclusions

Results from our current case-control study and meta-analysis offered insight of association between rs931794 and lung cancer risk, suggesting the variant of rs931794 might be related with increased lung cancer risk.     

Copy Number Variation of GSTT1 and GSTM1 and the Risk of Prostate Cancer in a Caribbean Population of African Descent

Background

Deletions of the glutathione S-transferase genes M1 and T1 (GSTM1 and GSTT1) have been studied as potential risk factors for prostate cancer. Conflicting results have been obtained. Moreover, most such studies could not discriminate heterozygous from homozygous carriers of the non-deleted alleles.

Objective

We investigated whether copy number variation (CNV) of the GSTM1 and/or GSTT1 genes contribute to the risk of prostate cancer in the Caribbean population of African descent of Guadeloupe.

Methods

In a population-based case-control study, we compared 629 prostate cancer patients and 622 control subjects. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Exact copy numbers of GSTM1 and GSTT1 were determined by real-time PCR.

Results

A higher copy number of GSTM1 was marginally associated with prostate cancer risk. Men with 2 and 3 or more GSTT1 genes were at higher risk of prostate cancer (OR: 1.55, 95% CI: 1.11–2.16 and OR: 4.89, 95% CI: 1.71–13.99, respectively; P_trend<0.001). Men with 3, 4 and 5 or more copies of both GSTM1 and GSTT1 genes were at higher risk of prostate cancer (OR: 2.18, 95% CI: 1.21–3.91, OR: 3.24, 95% CI: 1.63–6.46, and OR: 5.77, 95% CI: 1.40–23.84, respectively; P_trend<0.001).

Conclusions

Copy number of GSTT1 and combined GSTM1/GSTT1 appear to be associated with prostate cancer risk in our population study with gene dose relationship. Our results support the hypothesis that variations in copy number of GSTT1 modulate the risk of prostate cancer.     

Mobile Application-Based Seoul National University Prostate Cancer Risk Calculator: Development,Validation, and Comparative Analysis with Two Western Risk Calculators in Korean Men

Objectives

We developed a mobile application-based Seoul National University Prostate Cancer Risk Calculator (SNUPC-RC) that predicts the probability of prostate cancer (PC) at the initial prostate biopsy in a Korean cohort. Additionally, the application was validated and subjected to head-to-head comparisons with internet-based Western risk calculators in a validation cohort. Here, we describe its development and validation.

Patients and Methods

As a retrospective study, consecutive men who underwent initial prostate biopsy with more than 12 cores at a tertiary center were included. In the development stage, 3,482 cases from May 2003 through November 2010 were analyzed. Clinical variables were evaluated, and the final prediction model was developed using the logistic regression model. In the validation stage, 1,112 cases from December 2010 through June 2012 were used. SNUPC-RC was compared with the European Randomized Study of Screening for PC Risk Calculator (ERSPC-RC) and the Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC). The predictive accuracy was assessed using the area under the receiver operating characteristic curve (AUC). The clinical value was evaluated using decision curve analysis.

Results

PC was diagnosed in 1,240 (35.6%) and 417 (37.5%) men in the development and validation cohorts, respectively. Age, prostate-specific antigen level, prostate size, and abnormality on digital rectal examination or transrectal ultrasonography were significant factors of PC and were included in the final model. The predictive accuracy in the development cohort was 0.786. In the validation cohort, AUC was significantly higher for the SNUPC-RC (0.811) than for ERSPC-RC (0.768, p<0.001) and PCPT-RC (0.704, p<0.001). Decision curve analysis also showed higher net benefits with SNUPC-RC than with the other calculators.

Conclusions

SNUPC-RC has a higher predictive accuracy and clinical benefit than Western risk calculators. Furthermore, it is easy to use because it is available as a mobile application for smart devices.     

The Prognostic Value of Family History for the Estimation of Cardiovascular Mortality Risk in Men: Results from a Long-Term Cohort Study in Lithuania

Aim

To evaluate the additional prognostic value of family history for the estimation of cardiovascular (CVD) mortality risk in middle-aged urban Lithuanian men.

Methods

The association between family history of CVD and the risk of CVD mortality was examined in a population-based cohort of 6,098 men enrolled during 1972–1974 and 1976–1980 in Kaunas, Lithuania. After up to 40 years of follow-up, 2,272 deaths from CVD and 1,482 deaths from coronary heart disease (CHD) were identified. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HR) for CVD and CHD mortality.

Results

After adjustment for traditional CVD risk factors, the HR for CVD mortality was 1.24 (95% CI 1.09–1.42) and for CHD mortality 1.20 (1.02–1.42) in men with first-degree relatives having a history of myocardial infarction (MI), compared to men without positive family history. A significant effect on the risk of CVD and CHD mortality was also observed for the family history of sudden cardiac death and any CVD. Addition of family history of MI, sudden death, and any CVD to traditional CVD risk factors demonstrated modest improvement in the performance of Cox models for CVD and CHD mortality.

Conclusions

Family history of CVD is associated with a risk of CVD and CHD mortality significantly and independently of other risk factors in a middle-aged male population. Addition of family history to traditional CVD risk factors improves the prediction of CVD mortality and could be used for identification of high-risk individuals.     

Design of a High Density SNP Genotyping Assay in the Pig Using SNPs Identified and Characterized by Next Generation Sequencing Technology

Background

The dissection of complex traits of economic importance to the pig industry requires the availability of a significant number of genetic markers, such as single nucleotide polymorphisms (SNPs). This study was conducted to discover several hundreds of thousands of porcine SNPs using next generation sequencing technologies and use these SNPs, as well as others from different public sources, to design a high-density SNP genotyping assay.

Methodology/Principal Findings

A total of 19 reduced representation libraries derived from four swine breeds (Duroc, Landrace, Large White, Pietrain) and a Wild Boar population and three restriction enzymes (AluI, HaeIII and MspI) were sequenced using Illumina''s Genome Analyzer (GA). The SNP discovery effort resulted in the de novo identification of over 372K SNPs. More than 549K SNPs were used to design the Illumina Porcine 60K+SNP iSelect Beadchip, now commercially available as the PorcineSNP60. A total of 64,232 SNPs were included on the Beadchip. Results from genotyping the 158 individuals used for sequencing showed a high overall SNP call rate (97.5%). Of the 62,621 loci that could be reliably scored, 58,994 were polymorphic yielding a SNP conversion success rate of 94%. The average minor allele frequency (MAF) for all scorable SNPs was 0.274.

Conclusions/Significance

Overall, the results of this study indicate the utility of using next generation sequencing technologies to identify large numbers of reliable SNPs. In addition, the validation of the PorcineSNP60 Beadchip demonstrated that the assay is an excellent tool that will likely be used in a variety of future studies in pigs.     

Poor Glycemic Control of Diabetes Mellitus Is Associated with Higher Risk of Prostate Cancer Detection in a Biopsy Population

Objectives

To evaluate the impact of glycemic control of diabetes mellitus (DM) on prostate cancer detection in a biopsy population.

Patients and Methods

We retrospectively reviewed the records of 1,368 men who underwent prostate biopsy at our institution. We divided our biopsy population into three groups according to their history of DM, and their Hemoglobin A1c (HbA1c) level: a no-DM (DM−) group; a good glycemic control (DM+GC) group (HbA1c <6.5%); and a poor glycemic control (DM+PC) group (HbA1c ≥6.5%). For sub-analyses, the DM+PC group was divided into a moderately poor glycemic control (DM+mPC) group (6.5≤ HbA1c <7.5%) and a severely poor glycemic control (DM+sPC) group (HbA1c ≥7.5%).

Results

Among 1,368 men, 338 (24.7%) had a history of DM, and 393 (28.7%) had a positive biopsy. There was a significant difference in prostatic specific antigen density (PSAD) (P = 0.037) and the frequency of abnormal DRE findings (P = 0.031) among three groups. The occurrence rate of overall prostate cancer (P<0.001) and high-grade prostate cancer (P = 0.016) also presented with a significantly difference. In the multivariate analysis, the DM+PC group was significantly associated with a higher rate of overall prostate cancer detection in biopsy subjects compared to the DM− group (OR = 2.313, P = 0.001) but the DM+PC group was not associated with a higher rate of high-grade (Gleason score ≥7) diseases detected during the biopsy (OR = 1.297, P = 0.376). However, in subgroup analysis, DM+sPC group was significantly related to a higher risk of high-grade diseases compared to the DM− group (OR = 2.446, P = 0.048).

Conclusions

Poor glycemic control of DM was associated with a higher risk of prostate cancer detection, including high-grade disease, in the biopsy population.     

The SNP rs402710 in 5p15.33 Is Associated with Lung Cancer Risk: A Replication Study in Chinese Population and a Meta-Analysis

Background

Lung cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in the world. A single nucleotide polymorphism (SNP), rs402710, located in 5p15.33, was firstly identified to be associated with the lung cancer risk in a genome-wide association study. However, some following replication studies yielded inconsistent results.

Methodology and Findings

A case-control study of 611 cases and 1062 controls in a Chinese population was conducted, and then a meta-analysis integrating the current and previously published studies with a total 31811 cases and 36333 controls was performed to explore the real effect of rs402710 on lung cancer susceptibility. Significant associations between the SNP rs402710 and lung cancer risk were observed in both case-control study and meta-analysis, with ORs equal to 0.77 (95%CI = 0.63–0.95) and 0.83 (95%CI = 0.81–0.86) in dominant model, respectively. By stratified analysis of our case-control study, the associations were also observed in never smoker group and non-small cell lung cancer(NSCLC) group with ORs equal to 0.71 (95%CI = 0.53–0.95) and 0.69 (95%CI = 0.55–0.87), which was remarkable that larger effect of the minor allele T was seen in the two groups than that in overall lung cancer. Besides, the sensitive and cumulative analysis indicated the robust stability of the current results of meta-analysis.

Conclusion

The results from our replication study and the meta-analysis provided firm evidence that rs402710 T allele significantly contributed to decreased lung cancer risk, and the case-control study implied that the variant may yield stronger effect on NSCLC and never smokers. However, the mechanism underlying the polymorphism conferring susceptibility to lung cancer is warranted to clarify in the follow-up studies.     

Association of GSTM1 Null Allele with Prostate Cancer Risk: Evidence from 36 Case-Control Studies

Background

Glutathione S-transferase M1 (GSTM1) is thought to be involved in detoxifying several carcinogens and may play a vital role in tumorigenesis. Numerous studies have evaluated the association between GSTM1 null/present polymorphism and risk of prostate cancer (PCa). However, the results remain inconsistent. To derive a more precise estimation, we performed a meta-analysis.

Methodology/Principal Findings

A comprehensive search was conducted to identify all eligible case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall association was significant (OR = 1.28, 95% CI: 1.11–1.48, P = 0.001). Moreover, subgroup analyses showed GSTM1 null genotype significantly associated with PCa risk among Asians (OR = 1.35, 95% CI: 1.03–1.78, P = 0.03) but not among Caucasians (OR = 1.12, 95% CI: 0.96–1.31, P = 0.16). In addition, we did not find that smoking modified the genotype effect on the risk of PCa.

Conclusions/Significance

The present meta-analysis suggested that GSTM1 null allele was a low-penetrant risk factor for PCa among Asians.     

Characterization of novel and uncharacterized p53 SNPs in the Chinese population--intron 2 SNP co-segregates with the common codon 72 polymorphism

Multiple single nucleotide polymorphisms (SNPs) have been identified in the tumor suppressor gene p53, though the relevance of many of them is unclear. Some of them are also differentially distributed in various ethnic populations, suggesting selective functionality. We have therefore sequenced all exons and flanking regions of p53 from the Singaporean Chinese population and report here the characterization of some novel and uncharacterized SNPs - four in intron 1 (nucleotide positions 8759/10361/10506/11130), three in intron 3 (11968/11969/11974) and two in the 3'UTR (19168/19514). Allelic frequencies were determined for all these and some known SNPs, and were compared in a limited scale to leukemia and lung cancer patient samples. Intron 2 (11827) and 7 (14181/14201) SNPs were found to have a high minor allele frequency of between 26-47%, in contrast to the lower frequencies found in the US population, but similar in trend to the codon 72 polymorphism (SNP12139) that shows a distribution pattern correlative with latitude. Several of the SNPs were linked, such as those in introns 1, 3 and 7. Most interestingly, we noticed the co-segregation of the intron 2 and the codon 72 SNPs, the latter which has been shown to be expressed in an allele-specific manner, suggesting possible regulatory cross-talk. Association analysis indicated that the T/G alleles in both the co-segregating intron 7 SNPs and a 4tagSNP haplotype was strongly associated increased susceptibility to lung cancer in non-smoker females [OR: 1.97 (1.32, 3.394)]. These data together demonstrate high SNP diversity in p53 gene between different populations, highlighting ethnicity-based differences, and their association with cancer risk.     

Association of MDM2 SNP309 Variation with Lung Cancer Risk: Evidence from 7196 Cases and 8456 Controls

Background

Evidence suggests that MDM2 T309G polymorphism may be a risk factor for several cancers. Increasing investigations have been conducted on the association of MDM2 T309G polymorphisms with lung cancer risk and have yielded conflicting results. Previous meta-analyses on this issue have reported inconclusive data. The aim of the present study was to derive a more precise estimation of the relationship.

Methods and Findings

Updated meta-analyses examining the association between MDM2 T309G polymorphism and lung cancer risk were performed. Separate analyses on ethnicity, smoking status, histological types and gender as well as source of controls were also implemented. Eligible studies were identified for the period up to Feb 2012. Lastly, ten publications including eleven case-control studies were selected for analysis. The overall data failed to indicate a significant association between MDM2 T309G polymorphism and lung cancer risk (GG vs TT OR = 1.14; 95%CI = 0.95−1.37; dominant model: OR = 1.05; 95%CI = 0.92−1.19; recessive model: OR = 1.12; 95%CI = 0.99−1.27). In a subgroup analysis by smoking status, increased lung cancer risk was shown among never-smokers (GG vs TT: OR = 1.76; 95%CI = 1.36−2.29; dominant model: OR = 1.48; 95%CI = 1.22−1.81; recessive model: OR = 1.37; 95%CI = 1.11−1.69). In subgroup analysis by gender, elevated risk was presented among women under a recessive model (OR = 1.29; 95%CI = 1.04−1.59). In the subgroup analysis by ethnicity, histological types and source of controls, no marked associations were observed.

Conclusions

Compared to the previous meta-analyses, the results of this study confirmed that MDM2 T309G polymorphism might be a risk factor for lung cancer among never-smokers. However, the data failed to suggest a marked association between the G allele of MDM2 T309G and lung cancer risk among Asians. More interestingly, subgroup analysis by gender indicated that homozygous GG alleles might raise lung cancer risk among females.     

Association of the Innate Immunity and Inflammation Pathway with Advanced Prostate Cancer Risk

Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.