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Ferroptosis, a form of regulated cell death, is characterized by iron-dependent lipid peroxidation. It is recognized increasingly for its pivotal role in both cancer development and the response to cancer treatments. We assessed associations between 370,027 single-nucleotide polymorphisms (SNPs) within 467 ferroptosis-related genes and survival of non-small cell lung cancer (NSCLC) patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial served as our discovery dataset, while the Harvard Lung Cancer Susceptibility Study used as our validation dataset. For SNPs that remained statistically significantly associated with overall survival (OS) in both datasets, we employed a multivariable stepwise Cox proportional hazards regression model with the PLCO dataset. Ultimately, two independent SNPs, PARK7 rs225120 C>T and DDR2 rs881127 T>C, were identified with adjusted hazard ratios of 1.32 (95% confidence interval = 1.15-1.52, p = .0001) and 1.34 (95% confidence interval = 1.09-1.64, p = .006) for OS, respectively. We aggregated these two SNPs into a genetic score reflecting the number of unfavorable genotypes (NUG) in further multivariable analysis, revealing a noteworthy association between increased NUG and diminished OS (p trend  = .001). Additionally, an expression quantitative trait loci analysis indicated that PARK7 rs225120T genotypes were significantly associated with higher PARK7 mRNA expression levels in both whole blood and normal lung tissue. Conversely, DDR2 rs881127C genotypes were significantly associated with lower DDR2 mRNA expression levels in normal lung tissue. Our findings suggest that genetic variants in the ferroptosis-related genes PARK7 and DDR2 are associated with NSCLC survival, potentially through their influence on gene expression levels., (© 2024 UICC.)

Background: T cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported., Methods: We conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants., Results: Of all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood., Conclusion: Our findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Liu, Wang, Tang, Luo, Du, Christiani and Wei.)

B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis ( P ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D ( INPP5D ) rs13385922 C>T and exosome component 3 ( EXOSC3 ) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10 -4 ) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10 -9 ), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS ( P trend = 0.0002) and disease-specific survival (DSS, P trend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Liu, Wang, Tang, Luo, Du, Christiani and Wei.)

Background: Hypoxia is often involved in tumor microenvironment, and the hypoxia-induced signaling pathways play a key role in aggressive cancer phenotypes, including angiogenesis, immune evasion, and therapy resistance. However, it is unknown what role genetic variants in the hypoxia-related genes play in survival of patients with non-small cell lung cancer (NSCLC)., Methods: We evaluated the associations between 16,092 single-nucleotide polymorphisms (SNPs) in 182 hypoxia-related genes and survival outcomes of NSCLC patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were used as the discovery dataset, and the Harvard Lung Cancer Susceptibility (HLCS) Study served as the replication dataset. We also performed additional linkage disequilibrium analysis and a stepwise multivariable Cox proportional hazards regression analysis in the PLCO dataset., Results: An independent SNP, ERRFI1 rs28624 A > C, was identified with an adjusted hazards ratio (HR) of 1.31 (95% CI = 1.14-1.51, p = 0.0001) for overall survival (OS). In further analyses, unfavorable genotypes AC and CC, compared with the AA genotype, were associated a worse OS (HR = 1.20, 95% CI = 1.03-1.39, p = 0.014) and disease-specific survival (HR = 1.21, 95% CI = 1.04-1.42, p = 0.016). Further expression quantitative trait loci analysis indicated that ERRFI1 rs28624C genotypes were significantly associated with higher ERRFI1 mRNA expression levels in the whole blood. Additional analysis showed that high ERRFI1 mRNA expression levels were associated with a worse OS in patients with lung adenocarcinoma., Conclusion: Our findings suggest that genetic variants in the hypoxia-related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

ATM (ataxia-telangiectasia mutated) is an important cell-cycle checkpoint kinase required for cellular response to DNA damage. Activated by DNA double strand breaks, ATM regulates the activities of many downstream proteins involved in various carcinogenic events. Therefore, ATM or its genetic variants may have a pleiotropic effect on cancer development. We conducted a pleiotropic analysis to evaluate associations between genetic variants of ATM and risk of multiple cancers. With genotyping data extracted from previously published genome-wide association studies of various cancers, we performed multivariate logistic regression analysis, followed by a meta-analysis for each cancer site, to identify cancer risk-associated single-nucleotide polymorphisms (SNPs). In the ASSET two-sided analysis, we found that two ATM SNPs were significantly associated with risk of multiple cancers. One tagging SNP (rs1800057 C>G) was associated with risk of multiple cancers (two-sided P = 5.27 × 10-7). Because ATM rs1800057 is a missense variant, we also explored the intermediate phenotypes through which this variant may confer risk of multiple cancers and identified a possible immune-mediated effect of this variant. Our findings indicate that genetic variants of ATM may have a pleiotropic effect on cancer risk and thus provide an important insight into common mechanisms of carcinogenesis., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients., Methods: We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis., Results: Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10 -7 ], 0.86 (0.80-0.93, P = 9.4 × 10 -5 ) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (P trend  < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes., Conclusion: These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

The mitotic phase is a vital step in cell division and may be involved in cancer progression, but it remains unclear whether genetic variants in mitotic phase-related pathways genes impact the survival of these patients. Here, we investigated associations between 31 032 single nucleotide polymorphisms (SNPs) in 368 mitotic phase-related pathway genes and overall survival (OS) of patients with nonsmall cell lung cancer (NSCLC). We assessed the associations in a discovery data set of 1185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another data set of 984 patients from the Harvard Lung Cancer Susceptibility Study. As a result, we identified three independent SNPs (ie, CHEK1 rs76744140 T>C, PRIM2 rs6939623 G>T and CDK6 rs113181986 G>C) to be significantly associated with NSCLC OS with an adjusted hazard ratio of 1.29 (95% confidence interval = 1.11-1.49, P = 8.26 × 10 -4 ), 1.26 (1.12-1.42, 1.10 × 10 -4 ) and 0.73 (0.63-0.86, 1.63 × 10 -4 ), respectively. Moreover, the number of combined unfavorable genotypes of these three SNPs was significantly associated with NSCLC OS and disease-specific survival in the PLCO data set (P trend  < .0001 and .0003, respectively). Further expression quantitative trait loci analysis showed that the rs76744140C allele predicted CHEK1 mRNA expression levels in normal lung tissues and that rs113181986C allele predicted CDK6 mRNA expression levels in whole blood tissues. Additional analyses indicated CHEK1, PRIM2 and CDK6 may impact NSCLC survival. Taken together, these findings suggested that these genetic variants may be prognostic biomarkers of patients with NSCLC., (© 2021 UICC.)

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two-stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10 -6 , false discovery rate < 0.01). This locus containing seven single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R 2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55-2.54, P = 6.8 × 10 -8 ). Further analysis of ChIP-sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis-regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene-set enrichment analysis. In vitro, RNAi-mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings., (© 2021 Union for International Cancer Control.)

Human leukocyte antigen (HLA) is highly polymorphic, driving antigen presentation, complement cascade and leukocyte maturation against cancer cells. Therefore, we extracted genotyping data in the HLA region from an ongoing Chinese genome-wide association study of non-small cell lung cancer (NSCLC). Using deep sequencing data of 10 689 healthy Han Chinese, we imputed for untyped genetic variants in the HLA region, followed by a two-stage survival analysis of 1531 NSCLC patients. In the discovery stage of 758 patients, we identified 301 out of 15 138 single-nucleotide polymorphisms to be independently associated with overall survival [P < 0.05 and Bayesian false-discovery probability < 0.8]. In further validation of another 773 patients, we confirmed chromosome 6p21, rs241424 (located at intron 3 of TAP2) and rs6457642 as two independent survival predictors. In the combined analysis of 1531 NSCLC patients, rs241424 G>A and rs6457642 C>T were associated with a hazards ratio of 1.26 [95% confidence interval (CI) = 1.14-1.40 and P = 4.04 × 10-6] and 0.76 (95% CI = 0.66-0.87 and P = 1.16 × 10-4), respectively. The analysis of publically available ChIP-sequencing and Hi-C data found that the rs241424 locus was involved in potential cis-regulatory element by a long-range interaction with the HLA-DQA1 promoter. Additional expression quantitative trait loci analysis showed that the rs241424 G>A change decreased HLA-DQA1 mRNA expression. Furthermore, expression levels of HLA-DQA1 were lower in lung cancer tissues than in adjacent normal tissues, and the lower expression was associated with a worse prognosis for patients with lung adenocarcinoma. Collectively, HLA genetic variants may modulate OS of NSCLC patients, possibly via a mechanism of long-range promoter interaction regulating HLA-DQA1 expression., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Acquired platinum resistance impedes successful treatment of epithelial ovarian cancer (EOC), and this resistance may be associated with inherited DNA damage-repair response. In the present study, we performed a two-phase analysis to assess associations between 8191 single-nucleotide polymorphisms within 127 genes of nucleotide excision repair pathway from a genome-wide association study dataset and platinum treatment response in 803 Han Chinese EOC patients. As a result, we identified that platinum-based chemotherapeutic response was associated with two potentially functional variants MNAT1 rs2284704 T>C [TC + CC versus TT, adjusted odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.83-0.95 and P = 0.0005] and HUS1B rs61748571 A>G (AG + GG versus AA, OR = 1.10, 95% CI = 1.03-1.18 and P = 0.005). Compared with the prediction model for clinical factors only, models incorporating HUS1B rs61748571 [area under the curve (AUC) 0.652 versus 0.672, P = 0.026] and the number of unfavorable genotypes (AUC 0.652 versus 0.668, P = 0.040) demonstrated a significant increase in the AUC. Further expression quantitative trait loci analysis suggested that MNAT1 rs2284704 T>C significantly influenced mRNA expression levels of MNAT1 (P = 0.003). These results indicated that MNAT1 rs2284704 T>C and HUS1B rs61748571 A>G may serve as potential biomarkers for predicting platinum treatment response of Chinese EOC patients, once validated by further functional studies., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cutaneous melanoma (CM) is the most lethal type of skin cancers. Nicotinamide adenine dinucleotide phosphate (NADPH) plays an important role in anabolic reactions and tumorigenesis, but many genes are involved in the NADPH system., Methods: We used 10,912 single-nucleotide polymorphisms (SNPs) (2018 genotyped and 8894 imputed) in 134 NADPH-related genes from a genome-wide association study (GWAS) of 858 patients from The University of Texas MD Anderson Cancer Center (MDACC) in a single-locus analysis to predict CM survival. We then replicated the results in another GWAS data set of 409 patients from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS)., Results: There were 95 of 858 (11.1%) and 48 of 409 (11.7%) patients who died of CM, respectively. In multivariable Cox regression analyses, we identified two independent SNPs (TKT rs9864057 G > A and deoxyribose phosphate aldolase (DERA) rs12297652 A > G) to be significantly associated with CM-specific survival [hazards ratio (HR) of 1.52, 95% confidence interval (CI) = 1.18-1.96, P = 1.06 × 10 -3 and 1.51 (1.19-1.91, 5.89 × 10 -4 )] in the meta-analysis, respectively. Furthermore, an increasing number of risk genotypes of these two SNPs was associated with a higher risk of death in the MDACC, the NHS/HPFS, and their combined data sets (P trend <0.001, = 0.004 and <0.001, respectively). In the expression quantitative trait loci analysis, TKT rs9864057 G > A and DERA rs12297652 A > G were also significantly associated with higher mRNA expression levels in sun-exposed lower-leg skin (P = 0.043 and 0.006, respectively)., Conclusions: These results suggest that these two potentially functional SNPs may be valuable prognostic biomarkers for CM survival, but larger studies are needed to validate these findings., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Because the peroxisome proliferator-activated receptor (PPAR) signaling pathway is involved in development and progression of pancreatic cancer, we investigated associations between genetic variants of the PPAR pathway genes and pancreatic cancer risk by using three published genome-wide association study datasets including 8477 cases and 6946 controls of European ancestry. Expression quantitative trait loci (eQTL) analysis was also performed for correlations between genotypes of the identified genetic variants and messenger RNA (mRNA) expression levels of their genes by using available databases of the 1000 Genomes, TCGA, and GTEx projects. In the single-locus logistic regression analysis, we identified 1141 out of 17 532 significant single-nucleotide polymorphisms (SNPs) in 112 PPAR pathway genes. Further multivariate logistic regression analysis identified three independent, potentially functional loci (rs12947620 in MED1, rs11079651 in PRKCA, and rs34367566 in PRKCB) for pancreatic cancer risk (odds ratio [OR] = 1.11, 95% confidence interval [CI], [1.06-1.17], P = 5.46 × 10 -5 ; OR = 1.10, 95% CI, [1.04-1.15], P = 1.99 × 10 -4 ; and OR = 1.09, 95% CI, [1.04-1.14], P = 3.16 × 10 -4 , respectively) among 65 SNPs that passed multiple comparison correction by false discovery rate (< 0.2). When risk genotypes of these three SNPs were combined, carriers with 2 to 3 unfavorable genotypes (NUGs) had a higher risk of pancreatic cancer than those with 0 to 1 NUGs. The eQTL analysis showed that rs34367566 A>AG was associated with decreased expression levels of PRKCB mRNA in 373 lymphoblastoid cell lines. Our findings indicate that genetic variants of the PPAR pathway genes, particularly MED1, PRKCA, and PRKCB, may contribute to susceptibility to pancreatic cancer., (© 2020 Wiley Periodicals, Inc.)

The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing genotyping data from two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with nonsmall cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a singlelocus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression modeling of the PLCO dataset identified three potentially functional and independent SNPs (i.e., KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 (95% confidence interval [CI] = 0.79-0.94, p = 0.0007), 1.31 (1.16-1.47, p = 6.0 × 10 -5 ) and 1.27 (1.12-1.44, p = 0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (p trend < 0.0001 for OS and p trend < 0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes., (© 2019 UICC.)

A few single-nucleotide polymorphisms (SNPs) have been identified to be associated with cutaneous melanoma (CM) survival through genome-wide association studies, but stringent multiple testing corrections required for the hypothesis-free testing may have masked some true associations. Using a hypothesis-driven analysis approach, we sought to evaluate associations between SNPs in ketone body metabolic pathway genes and CM survival. We comprehensively assessed associations between 4196 (538 genotyped and 3658 imputed) common SNPs in 44 ketone body metabolic pathway genes and CM survival, using a dataset of 858 patients of a case-control study from The University of Texas M.D. Anderson Cancer Center as the discovery set and another dataset of 409 patients from the Nurses' Health Study and the Health Professionals Follow-up Study as the replication set. There were 95/858 (11.1%) and 48/409 (11.7%) patients who died of CM, respectively. We identified two independent SNPs (ie, PDSS1 rs12254548 G>C and SLC16A6 rs71387392 G>A) that were associated with CM survival, with allelic hazards ratios of 0.58 (95% confidence interval [CI] = 0.44-0.76, P = 9.00 × 10 -5 ) and 1.98 (95% CI = 1.34-2.94, P = 6.30 × 10 -4 ), respectively. Additionally, associations between genotypes of the SNPs and messenger RNA expression levels of their corresponding genes support the biologic plausibility of a role for these two variants in CM tumor progression and survival. Once validated by other larger studies, PDSS1 rs12254548 and SLC16A6 rs71387392 may be valuable biomarkers for CM survival., (© 2020 Wiley Periodicals, Inc.)

The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression., (© 2019 Wiley Periodicals, Inc.)

As mouse double minute 4 (MDM4) and HPV16 E6 oncoproteins play important roles in inhibition of p53 activity, a functional polymorphism (rs4245739) in the 3' untranslated regions of MDM4 targeted by microRNA-191 may alter its expression level or functional efficiency, thus affecting tumor status and survival in human papillomavirus (HPV)-positive squamous cell carcinoma of oropharynx (SCCOP). A total of 564 incident SCCOP patients with definitive radiotherapy were included for determination of tumor HPV16 status and genotypes of the polymorphism. Univariate and multivariable Cox models were performed to assess the associations between the polymorphism and outcomes. We found that MDM4 rs4245739 had statistically significant associations with tumor HPV-positivity and survival of SCCOP patients. Patients with AC/CC variant genotypes of MDM4 rs4245739 were approximately 3-fold more likely to be HPV16-positive tumors among SCCOP patients compared with common homozygous AA genotype (adjusted odds ratio = 3.2, 95% confidence interval = 1.9-5.5). Moreover, patients with MDM4 rs4245739 AC/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous AA genotype (all log-rank = P < .05); and these genotypes were significantly associated with an approximately three to four times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Finally, the significant effects of MDM4 rs4245739 polymorphism on survival were found among HPV16-positive SCCOP patients only after the stratified analyses by tumor HPV status. We concluded that MDM4 rs4245739 polymorphism is significantly associated with tumor HPV status and survival of SCCOP, especially in HPV16-positive SCCOP patients treated with definitive radiotherapy; nevertheless, prospective larger studies are warranted., (© 2019 Wiley Periodicals, Inc.)

To date, the 5-year overall survival of epithelial ovarian cancer (EOC) remains poor. Because studies suggest that RUVBL1 may be a chemotherapeutic target for the treatment of cancer, in this study, therefore, we investigated the role of potentially functional single nucleotide polymorphisms (SNPs) of RUVBL1 in the survival of Chinese patients with EOC, and we subsequently performed functional prediction and validation of the identified significant SNPs. We found that RUVBL1 rs1057156 A>G and RUVBL1 rs149652370 A>G were associated with survival of EOC patients in the multivariate Cox proportional hazards regression analysis. Specifically, the RUVBL1 rs149652370 AG genotype was associated with a shorter progression-free survival ([adjusted hazards ratio (HR)] = 3.32, 95% confidence interval (CI) = 1.76-6.25 and P = 2.01E-04), compared with the AA genotype. The RUVBL1 rs1057156 AG (only nine had GG) genotype was also associated with a poor overall survival (adjusted HR = 1.73, 95% CI = 1.19-2.52, P = 0.004), compared with the AA genotype. Further experiments showed that the RUVBL1 rs1057156 A>G change lowered its binding affinity to microRNA-4294 and led to upregulation of the RUVBL1 expression. We further found that overexpression of RUVBL1 promoted cell proliferation and metastatic potential. Overall, RUVBL1 enhanced EOC cell proliferation, invasion and migration presumably by stimulating the process of glycolysis. Thus, this study provides evidence that functional variants of RUVBL1 may regulate its gene expression, a possible mechanism affecting survival of EOC patients and that RUVBL1 may be a potential chemotherapeutic target for the treatment of EOC patients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The AURORA pathway participates in mitosis and cell division, and alterations in mitosis and cell division can lead to carcinogenesis. Therefore, genetic variants in the AURORA pathway genes may be associated with susceptibility to pancreatic cancer. To test this hypothesis, we used three large publically available pancreatic cancer genome-wide association study (GWAS) datasets (PanScan I, II/III and PanC4) to assess the associations of 7168 single nucleotide polymorphisms (SNPs) in a set of 62 genes of this pathway with pancreatic cancer risk in 8477 cases and 6946 controls of European ancestry. We identify 15 significant pancreatic cancer risk-associated SNPs in three genes (SMC2, ARHGEF7 and TP53) after correction for multiple comparisons by a false discovery rate < 0.20. Through further linkage disequilibrium analysis, SNP functional prediction and stepwise logistic regression analysis, we focused on three SNPs: rs3818626 in SMC2, rs79447092 in ARHGEF7 and rs9895829 in TP53. We found that these three SNPs were associated with pancreatic cancer risk [odds ratio (OR) = 1.12, 95% confidence interval (CI) = 1.07-1.17 and P = 2.20E-06 for the rs3818626 C allele; OR = 0.76, CI = 0.66-0.88 and P = 1.46E-04 for the rs79447092 A allele and OR = 0.82, CI = 0.74-0.91 and P = 1.51E-04 for the rs9895829 G allele]. Their joint effect as the number of protective genotypes also showed a significant association with pancreatic cancer risk (trend test P ≤ 0.001). Finally, we performed an expression quantitative trait loci analysis and found that rs3818626 and rs9895829 were significantly associated with SMC2 and TP53 messenger RNA expression levels in 373 lymphoblastoid cell lines, respectively. In conclusion, these three representative SNPs may be potentially susceptibility loci for pancreatic cancer and warrant additional validation., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high- and low-penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2-related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2-related genes and PanC risk using three published genome-wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype-phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk (P = 5.17 × 10 -7 , 5.61 × 10 -4 and 5.52 × 10 -4 , respectively). Combined analysis using the number of unfavorable genotypes (NUG) of these three SNP suggested that carriers of two to three NUG had an increased risk of PanC (P < 0.0001), compared with those carrying zero to one NUG. Furthermore, eQTL analysis showed that both rs3124761 T and rs17458086 C alleles were associated with increased mRNA expression levels of SLC2A6 and SLC2A13, respectively (P < 0.05). In conclusion, genetic variants in NRF2 pathway genes could play a role in susceptibility to PanC, and further functional exploration of the underlying molecular mechanisms is warranted., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Remodeling or deregulation of the calcium signaling pathway is a relevant hallmark of cancer including cutaneous melanoma (CM). In this study, using data from a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center, we assessed the role of 41,377 common single-nucleotide polymorphisms (SNPs) of 167 calcium signaling pathway genes in CM survival. We used another GWAS from Harvard University as the validation dataset. In the single-locus analysis, 1830 SNPs were found to be significantly associated with CM-specific survival (CMSS; P ≤ 0.050 and false-positive report probability ≤ 0.2), of which 9 SNPs were validated in the Harvard study (P ≤ 0.050). Among these, three independent SNPs (i.e. PDE1A rs6750552 T>C, ITPR1 rs6785564 A>G and RYR3 rs2596191 C>A) had a predictive role in CMSS, with a meta-analysis-derived hazards ratio of 1.52 (95% confidence interval = 1.19-1.94, P = 7.21 × 10-4), 0.49 (0.33-0.73, 3.94 × 10-4) and 0.67 (0.53-0.86, 0.0017), respectively. Patients with an increasing number of protective genotypes had remarkably improved CMSS. Additional expression quantitative trait loci analysis showed that these genotypes were also significantly associated with mRNA expression levels of the genes. Taken together, these results may help us to identify prospective biomarkers in the calcium signaling pathway for CM prognosis., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

TGF-β1rs1982073 polymorphism at the miRNA-187 binding site may alter TGF-β1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF-β1rs1982073 polymorphism at the miRNA-187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF-β1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer-free controls in the non-Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF-β1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never-smokers (OR, 165.9; 95% CI, 28.6-960.4) or never-drinkers (OR, 196.0; 95% CI, 28.2-1,000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3-87.0 vs. OR, 6.0; 95% CI, 1.7-17.9, respectively). The significant associations between this polymorphism and HPV16-associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF-β1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16-associated oral cancer, particularly in OPSCC subjects who are never-smokers, never-drinkers and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings., (© 2018 UICC.)

Prostate cancer (PCa) is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this correlation, we identified single-nucleotide polymorphisms (SNPs) of stemness-related genes and examined their associations with PCa survival. SNPs within stemness-related genes were analyzed for association with overall survival of PCa in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Significant SNPs predicted to be functional were selected for linkage disequilibrium analysis and combined and stratified analyses. Identified SNPs were evaluated for association with gene expression. SNPs of CD44 (rs9666607), ABCC1 (rs35605 and rs212091) and GDF15 (rs1058587) were associated with PCa survival and predicted to be functional. A role for rs9666607 of CD44 and rs35605 of ABCC1 in RNA splicing regulation, rs212091 of ABCC1 in miRNA binding site activity and rs1058587 of GDF15 in causing an amino acid change was predicted. These SNPs represent potential novel prognostic markers for overall survival of PCa and support a contribution of the stemness pathway to PCa patient outcome.

Given the crucial role of Mouse double minute 4 (MDM4) oncoprotein in p53 pathway, single nucleotide polymorphisms (SNPs) could serve as such biomarkers for prediction of SCCOP recurrence. Thus, we investigated associations between three tagging putatively functional variants of MDM4, two in the 3' untranslated region of 3' UTR [rs11801299 (NC&#95;000001.10:g.204529084G>A) and rs10900598(NC&#95;000001.10:g.204525568G>T)] and one in intron 1 [rs1380576(NC&#95;000001.10:g.204488278G>C)], and recurrence risk of SCCOP in 1,008 incident patients. A log-rank test and multivariable Cox models were used to assess associations. Patients with MDM4-rs10900598 GT/TT had a worse disease-free survival (DFS) compared with corresponding GG genotype, while those with rs11801299 AG/AA genotypes had a lower recurrence risk than the cases with rs11801299 GG genotype (both log-rank, P < 0.001). Multivariable analysis showed that significantly different recurrence risk were found among patients with MDM4-rs10900598 GT/TT and rs11801299 AG/AA variant genotypes (HR, 2.0, 95% CI, 1.4-2.9 and HR, 0.4, 95% CI, 0.3-0.6, respectively) compared with their corresponding common homozygous genotypes. Furthermore, after combining the risk genotypes of the three SNPs, patients among low-risk group had a significantly lower risk of SCCOP recurrence than those in high-risk group (HR, 0.2, 95% CI, 0.1-0.3). The risk for both individual SNPs or combined risk genotypes was restricted to HPV-positive SCCOP patients. Our findings suggest that the MDM4 polymorphisms may, individually or in combination, confer an independent risk of SCCOP recurrence, particularly in HPV-positive SCCOP patients. However, larger studies are needed to validate our findings., (© 2017 Wiley Periodicals, Inc.)

The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14 904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significant lung cancer risk-associated SNPs in two genes (CSNK2B and ZAK) after correction for multiple comparisons by a false discovery rate (FDR) <0.20. After removal of three CSNK2B SNPs that are located in the same locus previously reported by GWAS, we performed the LD analysis and found that rs3769201 and rs7604288 were in high LD. We then chose two independent representative SNPs of rs3769201 and rs722864 in ZAK for further analysis. We also expanded the analysis by including these two SNPs from additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26 380 controls). The overall effects of these two SNPs were assessed using all eight GWAS datasets (OR = 0.92, 95%CI = 0.89-0.95, and P = 1.03 × 10 -5 for rs3769201; OR = 0.91, 95%CI = 0.88-0.95, and P = 2.03 × 10 -6 for rs722864). Finally, we performed an expression quantitative trait loci (eQTL) analysis and found that these two SNPs were significantly associated with ZAK mRNA expression levels in lymphoblastoid cell lines. In conclusion, the ZAK rs3769201 and rs722864 may be functional susceptibility loci for lung cancer risk., (© 2017 Wiley Periodicals, Inc.)

Metzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (P trend  < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS., (© 2017 Wiley Periodicals, Inc.)

DNA repair protects genomic integrity and may modulate chemotherapy efficacy. Few large-scale studies have evaluated predictive roles of genetic variants of DNA repair genes in survival of Chinese gastric cancer (GCa) patients treated with chemotherapy. Here, we assessed the roles of 35 single nucleotide polymorphisms (SNPs) in DNA repair genes in survival of 1002 GCa patients, of whom 694 received chemotherapy and 308 did not. Among patients receiving chemotherapy, the ERCC1 rs2298881A allele was associated with a better survival [hazards ratio (HR) = 0.82, 95% confidence interval (CI) = 0.69-0.98; P = 0.03], whereas two XRCC4 SNPs were associated with a worse survival (HR = 1.26, 95% CI = 1.03-1.54 for the rs10040363G allele, P = 0.02; and HR = 1.30, 95% CI = 1.06-1.59 for the rs2075685T allele, P = 0.01). These three SNPs were unique survival predictors for patients treated with chemotherapy (P < 0.05 for all) but not for patients without chemotherapy (P > 0.05 for all), suggesting that they modulated chemotherapy efficacy. Patients who received chemotherapy and had haplotypes with at least one death-risk allele in XRCC4 had a poor survival, and the trend for an increase in the number of death-risk alleles adversely affecting the survival was also observed in an allelic dose-dependent manner (P trend  = 0.001). Further functional analysis revealed that the death-risk alleles up-regulated the gene expression, leading to a worse survival as suggested by our meta-analysis pooling both mRNA microarray data from the GEO database and published data (ERCC1: HR = 1.31 [1.08-1.58]; P = 0.006). These functional genetic variants may independently or jointly affect survival in chemotherapy-treated GCa patients by modulating the gene expression in the tumors., (© 2017 Wiley Periodicals, Inc.)

Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases-related genes and cutaneous melanoma-specific survival (CMSS) by re-analyzing a published melanoma genome-wide association study (GWAS) and validating the results in another melanoma GWAS. In the single-locus analysis of 36,018 SNPs in 129 Rho-related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false-positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta-analysis derived p = 9.04 × 10 -4 , 9.58 × 10 -4 , 1.21 × 10 -4 and 8.47 × 10 -4 , respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (p trend =1.47 × 10 -7 and 3.12 × 10 -5 ). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five-year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10 -6 ) and ARHGAP22 (p = 5.0 × 10 -6 ), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment., (© 2017 UICC.)

Cutaneous melanoma (CM) is the most lethal skin cancer. The Wnt pathway has an impact on development, invasion, and metastasis of CM, thus likely affecting CM prognosis. Using data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center, we assessed the associations of 19,830 common single-nucleotide polymorphisms (SNPs) in 151 Wnt pathway autosomal genes with CM-specific survival and then validated significant SNPs in another genome-wide association study from Harvard University. In the single-locus analysis, 1,855 SNPs were significantly associated with CM-specific survival at P < 0.05, of which 547 SNPs were still considered noteworthy after the correction by the false-positive report probability. In the replication, two SNPs remained significantly associated with CM-specific survival after multiple comparison correction. By performing functional prediction and stepwise selection, we identified two independent SNPs (i.e., WNT2B rs1175649 G>T and BTRC rs61873997 G>A) that showed a predictive role in CM-specific survival, with an effect-allele-attributed hazards ratio (adjusted hazards ratio) of 1.99 (95% confidence interval = 1.41-2.81, P = 8.10 × 10 -5 ) and 0.61 (0.46-0.80, 3.12×10 -4 ), respectively. Collectively, these variants in the Wnt pathway genes may be biomarkers for outcomes of patients with CM, if validated by larger studies., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10 -6 , FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10 -3 [odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P = 6.70 × 10 -5 ). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding., (© 2017 Wiley Periodicals, Inc.)

The T-cell protein tyrosine phosphatase (TCPTP) pathway consists of signaling events mediated by TCPTP. Mutations and genetic variants of some genes in the TCPTP pathway are associated with lung cancer risk and survival. In the present study, we first investigated associations of 5,162 single nucleotide polymorphisms (SNPs) in 43 genes of this TCPTP pathway with lung cancer risk by using summary data of six published genome-wide association studies (GWAS) of 12,160 cases and 16,838 controls. We identified 11 independent SNPs in eight genes after correction for multiple comparisons by a false discovery rate <0.20. Then, we performed in silico functional analyses for these 11 SNPs by eQTL analysis, two of which, PTPN2 SNPs rs2847297 and rs2847282, were chosen as tagSNPs. We further included two additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls), and the overall effects of these two SNPs among all eight GWAS studies remained significant (OR = 0.95, 95% CI = 0.92-0.98, and P = 0.004 for rs2847297; OR = 0.95, 95% CI = 0.92-0.99, and P = 0.009 for rs2847282). In conclusion, the PTPN2 rs2847297 and rs2847282 may be potential susceptible loci for lung cancer risk.

Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1 008 patients. A log-rank test and multivariable Cox models were used to assess the associations. Compared with patients with variant genotypes of E2F2-rs2742976 and E2F2-rs3218123, patients with common homozygous genotypes had better disease-free survival (both log-rank, P < 0.001) and lower SCCOP recurrence risk (HR, 0.4, 95% CI, 0.3-0.6 and HR, 0.3, 95% CI, 0.2-0.5, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of E2F2-rs2742976 and E2F2-rs3218123 had better disease-free survival rates (both log-rank, P < 0.001) and lower recurrence risk (HR, 0.1, 95% CI, 0.1-0.4 and HR, 0.1, 95% CI, 0.0-0.2, respectively) than patients with variant genotypes. However, no significant differences were found for the other three polymorphisms. After combining the risk genotypes of the five polymorphisms and using the high-risk group (2-5 risk genotypes) as the reference group, we found that the low-risk groups (0 or 1 risk genotype) had significantly lower recurrence risk among all patients (HR, 0.4, 95% CI, 0.3-0.6) and among HPV16-positive patients (HR, 0.2, 95% CI, 0.1-0.5). Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16-positive tumors. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Purpose: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk., Experimental Design: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci., Results: This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association., Conclusion: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Genetic polymorphisms at miRNA-binding sites may affect miRNA-mediated gene regulation. Thus, miRNA-binding site polymorphisms in double-strand break (DSB) repair genes may affect DNA repair capacity, which in turn could affect cancer prognosis. To determine whether miRNA-binding site polymorphisms in DSB repair genes are associated with the risk of recurrence of squamous cell carcinoma of the non-oropharynx (SCCNOP), we used a log-rank test and multivariable Cox models to evaluate the associations between miRNA-binding site polymorphisms in DSB repair genes and SCCNOP recurrence. Compared with patients without common homozygous genotypes, patients with the variant genotypes of ATM rs227091, LIG3 rs4796030, and RAD51 rs7180135 had significantly better disease-free survival (DFS) (log-rank P = 0.046, 0.002, and 0.041, respectively) and lower risk of disease recurrence [HR (95% CI) = 0.7 (0.6-0.9), 0.6 (0.5-0.9), and 0.7 (0.6-0.9), respectively]. Furthermore, patients with the variant genotypes of these 3 polymorphisms had significantly lower recurrence risk than those without common homozygous genotypes did [HR = 0.3 (95% CI = 0.2-0.7)]. Among patients who received chemoradiation, those with the individual or combined variant genotypes of the three polymorphisms had a significantly lower risk of disease recurrence than those with the individual or combined common homozygous genotypes did. The individual or combined variant genotypes of the ATM rs227091, LIG3 rs4796030, and RAD51 rs7180135 polymorphisms significantly modify the risk of SCCNOP recurrence, particularly for patients treated with chemoradiation. Future prospective studies with larger sample sizes are warranted to validate these findings to enable more effective personalized treatment for SCCNOP patients., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer.

To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re-analyzing a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM-specific survival (CMSS) (p ≤ 0.050 and false-positive report probability ≤ 0.20), and nine SNPs were validated in the Harvard study (p ≤ 0.050). Among these, three independent SNPs (i.e., DOCK1 rs11018104 T > A, rs35748949 C > T and PAK2 rs1718404 C > T) showed a predictive role in CMSS, with an effect-allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18-1.90, p = 7.46E-04), 1.53 (1.18-1.97, 1.18E-03) and 0.58 (0.45-0.76, 5.60E-05), respectively]. Haplotype analysis revealed that a haplotype carrying two risk alleles A-T in DOCK1 was associated with the poorest survival in both MDACC (adjHR = 1.73, 95% CI = 1.19-2.50, p = 0.004) and Harvard (adjHR = 1.95, 95% CI = 1.14-3.33, p = 0.010) studies. In addition, patients with an increasing number of unfavorable genotypes (NUGs) for these three SNPs had a poorer survival. Incorporating NUGs with clinical variables showed a significantly improved ability to classify CMSS (AUC increased from 86.8% to 88.6%, p = 0.031). Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients. Further large, prospective studies are needed to validate these findings., Competing Interests: The authors state no conflict of interest., (© 2016 UICC.)

Human papillomavirus (HPV) activates E2F1-driven transcription via the E7-RB1-E2F pathway. Genetic polymorphisms in the 3' untranslated region (UTR) targeted by miRNAs can affect the regulation of target genes and individual cancer risk. Thus, we hypothesized that a polymorphism at the 3'UTR miRNA binding site of E2F1 gene (rs3213180) was associated with risk of oral squamous cell carcinoma (OSCC) and tumor HPV status of oropharynx squamous cell carcinoma (OPSCC). We determined the E2F1rs3213180 polymorphism and HPV16 L1 serology of 325 OSCC patients and 335 controls, and tumor HPV16 status of 552 OPSCC. Logistic regression models were used to calculate associations of E2F1rs3213180 polymorphism with risk of HPV-associated OSCC and tumor HPV status of OPSCC. The risk of HPV-associated OSCC was modified by the E2F1rs3213180 polymorphism. Patients with both HPV seropositivity and the Ins/Del or Ins/Ins genotype of E2F1rs3213180 had the highest risk of OSCC, while the lowest risk was detected in patients with HPV seronegativity and the Del/Del genotype. A similar and more prominent effect was detected in OPSCC, but not in oral cavity squamous cell carcinoma (OCSCC) patients. Notably, that effect trend was pronounced in never-smokers and never-drinkers. Furthermore, the patients with the E2F1rs3213180 Ins/Del or Ins/Ins genotype were 2.9 times more likely to have HPV-positive tumors than those with the Del/Del genotype. Our results suggest that the E2F1rs3213180 polymorphism may influence susceptibility to HPV-associated OSCC, particularly for OPSCC, never-smokers and never-drinkers, but not for patients with OCSCC. Additional larger population and functional studies are warranted to confirm our findings. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Breslow thickness (BT) is a major prognostic factor of cutaneous melanoma (CM), the most fatal skin cancer. The genetic component of BT has only been explored by candidate gene studies with inconsistent results. Our objective was to uncover the genetic factors underlying BT using an hypothesis-free genome-wide approach. Our analysis strategy integrated a genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) for BT followed by pathway analysis of GWAS outcomes using the gene-set enrichment analysis (GSEA) method and epistasis analysis within BT-associated pathways. This strategy was applied to two large CM datasets with Hapmap3-imputed SNP data: the French MELARISK study for discovery (966 cases) and the MD Anderson Cancer Center study (1,546 cases) for replication. While no marginal effect of individual SNPs was revealed through GWAS, three pathways, defined by gene ontology (GO) categories were significantly enriched in genes associated with BT (false discovery rate ≤5% in both studies): hormone activity, cytokine activity and myeloid cell differentiation. Epistasis analysis, within each significant GO, identified a statistically significant interaction between CDC42 and SCIN SNPs (pmeta-int =2.2 × 10(-6) , which met the overall multiple-testing corrected threshold of 2.5 × 10(-6) ). These two SNPs (and proxies) are strongly associated with CDC42 and SCIN gene expression levels and map to regulatory elements in skin cells. This interaction has important biological relevance since CDC42 and SCIN proteins have opposite effects in actin cytoskeleton organization and dynamics, a key mechanism underlying melanoma cell migration and invasion., Competing Interests: The authors declare that they have no conflict of interest., (© 2016 UICC.)

Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10 -7 ) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11-1.24; P = 8.31 × 10 -9 ). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.

DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair leads to cancer. We hypothesize that functional genetic variants in DNA repair genes are associated with risk of lung cancer. We performed a large-scale meta-analysis of 123,371 single nucleotide polymorphisms (SNPs) in 169 DNA repair genes obtained from six previously published genome-wide association studies (GWASs) of 12160 lung cancer cases and 16838 controls. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) using the logistic regression model and used the false discovery rate (FDR) method for correction of multiple testing. As a result, 14 SNPs had a significant odds ratio (OR) for lung cancer risk with P FDR < 0.05, of which rs3115672 in MSH5 (OR = 1.20, 95% CI = 1.14-1.27) and rs114596632 in GTF2H4 (OR = 1.19, 95% CI = 1.12-1.25) at 6q21.33 were the most statistically significant (P combined = 3.99×10(-11) and P combined = 5.40×10(-10), respectively). The MSH5 rs3115672, but not GTF2H4 rs114596632, was strongly correlated with MSH5 rs3131379 in that region (r (2) = 1.000 and r (2) = 0.539, respectively) as reported in a previous GWAS. Importantly, however, the GTF2H4 rs114596632 T, but not MSH5 rs3115672 T, allele was significantly associated with both decreased DNA repair capacity phenotype and decreased mRNA expression levels. These provided evidence that functional genetic variants of GTF2H4 confer susceptibility to lung cancer., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (P trend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02-1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3'-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.

Background: Adjuvant chemotherapy in patients with resected esophageal squamous cell cancer (ESCC) remains controversial for its uncertain role in improving overall survival (OS). Nucleotide excision repair (NER) removes DNA-adducts in tumor cells induced by the platinum-based chemotherapy and thus may modulate efficacy of the treatment. The present study evaluated if single nucleotide polymorphisms (SNPs) of NER genes were prognostic biomarkers in ESCC patients treated with platinum-based adjuvant chemotherapy (PAC)., Methods: The analysis included 572 patients, for whom six SNPs of NER genes [i.e., XPC (rs1870134 and rs2228001), ERCC2/XPD rs238406 and ERCC5/XPG (rs2094258, rs2296147 and rs873601)] were detected with the TaqMan assay. Kaplan-Meier analyses and Cox proportional hazards models were used to evaluate their associations with disease free survival (DFS) and OS of these ESCC patients receiving PAC. Receiving operating characteristic curve analysis was used to evaluate the role of the risk genotypes in the DFS and OS., Results: We found that ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406 SNPs were independently associated with poorer DFS and OS of ESCC patients [ERCC5/XPG rs2094258: CT+TT vs. CC: adjusted hazards ratio (adjHR) = 1.68 and P = 0.012 for DFS; adjHR = 1.99 and P = 0.0001 for OS; ERCC5/XPG rs873601: GA+GG vs. AA: adjHR = 1.59 and P = 0.024 for DFS; adjHR = 1.91 and P = 0.0005 for OS; ERCC2/XPD rs238406: TT vs. GG+GT: adjHR = 1.43 and P = 0.020 for DFS; adjHR = 1.52 and P = 0.008 for OS]. These HRs increased as the number of risk genotypes increased in the combined analysis. The model combining the risk genotypes with clinical characteristics or the TNM stage system was better in predicting outcomes in ESCC patients with PAC., Conclusion: SNPs of ERCC2/XPD and ERCC5/XPG may independently and jointly predict survival of ESCC patients treated with PAC in this study population. Further validation in other study populations is warranted.

Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma (ESCC). Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC. Some single nucleotide polymorphisms (SNPs) in genes involved in this pathway may contribute to ESCC susceptibility. We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population. None of individual SNPs exhibited an association with ESCC risk. However, the combined analysis of three AKT1 SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio (OR) = 0.60, 95% CI = 0.42-0.87]. Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43-0.94) and non-drinkers (OR = 0.79, 95% CI = 0.64-0.99). Similar protective effects on women (adjusted OR = 0.56, 95% CI = 0.37-0.83) and non-drinker (adjusted OR = 0.75, 95% CI = 0.60-0.94) were also observed for the combined genotypes of AKT1 SNPs. Consistently, logistic regression analysis indicated significant gene-gene interactions among three AKT1 SNPs (P < 0.015). A three-AKT1 SNP haplotype (C-A-C) showed a significant association with a decreased ESCC risk (adjusted OR = 0.70, 95% CI = 0.52-0.94). Multifactor dimensionality reduction analysis confirmed a high-order gene-environment interaction in ESCC risk. Overall, we found that three AKT1 SNPs might confer protection against ESCC risk; nevertheless, these effects may be dependent on other risk factors. Our results provided evidence of important gene-environment interplay in ESCC carcinogenesis., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Single nucleotide polymorphisms (SNPs) in the vitamin D pathway genes have been implicated in cutaneous melanoma (CM) risk, but their role in CM disease-specific survival (DSS) remains obscure. We comprehensively analyzed the prognostic roles of 2669 common SNPs in the vitamin D pathway genes using data from a published genome-wide association study (GWAS) at The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated the SNPs of interest in another GWAS from the Nurses' Health Study and Health Professionals Follow-up Study. Among the 2669 SNPs, 203 were significantly associated with DSS in MDACC dataset (P < 0.05 and false-positive report probability < 0.2), of which 18 were the tag SNPs. In the replication, two of these 18 SNPs showed nominal significance: the VDBP rs12512631 T > C was associated with a better DSS [combined hazards ratio (HR) = 0.66]; and the same for RXRA rs7850212 C > A (combined HR = 0.38), which were further confirmed by the Fine and Gray competing-risks regression model. Further bioinformatics analyses indicated that these loci may modulate corresponding gene methylation status., Competing Interests: The authors state no conflict of interest., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Accumulative epidemiological evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in homologous recombination (HR) DNA repair pathway play an important role in glioma susceptibility. However, the effects of such SNPs on glioma risk remain unclear. We used a used a candidate pathway-based approach to elucidate the relationship between glioma risk and 12 putative functional SNPs in genes involved in the HR pathway. Genotyping was conducted on 771 histologically-confirmed glioma patients and 752 cancer-free controls from the Chinese Han population. Odds ratios (OR) were calculated both for each SNP individually and for grouped analyses, examining the effects of the numbers of adverse alleles on glioma risk, and evaluated their potential gene-gene interactions using the multifactor dimensionality reduction (MDR). In the single-locus analysis, two variants, the NBS1 rs1805794 (OR 1.42, 95% CI 1.15-1.76, P = 0.001), and RAD54L rs1048771 (OR 1.61, 95% CI 1.17-2.22, P = 0.002) were significantly associated with glioma risk. When we examined the joint effects of the risk-conferring alleles of these three SNPs, we found a significant trend indicating that the risk increases as the number of adverse alleles increase (P = 0.005). Moreover, the MDR analysis suggested a significant three-locus interaction model involving NBS1 rs1805794, MRE11 rs10831234, and ATM rs227062. These results suggested that these variants of the genes involved in the HR pathway may contribute to glioma susceptibility.

Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10(-38)); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10(-9)). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00-2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11-3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.

CD133 is one of the most common stem cell markers, and functional single nucleotide polymorphisms (SNPs) of CD133 may modulate its gene functions and thus cancer risk and patient survival. We hypothesized that potentially functional CD133 SNPs are associated with gastric cancer (GC) risk and survival. To test this hypothesis, we conducted a case-control study of 371 GC patients and 313 cancer-free controls frequency-matched by age, sex, and ethnicity. We genotyped four selected, potentially functional CD133 SNPs (rs2240688A>C, rs7686732C>G, rs10022537T>A, and rs3130C>T) and used logistic regression analysis for associations of these SNPs with GC risk and Cox hazards regression analysis for survival. We found that compared with the miRNA binding site rs2240688 AA genotype, AC + CC genotypes were associated with significantly increased GC risk (adjusted OR = 1.52, 95% CI = 1.09-2.13); for another miRNA binding site rs3130C>T SNP, the TT genotype was associated with significantly reduced GC risk (adjusted OR = 0.68, 95% CI = 0.48-0.97), compared with CC + CT genotypes. In all patients, the risk rs3130 TT variant genotype was significantly associated with overall survival (OS) (adjusted P(trend) = 0.016 and 0.007 under additive and recessive models, respectively). These findings suggest that these two CD133 miRNA binding site variants, rs2240688 and rs3130, may be potential biomarkers for genetic susceptibility to GC and possible predictors for survival in GC patients but require further validation by larger studies., (© 2013 Wiley Periodicals, Inc.)

Thymidylate synthase (TYMS) is involved in the folate metabolism and provision of nucleotides needed for DNA synthesis and repair. Thus, functional genetic variants in TYMS may alter cancer risk. In the study, we evaluated associations of three germline variants (rs2790 A > G, rs16430 6 bp > 0 bp, and rs1059394 C > T) in the predicted miRNA-binding sites of TYMS with risk of sporadic breast cancer in non-Hispanic white women aged ≤ 55. We found that carriers of the rs16430 0 bp variant allele had an increased risk of breast cancer [adjusted odd ratio (OR) = 1.37, 95% confidence interval (CI): 1.08-1.73; P = 0.010], compared with carriers of the 6 bp/6 bp genotype. This increased risk was more evident in older subjects (OR = 1.47, 95% CI = 1.06-2.03, P = 0.022), never smokers (OR = 1.67, 95% CI = 1.23-2.25, P < 0.001), never drinkers (OR = 1.44, 95% CI = 1.01-2.05, P = 0.043), and estrogen receptor-positive patients (OR = 1.46, 95% CI = 1.11-1.92, P = 0.006), regardless of tumor stages. The results are consistent with the functional analyses of rs16430 as previously reported, which showed that the 0 bp allele had a decrease in both luciferase activity by ∼ 70% and mRNA levels by ∼ 50% compared with the 6bp allele. Additionally, the rs16430 variant was predicted to influence the binding activity of miR-561. Taken together, these findings indicate that the TYMS rs16430 may contribute to the etiology of sporadic breast cancer in non-Hispanic white women aged ≤ 55 yr. Further validation in large population-based or cohort studies is needed., (© 2013 Wiley Periodicals, Inc.)

Functional genetic variants of DNA repair genes may alter the host DNA repair capacity, and thus influence efficiency of therapies. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in genes (i.e. ERCC1, XPA, XPC, XPD and XPG) involved in the nucleotide excision repair (NER) pathway in 496 Japanese gastric cancer patients, and assessed overall survival and recurrence-free survival. The combined effects of risk genotypes of these eight SNPs in Japanese patients were further replicated in 356 North-American gastric cancer patients. In Japanese patients, we found that the XPC rs2228000 TT genotype was associated with shorter overall survival [hazards ratio (HR) = 1.75, 95% confidence interval (95% CI) = 1.07-2.86] and recurrence-free survival (HR = 2.17, 95% CI = 1.19-3.95), compared with CC/CT genotypes, and the XPG rs17655 CC genotype was associated with shorter overall survival (HR = 1.60, 95% CI = 1.08-2.36), compared with GG/CG genotypes. The number of observed risk genotypes in the combined analysis was associated with shorter overall survival and recurrence-free survival in a dose-response manner (P(trend) = 0.006 and P(trend) < 0.000) in Japanese patients; specifically, compared with those with ≤1 risk genotypes, those with ≥2 risk genotypes showed markedly shorter overall survival (HR = 1.79, 95% CI = 1.18-2.70) and recurrence-free survival (HR = 2.80, 95% CI = 1.66-4.73). The association between ≥2 risk genotypes and shorter overall survival was not significant (HR = 1.26, 95% CI = 0.82-1.94) in North-American patients, but the trends were similar in these two groups of patients. These data show that functional SNPs in NER core genes may impact survival in Japanese gastric cancer patients., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: LIN28 is an RNA-binding protein that not only plays key roles in multiple cellular developmental processes and tumourigenesis, but also is involved in tissue inflammatory response. However, no published study has investigated associations between genetic variants in LIN28 and radiation-induced pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiation therapy., Methods: We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of LIN28A (rs11247946 T>C, rs3811464 C>T, rs11581746 T>C, and rs12728900 G>A) and LIN28B (rs314280 G>A, rs12194974 G>A, rs17065417 A>C and rs314276 C>A) in 362 patients with NSCLC, who received definitive radio(chemo)therapy. The associations between RP risk and genotypes were assessed by hazards ratio (HR) in Cox proportional hazards regression analysis with time to event considered with and without adjustment for potential confounders., Results: Multivariate analyses found that patients carrying LIN28B rs314280 AG and AA/AG or rs314276 AC and AA/AC genotypes had a higher risk of grade ⩾3 RP (for rs314280 AG and AA/AG versus GG, adjusted HR=2.97 and 2.23, 95% confidence interval (CI)=1.32-6.72 and 1.01-4.94, P=0.009 and 0.048, respectively; for rs314276 AC and AA/AC versus CC, adjusted HR=2.30 and 2.00, 95% CI=1.24-4.28 and 1.11-3.62, and P=0.008 and 0.022, respectively). Further stratified analyses showed a more consistent and profound risk in the subgroups of age <65years, males, stage III/IV, ever smokers, having radio-chemotherapy and mean lung dose (MLD) ⩾19.0Gy., Conclusion: Genetic variants of LIN28B, but not LIN28A, may be biomarkers for susceptibility to severe RP in NSCLC patients. Large, prospective studies are needed to confirm our findings., (Copyright © 2014. Published by Elsevier Ltd.)