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1.  Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans 
Human Molecular Genetics  2013;22(14):2948-2959.
Aiming to identify novel genetic loci for pigmentation and skin cancer, we conducted a series of genome-wide association studies on hair color, eye color, number of sunburns, tanning ability and number of non-melanoma skin cancers (NMSCs) among 10 183 European Americans in the discovery stage and 4504 European Americans in the replication stage (for eye color, 3871 males in the discovery stage and 2496 males in the replication stage). We targeted novel chromosome regions besides the known ones for replication. As a result, we identified a new region downstream of the EDNRB gene on 13q22 associated with hair color and the strongest association was the single-nucleotide polymorphism (SNP) rs975739 (P = 2.4 × 10−14; P = 5.4 × 10−9 in the discovery set and P = 1.2 × 10−6 in the replication set). Using blue, intermediate (including green) and brown eye colors as co-dominant outcomes, we identified the SNP rs3002288 in VASH2 on 1q32.3 associated with brown eye (P = 7.0 × 10−8; P = 5.3 × 10−5 in the discovery set and P = 0.02 in the replication set). Additionally, we identified a significant interaction between the SNPs rs7173419 and rs12913832 in the OCA2 gene region on brown eye color (P-value for interaction = 3.8 × 10−3). As for the number of NMSCs, we identified two independent SNPs on chr6 and one SNP on chromosome 14: rs12203592 in IRF4 (P = 7.2 × 10−14; P = 1.8 × 10−8 in the discovery set and P = 6.7 × 10−7 in the replication set), rs12202284 between IRF4 and EXOC2 (P = 5.0 × 10−8; P = 6.6 × 10−7 in the discovery set and P = 3.0 × 10−3 in the replication set) and rs8015138 upstream of GNG2 (P = 6.6 × 10−8; P = 5.3 × 10−7 in the discovery set and P = 0.01 in the replication set).
doi:10.1093/hmg/ddt142
PMCID: PMC3690971  PMID: 23548203
2.  Obesity-related genetic variants, human pigmentation, and risk of melanoma 
Human genetics  2013;132(7):793-801.
Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles=0.12, P-value=4 10−5). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R-square quality metric >0.8 using the 1000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity.
doi:10.1007/s00439-013-1293-4
PMCID: PMC3683389  PMID: 23539184
obesity; pigmentation; melanoma; genetic association; FTO gene
3.  Association between a rare novel TP53 variant (rs78378222) and melanoma, squamous cell carcinoma of head and neck and lung cancer susceptibility in non-Hispanic Whites 
Recently, several studies have investigated the association between a newly reported rare functional single nucleotide polymorphism (SNP) in TP53 (rs78378222) and cancer risk but generated inconsistent findings. The present study further investigated this association with risk of melanoma, squamous cell carcinoma of head and neck (SCCHN) and lung cancer. Using subjects of non-Hispanic whites recruited for three large case-control studies, we genotyped the TP53 rs78378222 SNP in 1,329 patients with melanoma, 1,096 with SCCHN, 1,013 with lung cancer, and 3000 cancer-free controls. Overall, we did not observe any variant homozygotes in this study population, nor significant associations between the TP53 rs78378222AC genotype or C allele and risk for melanoma (P=0.680 and 0.682, respectively) and lung cancer (P=0.379 and 0.382, respectively) but a protection against SCCHN (P=0.008 and 0.008, respectively), compared with the AA genotype or A allele. An additional meta-analysis including 19,423 cancer patients and 54,050 control subjects did not support such a risk association either. Our studies did not provide statistical evidence of an association between this rare TP53 variant and increased risk of melanoma, nor of lung cancer, but a possible protection against SCCHN.
doi:10.1111/jcmm.12076
PMCID: PMC3729608  PMID: 23742673
biomarker; genetic susceptibility; genotype; polymorphism
4.  Variants in melanocortin 1 receptor gene contribute to risk of melanoma – a direct sequencing analysis in a Texas population 
Pigment cell & melanoma research  2013;26(3):10.1111/pcmr.12070.
Summary
In this study, we directly sequenced the Melanocortin 1 Receptor (MC1R) gene in 2,212 individuals to detect all variants and assessed their associations with cutaneous melanoma (CM) risk in a hospital-based study of 1,106 CM patients and 1,106 control subjects. Of 61 MC1R variants identified, 16 rare variants have not been previously reported by others; three MC1R variants were associated with a significant CM risk [c.451C>T (OR = 1.78, 95% CI = 1.44–2.20), c.478C>T (OR = 1.31, 95% CI = 1.05–1.63), and c.880G>C (OR = 1.69, 95% CI = 1.15–2.48)]; and two with borderline CM risk [c.942A>G (OR =1.23, 95% CI =1.00–1.51, and c.274G>A (OR = 1.23,95% CI = 0.99–1.53)] under a dominant model. When combined these five MC1R variants for cumulative effect analysis, we found that subjects with an increased number of variant genotypes from any of these five variants had significantly increased risk of CM with ORs of 1.68 (95% CI = 1.39–2.04), 1.61 (95% CI = 1.27–2.04), and 2.64 (95% CI = 1.72–4.05) for one, two, and three or more variant genotypes, respectively (trend test: P <0.001). Further haplotype and diplotype analyses based on the above-mentioned five SNPs suggested that the c.451T allele contributed to the high risk of CM and that the five variants may have joint effects on the risk of CM. Additional analysis suggests that the three most significant SNPs may be the molecular mechanisms underlying the known risk factors of the colors of the eyes, skin and hair in this study population. In conclusion, our study provided confirmatory evidence that both common and rare variants in the MC1R coding region may be biomarkers for susceptibility to CM in US populations.
doi:10.1111/pcmr.12070
PMCID: PMC3721512  PMID: 23360207
melanocortin 1 receptor gene; direct sequencing; interaction; melanoma; case-control
5.  Association between putative functional variants in the PSMB9 gene and risk of melanoma - re-analysis of published melanoma genome-wide association studies 
Pigment cell & melanoma research  2013;26(3):10.1111/pcmr.12069.
Summary
To mine possibly hidden causal single nucleotide polymorphisms (SNPs) in the etiology of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) dataset with 1804 melanoma cases and 1,026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in other two GWAS datasets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL dataset (P = 0.013 and 0.004, respectively), but failed validation in the Australia dataset. Genotype-phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression levels of PSMB9. Further experiments revealed that the promoter SNP rs2071480, which is in high LD with rs1351383 and rs2127675, involved in influencing transcription factor binding and gene expression. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility.
doi:10.1111/pcmr.12069
PMCID: PMC3721546  PMID: 23360169
GWAS; Cell cycle; PSMB9; Polymorphism; melanoma
6.  Functional repeats (TGYCC)n in the p53-inducible gene 3 (PIG3) promoter and susceptibility to squamous cell carcinoma of the head and neck 
Carcinogenesis  2012;34(4):812-817.
A polymorphic pentanucleotide microsatellite sequence (TGYCC)n within the p53-inducible gene 3 (PIG3) promoter is correlated with the extent of transcriptional activation by p53 and thought to modulate susceptibility to cancer. Using a PCR–silver staining-based single-strand conformation assay, we visualized variant genotypes of the PIG3 promoter (TGYCC)n motif in a subset of 100 subjects for each of four ethnic groups: non-Hispanic whites, African Americans, Hispanic Americans and Native Chinese. We found that PIG3 (TGYCC)15 was the most common allele but less frequent in non-Hispanic whites (0.660) than in Chinese (0.785) (P = 0.016). In an additional study of 616 patients with squamous cell carcinoma of the head and neck (SCCHN) and 623 cancer-free controls in a non-Hispanic white population, we found that compared with those who were PIG3 (TGYCC)15 homozygotes, subjects without the PIG3 (TGYCC)15 allele had a significantly increased SCCHN risk [adjusted odds ratio (OR) = 1.34; 95% CI = 1.04–1.73 for heterozygotes and OR = 1.69; 95% CI = 1.18–2.44 for variant homozygotes] in an allele-dose response manner (P = 0.002). Consistently, subsequent luciferase reporter assay revealed that the wild-type (TGYCC)15 allele had the highest p53-mediated transcriptional activity, compared with the other (TGYCC)n motifs. Our data suggest that the PIG3 variant polymorphic repeats alleles other than (TGYCC)15 may affect p53 binding and thus may be a marker for susceptibility to SCCHN, but our findings need to be validated in larger studies.
doi:10.1093/carcin/bgs388
PMCID: PMC3616663  PMID: 23241165
7.  Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk 
Carcinogenesis  2013;34(4):885-892.
Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P < 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3ʹ untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82–0.96, P = 0.003, false discovery rate = 0.056). Further genotype–phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings.
doi:10.1093/carcin/bgs407
PMCID: PMC3616673  PMID: 23291271
8.  ATM POLYMORPHISMS PREDICT SEVERE RADIATION PNEUMONITIS IN PATIENTS WITH NON-SMALL CELL LUNG CANCER TREATED WITH DEFINITIVE RADIATION THERAPY 
Purpose
The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP).
Methods and Materials
We genotyped three potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [−111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive radio(chemo)therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered.
Results
Of 362 patients with 82% of non-Hispanic whites, 56 (15.5%) experienced grade ≥ 3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes, or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs. AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29–0.83, P = 0.009; rs228590: TT/CT vs. CC, HR=0.57, 95% CI, 0.33–0.97, P =0.036; haplotype: G-T-G vs. A-C-G, HR=0.52, 95% CI, 0.35–0.79, P =0.002). Such positive findings remained in non-Hispanic whites.
CONCLUSIONS
ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings.
doi:10.1016/j.ijrobp.2012.09.024
PMCID: PMC3594431  PMID: 23154078
Non–small cell lung cancer; radiation pneumonitis; single-nucleotide polymorphisms; ataxia telangiectasia mutated gene
9.  INCORPORATING SINGLE NUCLEOTIDE POLYMORPHISMS INTO THE LYMAN MODEL TO IMPROVE PREDICTION OF RADIATION PNEUMONITIS 
Purpose
To determine whether single nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor beta, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC).
Methods and Materials
Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGFβ, TNFα, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiotherapy, with or without chemotherapy. The LKB model was used to estimate the risk of severe (Grade ≥3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate (MV) analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data.
Results
Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGFβ, VEGF, TNFα, XRCC1 and APEX1. With smoking status included in the MV model, the SNPs significantly associated with increased risk of RP were in genes for TGFβ, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often.
Conclusions
This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk versus <10% risk of RP when exposed to high MLDs.
doi:10.1016/j.ijrobp.2012.02.021
PMCID: PMC3521878  PMID: 22541966
SNP; NTCP; biomarker; non-small cell lung cancer
10.  Genome-Wide Association Study Reveals Novel Genetic Determinants of DNA Repair Capacity in Lung Cancer 
Cancer research  2012;73(1):256-264.
Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenotype and genotypes detected by the Illumina 317K platform in 1,774 individuals of European ancestry from a Texas lung cancer genome-wide association study. The discovery phase was followed by a replication in an independent set of 1,374 cases and controls of European ancestry. We applied a generalized linear model with SNPs as predictors and DRC (a continuous variable) as the outcome. Covariates of age, sex, pack-years of smoking, DRC assay-related variables and case-control status of the study participants were adjusted in the model. We validated that reduced DRC was associated with an increased risk of lung cancer in both independent datasets. Several suggestive loci that contributed to the DRC phenotype were defined in ERCC2/XPD, PHACTR2 and DUSP1. In summary, we determined that DRC is an independent risk factor for lung cancer and we defined several genetic loci contributing to DRC phenotype.
doi:10.1158/0008-5472.CAN-12-1915
PMCID: PMC3537906  PMID: 23108145
DNA repair capacity; genetic susceptibility; genome-wide association; molecular epidemiology
11.  Polymorphisms of Nucleotide Excision Repair Genes Predict Melanoma Survival 
Melanoma is the most highly malignant skin cancer, and nucleotide excision repair (NER) is involved in melanoma susceptibility. In this analysis of 1042 melanoma patients, we evaluated whether genetic variants of NER genes may predict survival outcome of melanoma patients. We used genotyping data of 74 tagging single nucleotide polymorphisms (tagSNPs) in eight core NER genes from our genome-wide association study (including 2 in XPA, 14 in XPC, 3 in XPE, 4 in ERCC1, 10 in ERCC2, 8 in ERCC3, 14 in ERCC4, and 19 in ERCC5) and evaluated their associations with prognosis of melanoma patients. Using the Cox proportional hazards model and Kaplan-Meier analysis, we found a predictive role of XPE rs28720291, ERCC5 rs4150314, XPC rs2470458 and ERCC2 rs50871 SNPs in prognosis of melanoma patients (rs28720291: AG vs. GG, adjusted hazard ratio [adjHR] = 11.2, 95% confidence interval [CI] 3.04–40.9, P = 0.0003; rs4150314: AG vs. GG, adjHR = 4.76, 95% CI 1.09–20.8, P = 0.038; rs2470458: AA vs. AG/GG, adjHR = 2.11, 95% CI 1.03–4.33, P = 0.040; and rs50871: AA vs. AC/CC adjHR =2.27, 95% CI 1.18–4.35, P = 0.015). Patients with an increasing number of unfavorable genotypes had dramatically increased death risk. Genetic variants of NER genes, particularly XPE rs28720291, ERCC5 rs4150314, XPC rs2470458 and ERCC2 rs50871, may independently or jointly modulate survival outcome of melanoma patients. Because our results were based on a median follow-up of 3 years without multiple test corrections, additional large prospective studies are needed to confirm our findings.
doi:10.1038/jid.2012.498
PMCID: PMC3660504  PMID: 23407396
melanoma; nucleotide excision repair; survival; association
12.  Joint Effect of Multiple Common SNPs Predicts Melanoma Susceptibility  
PLoS ONE  2013;8(12):e85642.
Single genetic variants discovered so far have been only weakly associated with melanoma. This study aims to use multiple single nucleotide polymorphisms (SNPs) jointly to obtain a larger genetic effect and to improve the predictive value of a conventional phenotypic model. We analyzed 11 SNPs that were associated with melanoma risk in previous studies and were genotyped in MD Anderson Cancer Center (MDACC) and Harvard Medical School investigations. Participants with ≥15 risk alleles were 5-fold more likely to have melanoma compared to those carrying ≤6. Compared to a model using the most significant single variant rs12913832, the increase in predictive value for the model using a polygenic risk score (PRS) comprised of 11 SNPs was 0.07(95% CI, 0.05-0.07). The overall predictive value of the PRS together with conventional phenotypic factors in the MDACC population was 0.69 (95% CI, 0.64-0.69). PRS significantly improved the risk prediction and reclassification in melanoma as compared with the conventional model. Our study suggests that a polygenic profile can improve the predictive value of an individual gene polymorphism and may be able to significantly improve the predictive value beyond conventional phenotypic melanoma risk factors.
doi:10.1371/journal.pone.0085642
PMCID: PMC3877376  PMID: 24392023
13.  Genetic variants of a BH3-only pro-apoptotic gene, PUMA, and risk of HPV16-associated squamous cell carcinoma of the head and neck 
Molecular carcinogenesis  2011;51(Suppl 1):E54-E64.
P53 up-regulated modulator of apoptosis (PUMA) is a critical factor in the intrinsic apoptotic pathway. Through PUMA-dependent mechanisms, human papillomavirus 16 (HPV16) oncoprotein may affect apoptosis by E6-mediated p53 degradation. To examine whether the PUMA variants modify the association between HPV16 serology and risk of squamous cell carcinoma of the head and neck (SCCHN), we genotyped two polymorphisms in the PUMA promoter (rs3810294 and rs2032809) in 380 cases and 335 cancer-free controls of non-Hispanic whites, who were frequency-matched by age (± 5 years), sex, smoking and drinking status. We found that each individual polymorphism had only a modest impact on risk of SCCHN, particularly in oropharyngeal cancer for rs3810294 and non-oropharyngeal cancer for rs2032809. After we stratified the individuals by HPV16 serology, and used those with the corresponding common homozygous genotype and HPV16 seronegativity as the reference group, for each polymorphism we found that the risk of SCCHN associated with HPV16 seropositivity was higher among those with variant genotypes than those with the corresponding common homozygous genotype. Notably, this effect modification was particularly pronounced in several subgroups including never smokers, never drinkers, younger patients, and patients with oropharyngeal cancer. Furthermore, we also characterized the functional relevance of the two polymorphisms to explore the genotype-phenotype correlation. Our results suggested that the PUMA promoter polymorphisms may be a biomarker for risk of HPV16-associated SCCHN, particularly in never smokers, never drinkers, younger patients, and patients with oropharyngeal cancer. Larger studies are needed to validate our findings.
doi:10.1002/mc.21838
PMCID: PMC3326219  PMID: 22086558
PUMA polymorphisms; HPV16; genetic susceptibility; molecular epidemiology; squamous cell carcinoma of the head and neck
14.  Combined effects of E2F1 and E2F2 polymorphisms on risk and early onset of squamous cell carcinoma of the head and neck 
Molecular carcinogenesis  2012;51(Suppl 1):E132-E141.
Deregulated expression of most members of the E2F family has been detected in many human cancers. We examined the association of common single nucleotide polymorphisms (SNPs) of E2F1 and E2F2 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,096 SCCHN patients and 1,090 cancer-free controls. We genotyped ten selected SNPs in E2F1 and E2F2, including those at the near 5′ UTR, miRNA binding sites at the near 3′ UTR and tagSNPs according to bioinfotmatics analysis. Although none of the selected SNPs alone was significantly associated with risk of SCCHN, there was a statistically significantly increased risk of SCCHN associated with the combined risk genotypes (i.e. rs3213182 AA, rs3213183 GG, rs3213180 GG, rs321318121 GG, rs2742976 GT+TT, rs6667575 GA+AA, rs3218203 CC, rs3218148 AA, rs3218211 CC, rs3218123 GT+TT). Compared with those with 0–4 risk genotypes, an increased risk was observed for those who carried 5–8 risk genotypes (adjusted OR = 1.04; 95% CI = 0.86–1.26) and 9–10 risk genotypes (adjusted OR = 1.62; 95% CI = 1.14–2.30) in a dose-response manner (P = 0.045). Furthermore, the joint effect was more pronounced among patients with oropharyngeal cancer, younger adults (≤57 years old), men, non-smokers, non-drinkers, and individuals with family history of cancer first-degree relatives. Additionally, we also observed that those with 5–10 risk genotypes had an earlier SCCHN onset than those with 0–4 risk genotypes, particularly for non-smokers and/or non-drinkers. We concluded that E2F1 and E2F2 genetic variants may jointly play important roles in head and neck carcinogenesis.
doi:10.1002/mc.21882
PMCID: PMC3370129  PMID: 22344756
E2F1; E2F2; head and neck cancer; polymorphisms; age at onset
15.  HSPB1 Gene Polymorphisms Predict Risk of Mortality for U.S. Patients after Radio(chemo)therapy for Non-Small-Cell Lung Cancer 
Purpose
We investigated potential associations between single-nucleotide polymorphisms (SNPs) in the heat shock protein beta-1 (HSPB1) gene and overall survival in U.S. patients with non–small-cell lung cancer (NSCLC).
Materials and Methods
Using available genomic DNA samples from 224 patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped two SNPs of HSPB1 (rs2868370 and rs2868371). We used both Kaplan-Meier cumulative probability and Cox proportional hazards analyses to evaluate the effect of HSPB1 genotypes on survival.
Results
Our cohort comprised 117 men and 107 women, mostly white (79.5%), with a median age of 70 years. The median radiation dose was 66 Gy (range 63–87.5 Gy), and 183 patients (82%) received concurrent platinum-based chemotherapy. The most common genotype of the rs2868371 SNP was CC (61%). Univariate and multivariate analyses showed that this genotype was associated with poorer survival than carriers of CG/GG genotypes (univariate hazard ratio [HR]=1.39, 95% confidence interval [CI] 1.02–1.90, P = 0.037; multivariate HR=1.39; 95% CI 1.01–1.92; P = 0.045).
Conclusion
Our results show that the CC genotype of HSPB1 rs2868371 was associated with poorer overall survival in patients with NSCLC after radio(chemo)therapy, findings that contradict those of a previous study of Chinese patients. Validation of our findings with larger numbers of similar patients is needed, as are mechanical and clinical studies to determine the mechanism underlying these associations.
doi:10.1016/j.ijrobp.2012.03.032
PMCID: PMC3426644  PMID: 22608953
Non–small cell lung cancer; radiation therapy; overall survival; single-nucleotide polymorphisms; heat shock protein beta-1
16.  Influence of single nucleotide polymorphisms in the MMP1 promoter region on cutaneous melanoma progression 
Melanoma Research  2012;22(2):169-175.
Recently, we reported on the associations of seven single-nucleotide polymorphisms (SNPs) in the promoter region of MMP1 gene with susceptibility to cutaneous melanoma (CM). Considering the reported correlation between MMP1 expression and melanoma progression, we hypothesized that these promoter SNPs might affect CM progression and prognosis. In this study, we examined the associations of the seven SNPs with overall survival as well as six clinicopathologic factors in 754 patients with CM. After adjustment for 11 covariates, we observed significant association of the SNP −422A > T (rs475007) with ulceration status (P = 0.012), primary tumor thickness (P = 0.040), and anatomic site (P = 0.030). We also observed significant association of the SNP −755T > G (rs498186) with ulceration status (P = 0.038) and anatomic site (P = 0.003). Two SNPs −839G > A and −519A > G were marginally associated with primary tumor thickness, ulceration status, and anatomic site. Furthermore, the frequency of haplotype 2G-G-G-A-A-G-T was higher in patients with ulceration (odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.08–4.40, P = 0.030) than that in those without ulceration. However, we did not find significant associations of these SNPs with overall survival and other clinical factors. Since primary tumor thickness and ulceration status are two important indicators of tumor progression and have significant associations with melanoma prognosis, our results suggested that these promoter SNPs in MMP1 might have potential effects on melanoma progression and prognosis by influencing related clinical factors.
doi:10.1097/CMR.0b013e32834fc46b
PMCID: PMC3296883  PMID: 22198560
Genotypes; Melanoma; Survival; Tumor characters; Molecular epidemiology
17.  ERCC1 and ERCC2 Variants Predict Survival in Gastric Cancer Patients 
PLoS ONE  2013;8(9):e71994.
Purpose
ERCC1 and ERCC2 play critical roles in the nucleotide excision repair pathway that effectively repairs DNA damage induced by chemotherapeutic agents. Therefore, functional single nucleotide polymorphisms (SNPs) in these genes could have an impact on clinical outcomes in cancer patients who received chemotherapy. However, few studies have simultaneously investigated the roles of ERCC1 and ERCC2 SNPs in clinical outcomes in gastric cancer patients.
Experimental Design
We genotyped by the TaqMan assay three common, potentially functional ERCC1 (rs3212986) and ERCC2 SNPs (rs13181 and rs1799793) in 360 gastric cancer patients. We used both Kaplan-Meier tests and Cox proportional hazards models to evaluate the effects of ERCC1 and ERCC2 genotypes and haplotypes on clinical outcomes.
Results
We found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS) (AA vs. GG+AG, log-rank P = 0.012) and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [HR] 2.13; 95% CI, 1.28 to 3.56; P = 0.004). In combined analyses, patients with any one of the three unfavorable genotypes (i.e. ERCC1 rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA) had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P = 0.025), compared with those without any unfavorable genotypes. Furthermore, the haplotype A-G-G (rs1799793/rs13181/rs3212986) had a significant impact on OS (Adjusted HR, 1.57; 95% CI, 1.11 to 2.21; P = 0.011), compared with the common haplotype G-T-G.
Conclusion
ERCC1 and ERCC2 functional SNPs may jointly affect OS in Caucasian gastric cancer patients. Additional large prospective studies are essential to confirm our findings.
doi:10.1371/journal.pone.0071994
PMCID: PMC3759385  PMID: 24023723
18.  Genome-wide gene–environment interaction analysis for asbestos exposure in lung cancer susceptibility 
Carcinogenesis  2012;33(8):1531-1537.
Asbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene–environment interactions. To determine gene–asbestos interactions in lung cancer risk, we conducted genome-wide gene–environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10–6, which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10–5). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene–asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk.
Abbreviations:CIconfidence intervalEenvironmentFDRfalse discovery rateGgeneGSEAgene-set-enrichment analysisGWASgenome-wide association studiesi-GSEAimproved gene-set-enrichment analysis approachORodds ratioSNPsingle nucleotide polymorphism
doi:10.1093/carcin/bgs188
PMCID: PMC3499061  PMID: 22637743
19.  The miR-184 Binding-Site rs8126 T>C Polymorphism in TNFAIP2 Is Associated with Risk of Gastric Cancer 
PLoS ONE  2013;8(5):e64973.
Background
TNFAIP2 is a crucial gene involved in apoptosis. Single nucleotide polymorphisms (SNPs) in its miRNA binding sites could modulate functions of the miRNA-target genes and thus risk of cancers. In this study, we investigated associations between potentially functional SNPs in the miRNA binding sites of the 3′UTR of TNFAIP2 and gastric cancer risk in a US population.
Methods
We conducted a case-control study of 301 gastric cancer patients and 313 cancer-free controls frequency-matched by age, sex and ethnicity. We genotyped four selected TNFAIP2 SNPs (rs8126 T>C, rs710100 G>A, rs1052912 G>A and rs1052823 G>T) and used the logistic regression analysis to assess associations of these SNPs with cancer risk.
Results
The rs8126 CC genotype was associated with a significantly elevated risk of gastric cancer (adjusted OR = 2.00, 95% CI = 1.09–3.64 and P = 0.024), compared with the combined rs8126 TT+TC genotypes, particularly in current drinkers. However, none of other TNFAIP2 SNPs was associated with risk of gastric cancer.
Conclusions
Our data suggested that the TNFAIP2 miRNA binding site rs8126 T>C SNP may be a marker for susceptibility to gastric cancer, and this finding requires further validation by larger studies.
doi:10.1371/journal.pone.0064973
PMCID: PMC3665554  PMID: 23724109
20.  Polymorphisms of the VEGF Gene and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy 
Cancer Science  2012;103(5):945-950.
Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and lung cancer progression. We hypothesized that VEGF polymorphisms may modulate the risk of radiation pneumonitis (RP) in non-small cell lung cancer (NSCLC) patients treated with definitive radiotherapy. We genotyped three potentially functional VEGF SNPs [−460 T>C (rs833061), −634 G>C (rs2010963), and +936 C >T (rs3025039)] and estimated the associations of their genotypes and haplotypes with severe radiation pneumonitis (RP ≥ grade 3) in 195 NSCLC patients. We found that the VEGF genotypes of rs2010963 and rs3025039 SNPs as well as the −460C/−634G/+936C haplotype were predictors of RP development (adjusted hazard ratio [adjHR] = 2.33, 95% confidence interval [CI], 1.01–5.37, P = 0.047 for CC vs. GG genotypes; adjHR = 28.13, 95% CI, 5.24–151.02, P < 0.001 for TT vs. CC genotypes; and adjHR = 2.51, 95% CI, 1.27–4.98, P = 0.008 for T-C-T vs. C-G-C halotypes). In addition, there was a trend towards reduced RP risk in patients carrying an increased number of protective VEGF genotypes. Our data suggest that VEGF polymorphisms can modulate the risk of radiation pneumonitis in NSCLC patients treated with definitive radiotherapy. Large and independent studies are needed to confirm our findings.
doi:10.1111/j.1349-7006.2012.02229.x
PMCID: PMC3337362  PMID: 22320189
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
21.  Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx 
Cancer  2011;118(6):1684-1692.
BACKGROUND
The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16-associated squamous cell carcinoma of head and neck (SCCHN).
METHODS
Genotyping was conducted on three tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer-free controls that were frequency-matched by age, sex, smoking, and drinking status.
RESULTS
None of three MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers.
CONCLUSION
The risk of HPV16-associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings.
doi:10.1002/cncr.26423
PMCID: PMC3213304  PMID: 21823114
MDM4 polymorphisms; genetic susceptibility; human papillomavirus; molecular epidemiology; squamous cell carcinoma of head and neck cancer; squamous cell carcinoma of the oropharynx
22.  Genetic Variants of the Non-homologous End Joining Gene LIG4 and Severe Radiation Pneumonitis in Non-small Cell Lung Cancer Patients Treated with Definitive Radiotherapy 
Cancer  2011;118(2):528-535.
Background
Non-homologous end joining (NHEJ) is a pathway that repairs DNA double-strand breaks (DSBs) to maintain genomic stability in response to irradiation. We hypothesized that single nucleotide polymorphisms (SNPs) in NHEJ repair genes may affect clinical outcomes among non-small cell lung cancer (NSCLC) patients treated with definitive radio(chemo)therapy.
Methods
We genotyped five potentially functional SNPs (i.e., XRCC4 rs6869366 [-1394G>T] and rs28360071 [intron 3, del/ins], XRCC5 rs3835 [2408G>A], XRCC6 rs2267437 [-1310C>G] and LIG4 rs1805388 [T9I]) and estimated their associations with severe radiation pneumonitis (RP, ≥ grade 3) in 195 NSCLC patients.
Results
We found a predictive role of LIG4 rs1805388 SNP in RP development (adjusted hazard ratio [HR] = 2.08, 95% confidence interval [CI], 1.04-4.12, P = 0.037 for CT/TT vs. CC). In addition, male patients with the TT genotype of XRCC4 rs6869366 SNP and female patients with AG/AA genotypes of XRCC5 rs3835 SNP were also at increased risk of severe RP development.
Conclusions
Our results suggest that NHEJ genetic polymorphisms, particularly LIG4 rs1805388, may modulate the risk of radiation pneumonitis in NSCLC patients treated with definitive radio(chemo)therapy. Large studies are needed to confirm our findings.
doi:10.1002/cncr.26214
PMCID: PMC3184314  PMID: 21717429
Radiation pneumonitis; Polymorphism; Non-small cell lung cancer
23.  Polymorphisms of XPG/ERCC5 and risk of squamous cell carcinoma of the head and neck 
Pharmacogenetics and genomics  2012;22(1):50-57.
Objectives
Xeroderma pigmentosum group G (XPG) protein is essential for the nucleotide excision repair (NER) system, and genetic variations in XPG/ERCC5 that affect DNA repair capacity may contribute to the risk of tobacco-induced cancers, including squamous cell carcinoma of the head and neck (SCCHN). We investigated the association between XPG/ERCC5 polymorphisms and risk of squamous cell carcinoma of the head and neck (SCCHN).
Methods
We genotyped 12 tagging and potentially functional single nucleotide polymorphisms (SNPs) of XPG/ERCC5 in a case-control study of 1,059 non-Hispanic white patients with SCCHN and 1,066 cancer-free age-and sex matched controls and evaluated their associations with SCCHN risk.
Results
Multivariate logistic regression showed that only an intronic tagging SNP (rs4150351A/C) of XPG/ERCC5 was associated with a decreased risk of SCCHN (adjusted OR=0.76, 95% CI=0.62–0.92 for AC vs. AA; adjusted OR=0.81, 95% CI=0.67–0.98 for AC/CC vs. AA), but this association was nonsignificnant after corrections by the permutation test (empirical P=0.105). In the genotype-phenotype correlation analysis using peripheral lymphocytes from 44 SCCHN patients, we found that rs4150351 AC/CC was associated with a statistically significant increase in XPG/ERCC5 mRNA expression.
Conclusion
These findings suggest that genetic variation in XPG/ERCC5 may not affect the SCCHN risk, although rs4150351 C variant genotypes were associated with the increased expression of XPG/ERCC5 mRNA and nonsignificantly decreased risk of SCCHN. Larger population-based and additional functional studies are warranted to validate our findings.
doi:10.1097/FPC.0b013e32834e3cf6
PMCID: PMC3237901  PMID: 22108238
ERCC5; polymorphism; SCCHN; risk
24.  Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes 
Purpose
The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mTOR and Ras/Raf/MEK/ERK pathways have been implicated in endometrial tumorigenesis. In this candidate pathway analysis, we investigated associations between genetic variations in these two pathways and both risk and clinical outcomes of endometrial cancer.
Methods
We genotyped a total of 48 potentially functional SNPs in 11 key genes (AKT1, AKT2, AKT3, BRAF, FRAP1, KRAS, PDPK1, PIK3CA, PIK3CB, PIK3R1, and PTEN) with the Sequenom genotyping platform in 115 endometrial cancer patients and 230 cancer-free women to evaluate their associations with risk, survival, and recurrence of endometrial cancer.
Results
We found the following: (1) PIK3CA rs6443624 and rs9838411 variants either borderline or significantly decreased risk of endometrial cancer in a dominant model (adjusted odds ratio [OR], 0.62; 95% CI, 0.39–1.00 and 0.59; 95% CI, 0.36–0.95, respectively). Furthermore, there was a statistically significant multiplicative interaction (Pint = 0.036) between these two loci in risk of endometrial cancer. In contrast, the AKT1 rs2498801 genotype significantly increased risk of endometrial cancer (adjusted OR, 1.94; 95% CI, 1.02–3.67 in a recessive model). (2) In Cox regression analyses, three SNPs (PIK3R1 rs1862162, AKT2 rs892119, and PIK3CA rs2699887) showed significant associations with survival of endometrial cancer patients. (3) KRAS rs7312175 and PIK3CA rs6443624 had significant effects on recurrence of endometrial cancer individually and combined in a locus–dosage manner (adjusted Ptrend = 0.003).
Conclusion
These results suggest that common genetic variations in these pathways may modulate risk and clinical outcomes of endometrial cancer. Further replication and functional studies are needed to confirm these findings.
doi:10.1007/s00432-011-1103-0
PMCID: PMC3526101  PMID: 22146979
PI3K/PTEN/AKT/mTOR and RAS/RAF/MEK/ERK pathways; Polymorphisms; Endometrial cancer risk; Survival; Recurrence
25.  Gamma-ray-induced mutagen sensitivity and risk of sporadic breast cancer in young women: a case–control study 
Breast cancer research and treatment  2012;132(3):1147-1155.
Hypersensitivity to radiation exposure has been suggested to be a risk factor for the development of breast cancer. In this case–control study of 515 young women (≤55 years) with newly diagnosed sporadic breast cancer and 402 cancer-free controls, we examined the radiosensitivity as measured by the frequency of chromatid breaks induced by gamma-radiation exposure in the G2 phase of phytohemagglutinin-stimulated and short-term cultured fresh lymphocytes. We found that the average chromatid breaks per cell from 50 well-spread metaphases were statistically significantly higher in 403 non-Hispanic White breast cancer patients (0.52 ± 0.22) than that in 281 non-Hispanic White controls (0.44 ± 0.16) (P value < 0.001), and in 60 Mexican American breast cancer patients (0.52 ± 0.19) than that in 65 Mexican American controls (0.44 ± 0.16) (P value = 0.021), but the difference was not significant in African Americans (52 cases [0.45 ± 0.16] versus 56 controls [0.47 ± 0.16], P = 0.651). The frequency of chromatid breaks per cell above the median of control subjects was associated with two-fold increased risk for breast cancer in non-Hispanic Whites and Mexican Americans. A dose–response relationship was evident between radiosensitivity and risk for breast cancer (Ptrend < 0.001) in these two ethnic groups. We concluded that gamma-ray-induced mutagen sensitivity may play a role in susceptibility to breast cancer in young non-Hispanic White and Mexican American women.
doi:10.1007/s10549-011-1940-1
PMCID: PMC3523666  PMID: 22218884
Radiation; Chromosomal instability; Breast neoplasm; Molecular epidemiology

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