Abstract Background Formaldehyde (FA) has been classified as a human carcinogen by the International Agency for Research on Cancer (IARC) and has toxic effects on various tissues and cells. It is reported that FA can accelerate cellular senescence in mice HT22 cells and induce the apoptosis of BALB/c mice BMSCs. Our previous study has confirmed that FA has genotoxic effects on BMSCs by the formation of DNA-protein crosslinks (DPC), sister chromatid exchange (SCE) and micronucleus (MN). However, whether FA causes apoptosis and senescence effects on human BMSCs has not been fully investigated. The aim of this study is to explore the toxic effects and mechanisms of FA on BMSCs based on senescence and apoptosis. Method In this study, Human BMSCs were cultured in vitro and randomly divided into a blank group, a control group and five groups of cells treated with different concentrations (60, 90, 120, 150 and 180 umol/L) of FA. And the cell groups were cultured for 6, 12 and 24 hours. The effect of different concentrations of FA on the viability of human BMSCs was investigated using the MTT assay. Based on the results of MTT assay, we selected the cell group with 120 µmol/L FA for 24 hours for the following experiments. Changes of FA on the morphology of BMSCs were analyzed using the phase-contrast microscope and phalloidin/hoechst33258 staining. We performed bioinformatic analysis on the RNA-Seq data, including differential expression analysis, GO and KEGG analysis in order to further understand the mechanisms of toxicity of FA on BMSCs. The changes in the mRNA and protein expression levels of PIK3CA, Caspase3, Bcl2, P53 and P21 of BMSCs following exposure to FA were detected using qRT-PCR and western blotting. Result When FA concentration reached 90 umol/L, the inhibition of proliferation activity of human BMSCs began to appear, and increased with the increase of FA concentration and time. By morphological detection, we observed that BMSCs treated with 120 µmol/L FA became smaller and rounder, of which the cytoskeleton was disordered and the nuclei were pyknotic, dense stained and fragmented, even with apoptotic bodies formed. The results of the bioinformatics analysis showed that 249 differentially expressed mRNAs (DE mRNAs) were identified in the RNA-seq samples, which included 158 upregulated and 91 downregulated mRNAs. And functional enrichment analysis revealed the pathway of accumulation to cellular senescence and apoptosis. Further assays were performed on factors of the PI3K/P53 pathway, which was a pathway related to senescence and apoptosis. The mRNA and protein expression levels of Caspase3, P53 and P21 in the 120 µmol/L FA-treated group were significantly higher than those in the control group, while the mRNA expression levels of PIK3CA and Bcl2 were significantly lower than those in the control group. Treatment with 120 µmol/L FA reduced the protein expression levels of PIK3CA. Conclusion FA had toxic effects on human BMSCs and the mechanism might be related to the regulation of PI3K/P53 signaling pathway to promote cellular senescence and apoptosis.

Cytotoxic peptides derived from spider venoms have been considered as promising candidates for anticancer treatment. The novel cell penetrating peptide LVTX-8, which is a 25-residue amphipathic α-helical peptide isolated from spider Lycosa vittata, exhibited potent cytotoxicity and is a potential precursor for further anticancer drug development. Nevertheless, LVTX-8 may be easily degraded by multiple proteases, inducing the proteolytic stability problem and short half-life. In this study, ten LVTX-8-based analogs were rationally designed and the efficient manual synthetic method was established by the DIC/Oxyma based condensation system. The cytotoxicity of synthetic peptides was systematically evaluated against seven cancer cell lines. Seven of the derived peptides exhibited high cytotoxicity towards tested cancer in vitro, which was better than or comparable to that of natural LVTX-8. In particular, both N-acetyl and C-hydrazide modified LVTX-8 (825) and the conjugate methotrexate (MTX)-GFLG-LVTX-8 (827) possessed more durable anticancer efficiency, higher proteolytic stability, as well as lower hemolysis. Finally, we confirmed that LVTX-8 could disrupt the integrity of cell membrane, target the mitochondria and reduce the mitochondrial membrane potential to induce the cell death. Taken together, the structural modifications were conducted on LVTX-8 for the first time and the stability significantly improved derivatives 825 and 827 may provide useful references for the modifications of cytotoxic peptides.

Mutagen sensitivity assay, which measures the enhanced cellular response to DNA damage induced in vitro by mutagens/carcinogens, has been used in the study of cancer susceptibility. 4-Nitroquinoline-1-oxide (4-NQO), an ultraviolet (UV) radiation-mimetic chemical, can produce chromosomal breaks in mammalian cells and induce cancer. Given the potential role of 4-NQO as the experimental mutagen substituting for UV as the etiological carcinogen of cutaneous melanoma (CM), we tested the hypothesis that cellular sensitivity to 4-NQO is associated with the risk of developing CM in a case-control study of 133 patients with primary CM and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 mu mol/l for 24 h and scored chromatid breaks in 50 well-spread metaphases. Multivariate logistic regression was used to calculate odds ratios and 95% confidence intervals. We found that the log-transformed frequency of chromatid breaks was significantly higher in 133 patients than in 176 controls (P=0.004) and was associated with an increased risk for CM (adjusted odds ratio=1.78, 95% confidence interval: 1.12-2.84) after adjustment for age and sex. Moreover, as the chromatid break values increased, the risk for CM increased in a dose-dependent manner (P-trend=0.003). Further analysis explored a multiplicative interaction between the sensitivity to 4-NQO and a family history of skin cancer (P-interaction=0.004) on the risk of CM. Therefore, our findings suggest that sensitivity to 4-NQO may be a risk factor for the risk of CM, which is more sensitive than UV-induced chromotid breaks.

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 0bp 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.

Thymidylate synthase (TYMS) plays a crucial role in folate metabolism as well as DNA synthesis and repair. We hypothesized that functional polymorphisms in the 3 UTR of TYMS are associated with gastric cancer risk and survival. In the present study, we tested our hypothesis by genotyping three potentially functional (at miRNA binding sites) TYMS SNPs (rs16430 6bp del/ins, rs2790 A>G and rs1059394 C>T) in 379 gastric cancer patients and 431 cancer-free controls. Compared with the rs16430 6bp/6bp+6bp/0bp genotypes, the 0bp/0bp genotype was associated with significantly increased gastric cancer risk (adjusted OR=1.72, 95% CI=1.15-2.58). Similarly, rs2790 GG and rs1059394 TT genotypes were also associated with significantly increased risk (adjusted OR=2.52, 95% CI=1.25-5.10 and adjusted OR=1.57, 95% CI=1.04-2.35, respectively), compared with AA+AG and CC+CT genotypes, respectively. In the haplotype analysis, the T-G-0bp haplotype was associated with significantly increased gastric cancer risk, compared with the C-A-6bp haplotype (adjusted OR=1.34, 95% CI=1.05-1.72). Survival analysis revealed that rs16430 0bp/0bp and rs1059394 TT genotypes were also associated with poor survival in gastric cancer patients who received chemotherapy treatment (adjusted HR=1.61, 95% CI=1.05-2.48 and adjusted HR=1.59, 95% CI=1.02-2.48, respectively). These results suggest that these three variants in the miRNA binding sites of TYMS may be associated with cancer risk and survival of gastric cancer patients. Larger population studies are warranted to verify these findings. (c) 2014 Wiley Periodicals, Inc.

We identified 393 patients with nonesmall cell lung cancer and genotyped 3 potentially functional single nucleotide polymorphisms of CBLB. We found that patients with the CBLB rs2305035 AA/AG genotypes had better clinical outcomes but were at higher risk of developing severe radiation pneumonitis. The findings could assist in generating hypotheses for mechanistic studies of immunology and cancer treatment outcomes. Background: The immune system has important roles in tumor development and outcomes after cancer treatment. We evaluated whether single-nucleotide polymorphisms (SNPs) in the gene encoding casitas B-lineage lymphoma b protein (Cbl-b), an E3 ubiquitin ligase that maintains immune tolerance by negatively regulating T-cell activation and function, were associated with outcomes after treatment of nonesmall-cell lung cancer (NSCLC). Patients and Methods: Samples from 393 patients with NSCLC treated with definitive radiotherapy at a single institution between March 1998 and February 2009 were used to genotype 3 potentially functional SNPs in CBLB (rs1042852 C>T, rs2305035 G> A, and rs7649466 C> G). We evaluated associations between these SNPs and local recurrence-free survival, distant metastasis-free survival, overall survival, and risk of radiation pneumonitis (RP). Results: Having the rs2305035 A variant genotypes (AA or AG) was associated with better local recurrence-free survival (median 15.8 vs. 15.3 months; adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.60-0.98; P =.033), distant metastasis-free survival (median 15.4 vs. 14.0 months; adjusted HR, 0.74; 95% CI, 0.57-0.96; P =.024) and overall survival (median 23.5 vs. 22.8 months; adjusted HR, 0.72; 95% CI, 0.56-0.93; P =.013) after adjustment in a Cox proportional hazard model. Patients with these genotypes were also at greater risk of developing grade 3 or higher RP than were patients with GG genotypes in an adjusted Cox proportional hazard model. Conclusion: This is the first report that rs2305035 genotypes in CBLB were associated with clinical and RP risk among patients with NSCLC treated with definitive radiotherapy. These findings could assist in generating hypothesis for further mechanistic studies. (C) 2015 Elsevier Inc. All rights reserved.

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.

Objectives: Patients with oropharyngeal cancer (OPC) have distinct risk factor profiles reflected in the human papillomavirus (HPV) status of their tumor, and these profiles may also be influenced by factors related to socioeconomic status (SES). The goal of this study was to describe the socioeconomic characteristics of a large cohort of patients with OPC according to HPV status, smoking status, and sexual behavior.Materials and Methods: Patients with OPC prospectively provided information about their smoking and alcohol use, socioeconomic characteristics, and sexual behaviors. HPV status was determined by a composite of immunohistochemistry for p16 expression, HPV in situ hybridization, and PCR assay in 356 patients. Standard descriptive statistics and logistic regression were used to compare socioeconomic characteristics between patient subgroups.Results: Patients with HPV-positive OPC had higher levels of education, income, and overall SES. Among patients with HPV-positive OPC, never/light smokers had more than 5 times the odds of having at least a bachelor's degree and being in the highest level of SES compared with smokers. Patients with HPV-positive OPC and those with higher levels of education and SES had higher numbers of lifetime any and oral sex partners, although not all of these differences were significant.Conclusion: Socioeconomic differences among subgroups of OPC patients have implications for OPC prevention efforts, including tobacco cessation, behavior modification, and vaccination programs. (C) 2015 Elsevier Ltd. All rights reserved.

BACKGROUNDAcne reflects hormone imbalance and is a key component of several systemic diseases. We hypothesized that diagnosis of acne as a teenager might predict subsequent risk of hormone‐related cancers.METHODSWe followed 99,128 female nurses in the Nurses' Health Study II cohort for 20 years (1989‐2009) and used Cox proportional hazards models to estimate the hazard ratios (HRs) of 8 specific cancers (breast, thyroid, colorectal, ovarian, cervical, and endometrial cancers, melanoma, and non‐Hodgkin lymphoma) for women with a history of severe teenage acne.RESULTSAfter thoroughly adjusting for the previously known risk factors for each cancer, we found that among women with a history of severe teenage acne, the relative risk increased, with a multivariable‐adjusted HR of 1.44 (95% confidence interval [CI], 1.03‐2.01) for melanoma. We replicated this association in an independent melanoma case‐control study of 930 cases and 1026 controls (multivariable‐adjusted odds ratio, 1.27; 95% CI, 1.03‐1.56). We also found that in both studies the individuals with teenage acne were more likely to have moles (52.7% vs 50.1%, P < .001 in the cohort study; and 55.2% vs 45.1%, P = .004 in the case‐control study).CONCLUSIONSOur findings suggest that a history of teenage acne might be a novel risk factor for melanoma independent from the known factors, which supports a need for continued investigation of these relationships. Cancer 2015;121:1681–1687. © 2015 American Cancer Society.

PURPOSE:To investigate the association between blood levels of C-reactive protein (CRP) in patients with melanoma and overall survival (OS), melanoma-specific survival (MSS), and disease-free survival.PATIENTS AND METHODS:Two independent sets of plasma samples from a total of 1,144 patients with melanoma (587 initial and 557 confirmatory) were available for CRP determination. Kaplan-Meier method and Cox regression were used to evaluate the relationship between CRP and clinical outcome. Among 115 patients who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in CRP using nonparametric tests.RESULTS:Elevated CRP level was associated with poorer OS and MSS in the initial, confirmatory, and combined data sets (combined data set: OS hazard ratio, 1.44 per unit increase of logarithmic CRP; 95% CI, 1.30 to 1.59; P < .001; MSS hazard ratio, 1.51 per unit increase of logarithmic CRP; 95% CI, 1.36 to 1.68; P < .001). These findings persisted after multivariable adjustment. As compared with CRP < 10 mg/L, CRP ≥ 10 mg/L conferred poorer OS in patients with any-stage, stage I/II, or stage III/IV disease and poorer disease-free survival in those with stage I/II disease. In patients who underwent sequential evaluation of CRP, an association was identified between an increase in CRP and melanoma disease progression.CONCLUSION:CRP is an independent prognostic marker in patients with melanoma. CRP measurement should be considered for incorporation into prospective studies of outcome in patients with melanoma and clinical trials of systemic therapies for those with melanoma.

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. (c) 2013 Wiley Periodicals, Inc.

Abstract Background: Hypersensitivity to radiation has been shown to be a risk factor for the development of breast cancer. We aim to determine whether the same hypersensitivity predicts for adverse clinical outcomes in patients diagnosed with carcinoma of the breast. Methods: 465 young, female, non-Hispanic white patients diagnosed with carcinoma of the breast at our institution from 1/1997 to 12/2005 were included in this study. All cases were histologically confirmed and all blood was drawn prior to any systemic or local therapy. Patient age, body mass index (BMI), menopause status, tumor laterality, AJCC stage, ER status, nuclear grade, and receipt of chemotherapy and radiation were extracted from patient medical records. A gamma-ray-induced mutagen sensitivity assay was performed using standard published methods to evaluate individual responses to radiation. The number of simple chromatid breaks per sample was counted from 50 well-spread metaphases. Each simple chromatid break was counted as a single break and each isochromatid break, exchange figure, or interstitial deletion as two breaks. The mean value of chromatid breaks per cell (b/c) was then calculated and recorded. Cox multivariable proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between b/c and overall survival. Results: A total of 402 patients had a b/c value recorded and were included in the final analysis. The patient median age was 46 years (range 22-55). 341 patients (84.8%) had invasive cancer and 253 patients (69.9%) had ER+ disease. AJCC stage distribution was stage 0 (15.2%), stage 1 (41.5%), stage 2 (33.5%), stage 3 (9.5%) and stage 4 (0.3%). The median follow-up for all patients was 97.2 months (interquartile range, IQR 83.3-119.6 months). The median b/c was 0.5 (IQR 0.38-0.62). The 5 and 10-year survival for all patients was 92.6% and 87.5%. A statistically significant decrease in 5 and 10-year overall survival was seen in patients with b/c greater than the median value of 0.5 (96.2% vs. 89.2%, p=.007 and 90.8% vs. 84.5%, p=.046, respectively). On multivariable analysis (MVA), age at diagnosis (HR 0.95, CI 0.91-0.99, p=.017), BMI (HR 1.07, CI 1.03-1.12, p=.003), ER status (HR= 0.31, CI 0.16-0.61, p=.01), AJCC stage (HR 1.91, CI 1.2-3.0, p=.006), and b/c level (HR 5.67, CI 1.5-18.2, p=.01) all predicted for overall survival. Excluding the 61 patients with in situ disease, there remains a significant difference in survival at both 5 and 7 years (95.5% vs. 88.5%, p=.017 and 93.5% vs. 86%, p=.021). A trend for decrease survival was seen at 10 years (p=0.09). On MVA for patients with invasive disease, age at diagnosis (HR=0.95, 95% CI 0.91-0.99, p=.026), BMI (HR=1.06, 95% CI 1.01-1.11, p=.023), AJCC stage (HR=2.41, CI 1.51-3.91, p=.0003), and ER status (HR=0.25, CI 0.12-0.49, p< .0001) and b/c level (HR=3.76, CI 1.39-8.06, p=.012) were associated with overall survival. Conclusions: In this cohort of young, female, non-Hispanic white breast cancer patients, a greater b/c level predicted for decreased overall survival. The use of a gamma-ray-induced mutagen sensitivity assay may be prognostic and help select for those at increased risk of death. Citation Format: Michael C Stauder, Simona F Shaitelman, Pamela K Allen, Abenaa M Brewster, Banu K Arun, Wendy A Woodward, Thomas A Buchholz, Li-E Wang. Gamma-ray induced mutagen sensitivity and overall survival in young women with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-08-01.

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 <65 years, males, stage III/IV, ever smokers, having radio-chemotherapy and mean lung dose (MLD) >= 19.0 Gy.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. (C) 2014 Published by Elsevier Ltd.

Background and purposeMicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC).Material and methodsWe measured serum miR-155, miR-221 and miR-21, before and during week 1–2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression.ResultsWe found that patients with stage IIIB–IV disease, higher mean esophagus dose or esophageal V50 had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1–2 of CRT were also risk factors for severe RIET (miR-155: OR=1.53, 95% CI: 1.04–2.25, P=0.03; miR-221: OR=2.07, 95% CI: 1.17–3.64, P=0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR=1.18, 95% CI: 1.02–1.37, P=0.026). However, pretreatment miRNAs was not predictive of severe RIET.ConclusionsHigh serum miR-155 and miR-221 during the first 2weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity.

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.

Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosonnal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)= 1.85, 95% confidence interval (CI) = 1.16-2.95, P = 0.010), rs206118 (CC vs. TT + TC: adjHR = 2.44, 95% Cl =1.27-4.67, P = 0.007), rs3752447 (CC vs. TT + TC: adjHR = 2.10, 95% Cl = 1.38-3.18, P = 0.0005), and FANCA rs62068372 (TT vs. CC + CT: adjHR = 1.85, 95% Cl =1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

Cytokines such as Interleukin (IL)−12p70 (“IL‐12”) and IL‐23 can influence tumor progression. We tested the hypothesis that blood levels of IL‐12p40, the common subunit of both cytokines, are associated with melanoma progression. Blood from 2,048 white melanoma patients were collected at a single institution between March 1998 and March 2011. Plasma levels of IL‐12p40 were determined for 573 patients (discovery), 249 patients (Validation 1) and 244 patients (Validation 2). Per 10‐unit change of IL‐12p40 level was used to investigate associations with melanoma patient outcome among all patients or among patients with early or advanced stage. Among stage I/II melanoma patients in the pooled data set, after adjustment for sex, age, stage and blood draw time from diagnosis, elevated IL‐12p40 was associated with melanoma recurrence [hazard ratio (HR) = 1.04 per 10‐unit increase in IL‐12p40, 95% CI 1.02–1.06, p = 8.48 × 10−5]; Elevated IL‐12p40 was also associated with a poorer melanoma specific survival (HR = 1.06, 95% CI 1.03–1.09, p = 3.35 × 10−5) and overall survival (HR = 1.05, 95% CI 1.03–1.08, p = 8.78×10−7) in multivariate analysis. Among stage III/IV melanoma patients in the pooled data set, no significant association was detected between elevated IL‐12p40 and overall survival, or with melanoma specific survival, with or without adjustment for the above covariates. Early stage melanoma patients with elevated IL‐12p40 levels are more likely to develop disease recurrence and have a poorer survival. Further investigation with a larger sample size will be needed to determine the role of IL‐12p40 in advanced stage melanoma patients.

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 3 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 (chemo) radiation 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 (72.4% 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 = .009; rs228590: TT/CT vs CC, HR=0.57, 95% CI, 0.33-0.97, P = .036; haplotype: G-T-G vs A-C-G, HR=0.52, 95% CI, 0.35-0.79, P = .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. (C) 2013 Elsevier Inc.