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BackgroundT 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.MethodsWe 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.ResultsOf 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.ConclusionOur 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.

Abstract 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.

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 (Ptrend = 0.0002) and disease-specific survival (DSS, Ptrend < 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.

Summary: Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. Methods: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan–Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. Findings: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48–1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41–0.66, p

Abstract Purpose Previous randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight. Methods We used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups. Results We identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 – 1.39, Table 3) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 – 1.37). Conclusion The findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.

Abstract Background Effective risk prediction models are lacking for personalized endoscopic screening of gastric cancer (GC). We aimed to develop, validate, and evaluate a questionnaire-based GC risk assessment tool for risk prediction and stratification in the Chinese population. Methods In this three-stage multicenter study, we first selected eligible variables by Cox regression models and constructed a GC risk score (GCRS) based on regression coefficients in 416,343 subjects (aged 40–75 years) from the China Kadoorie Biobank (CKB, development cohort). In the same age range, we validated the GCRS effectiveness in 13,982 subjects from another independent Changzhou cohort (validation cohort) as well as in 5348 subjects from an endoscopy screening program in Yangzhou. Finally, we categorized participants into low (bottom 20%), intermediate (20–80%), and high risk (top 20%) groups by the GCRS distribution in the development cohort. Results The GCRS using 11 questionnaire-based variables demonstrated a Harrell’s C-index of 0.754 (95% CI, 0.745–0.762) and 0.736 (95% CI, 0.710–0.761) in the two cohorts, respectively. In the validation cohort, the 10-year risk was 0.34%, 1.05%, and 4.32% for individuals with a low (≤ 13.6), intermediate (13.7~30.6), and high (≥ 30.7) GCRS, respectively. In the endoscopic screening program, the detection rate of GC varied from 0.00% in low-GCRS individuals, 0.27% with intermediate GCRS, to 2.59% with high GCRS. A proportion of 81.6% of all GC cases was identified from the high-GCRS group, which represented 28.9% of all the screened participants. Conclusions The GCRS can be an effective risk assessment tool for tailored endoscopic screening of GC in China. Risk Evaluation for Stomach Cancer by Yourself (RESCUE), an online tool was developed to aid the use of GCRS.

Summary: Background: Lymphocyte telomere length (LTL)-related genetic variants may modulate LTL and affect recurrence of squamous cell carcinoma of the oropharynx (SCCOP). Methods: A total of 1013 patients with incident SCCOP were recruited and genotyped for 16 genome-wide association study (GWAS)-identified TL-related polymorphisms. Of these patients, 489 had tumour HPV16 status determination. Univariate and multivariate analyses were performed to evaluate associations. Findings: Of the 16 TL-related polymorphisms, four were significantly associated with LTL: rs1920116, rs3027234, rs6772228, and rs11125529, and the patients with putatively favourable genotypes had approximately 1.5–3 times the likelihood of shorter LTL compared with patients with the corresponding risk genotypes. Moreover, patients with one to four favourable genotypes of the four combined polymorphisms had approximately 3–11 times the likelihood of shorter LTL compared with patients with no favourable genotype. The four LTL-related polymorphisms were significantly associated with approximately 40% reduced risk (for favourable genotypes) or doubled risk (for risk genotypes) of recurrence, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP. Similarly, patients with one to four risk genotypes had significantly approximately 2.5–4 times increased recurrence risk compared with patients with no risk genotype, and similar but more pronounced associations were observed in patients with tumour HPV16-positive SCCOP. Interpretation: Four LTL-related polymorphisms individually or jointly modify LTL and risk of recurrence of SCCOP, particularly HPV-positive SCCOP. These LTL-related polymorphisms could have potential to further stratify patients with HPV-positive SCCOP for individualized treatment and better survival. Funding: Not applicable.

BackgroundCancers arising within the gastrointestinal tract are complex disorders involving genetic events that cause the conversion of normal tissue to premalignant lesions and malignancy. Shared genetic features are reported in epithelial-based gastrointestinal cancers which indicate common susceptibility among this group of malignancies. In addition, the contribution of rare variants may constitute parts of genetic susceptibility.MethodsA cross-cancer analysis of 38,171 shared rare genetic variants from genome-wide association assays was conducted, which included data from 3,194 cases and 1,455 controls across three cancer sites (esophageal, gastric and colorectal). The SNP-level association was performed by multivariate logistic regression analyses for single cancer, followed by association analysis for SubSETs (ASSET) to adjust the bias of overlapping controls. Gene-level analyses were conducted by SKAT-O, with multiple comparison adjustments by false discovery rate (FDR). Based on the significant genes indicated by SKATO analysis, pathways analysis was conducted using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases.ResultsMeta-analysis in three gastrointestinal (GI) cancers identified 13 novel susceptibility loci that reached genome-wide significance (PASSET< 5×10-8). SKAT-O analysis revealed EXOC6, LRP5L and MIR1263/LINC01324 to be significant genes shared by GI cancers (Padj

Dimethoate contaminants in food pose a threat to human health. Rapid and sensitive trace detection methods are required to keep food safe. In this study, a novel fluorescent aptasensor was developed for the sensitive detection of dimethoate based on carbon quantum dots labeled with double-stranded DNA (CQDs−apt−cDNA) and Ti3C2Tx flakes. Under optimal conditions, the aptasensor showed a good linear range of 1 × 10−9 to 5 × 10−5 M for dimethoate with a coefficient of determination (R2) of 0.996. Besides, a low detection limit of 2.18 × 10−10 M was obtained. The aptasensor showed high selectivity in interference samples and good reproducibility with an RSD of 3.06% (

Abstract Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E−09), rs2285521 in GGA2 (P = 4.43E−08), and rs198459 in MYRF (P = 1.60E−06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E−08, P = 6.21E−08, and P = 7.93E−04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E−05, P = 2.70E−04, and P = 2.90E−05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.

To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer (GC), we performed two genome-wide association studies (GWASs) of GC survival in the Jiangsu (N = 1049) and Shanghai (N = 1405) cohorts. By using a TCGA dataset, we validated genetic markers identified from a meta-analysis of these two Chinese cohorts to determine GC survival-associated loci. Then, we constructed a weighted polygenic hazard score (PHS) and developed a nomogram in combination with clinical variables. We also evaluated prognostic accuracy with the time-dependent receiver operating characteristic (ROC) curve, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We identified a single nucleotide polymorphism (SNP) of rs1618332 at 15q15.1 that was associated with the survival of GC patients with a P value of 4.12 × 10-8, and we also found additional 25 SNPs having consistent associations among these two Chinese cohort and TCGA cohort. The PHS derived from these 26 SNPs (PHS-26) was an independent prognostic factor for GC survival (all P < 0.001). The 5-year AUC of PHS-26 was 0.68, 0.66 and 0.67 for Jiangsu, Shanghai and their pooled cohorts, respectively, which increased to 0.80, 0.82 and 0.81, correspondingly, after being integrated into a nomogram together with variables of the clinical model. The PHS-26 could improve the NRIs by 16.20%, 4.90% and 8.70%, respectively, and the IDIs by 11.90%, 8.00% and 9.70%, respectively. The 26-SNP based PHS could substantially improve the accuracy of prognostic assessment and might facilitate precision medicine for GC patients. [ABSTRACT FROM AUTHOR]

Efficient detection and degradation of fungicides are greatly concerned with aquatic food safety. Herein, a multifunction CoFe2O4/MoS2@Au (ACMS) composite was synthesized for crystal violet (CV) and malachite green (MG) photocatalytic degradation and SERS determination. As the construction of the Z-scheme heterostructure of ACMS, which enhanced the light absorption capability and the separation efficiency of photoexcited carrier significantly, ACMS possessed an excellent photocatalytic performance with a degradation rate of 94.76% for CV under simulated solar light irradiation. Furthermore, the multifunction ACMS exhibited superior SERS capability with a detection limit (LOD) of 4.309 × 10−2 μg L−1 for MG residues in water. And the ACMS substrates could be utilized to determine the MG residues in crucian carp extract, resulting in a recovery rate of 96.00~116.00%. In addition, such multifunction heterojunctions were performed for in situ monitoring of the photodegradation process. This research opened up a novel perspective on the applications of heterojunction-based multifunction materials for food safety control.

Abstract Ovarian cancer survival varies considerably among patients, to which germline variation may also contribute in addition to mutational signatures. To identify genetic markers modulating ovarian cancer outcome, we performed a genome-wide association study in 2130 Chinese ovarian cancer patients and found a hitherto unrecognized locus at 3p26.1 to be associated with the overall survival (P combined = 8.90 × 10−10). Subsequent statistical fine-mapping, functional annotation, and eQTL mapping prioritized a likely casual SNP rs9311399 in the non-coding regulatory region. Mechanistically, rs9311399 altered its enhancer activity through an allele-specific transcription factor binding and a long-range interaction with the promoter of a lncRNA BHLHE40-AS1. Deletion of the rs9311399-associated enhancer resulted in expression changes in several oncogenic signaling pathway genes and a decrease in tumor growth. Thus, we have identified a novel genetic locus that is associated with ovarian cancer survival possibly through a long-range gene regulation of oncogenic pathways.

Abstract Background Neuroblastoma is the most common pediatric solid tumor. MYCN‐amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes. Methods We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN‐amplification status, and compared to 3390 European‐ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature. Results An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre‐pubertal height, was associated with greater risk of MYCN‐amplified neuroblastoma (OR = 1.14, P = .047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN‐amplified neuroblastoma (OR = 0.87, P = .047). These associations persisted in case‐case analyses comparing MYCN‐amplified to MYCN‐unamplified neuroblastoma. No polygenic height scores were associated with MYCN‐unamplified neuroblastoma risk. Previously identified genome‐wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10−3) and adult height (P = 8.9 × 10−3) in >250 000 UK Biobank study participants. Conclusions Genetic propensity to taller childhood height and shorter adult height were associated with MYCN‐amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN‐amplified neuroblastoma etiology.

For survival and quality of human life, the search for better ways to ensure food safety is constant. However, food contaminants still threaten human health throughout the food chain. In particular, food systems are often polluted with multiple contaminants simultaneously, which can cause synergistic effects and greatly increase food toxicity. Therefore, the establishment of multiple food contaminant detection methods is significant in food safety control. The surface-enhanced Raman scattering (SERS) technique has emerged as a potent candidate for the detection of multicomponents simultaneously. The current review focuses on the SERS-based strategies in multicomponent detection, including the combination of chromatography methods, chemometrics, and microfluidic engineering with the SERS technique. Furthermore, recent applications of SERS in the detection of multiple foodborne bacteria, pesticides, veterinary drugs, food adulterants, mycotoxins and polycyclic aromatic hydrocarbons are summarized. Finally, challenges and future prospects for the SERS-based detection of multiple food contaminants are discussed to provide research orientation for further.

Accumulating evidence supports a role of various damage-associated molecular patterns (DAMPs) in progression of lung cancer, but roles of genetic variants of the DAMPs-related pathway genes in lung cancer survival remain unknown. We investigated associations of 18,588 single-nucleotide polymorphisms (SNPs) in 195 DAMPs-related pathway genes with non-small cell lung cancer (NSCLC) survival in a subset of genotyping data for 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another independent subset of genotyping data for 984 patients from Harvard Lung Cancer Susceptibility Study. We performed multivariate Cox proportional hazards regression analysis, followed by expression quantitative trait loci (eQTL) analysis, Kaplan-Meier survival analysis and bioinformatics functional prediction. We identified that two SNPs (i.e., CLEC4E rs10841847 G>A and BIRC3 rs11225211 G>A) were independently associated with NSCLC overall survival, with adjusted allelic hazards ratios of 0.89 (95% confidence interval=0.82-0.95 and P=0.001) and 0.82 (0.73-0.91 and P=0.0003), respectively; so were their combined predictive alleles from discovery and replication datasets (Ptrend=0.0002 for overall survival). We also found that the CLEC4E rs10841847 A allele was associated with elevated mRNA expression levels in normal lymphoblastoid cells and whole blood cells, while the BIRC3 rs11225211 A allele was associated with increased mRNA expression levels in normal lung tissues. Collectively, these findings indicated that genetic variants of CLEC4E and BIRC3 in the DAMPs-related pathway genes were associated with NSCLC survival, likely by regulating the mRNA expression of the corresponding genes.

BackgroundSingle nucleotide polymorphisms (SNPs) are often associated with distinct phenotypes in cancer. The present study investigated associations of cancer risk and outcomes with SNPs discovered by whole exome sequencing of normal lung tissue DNA of 15 non-small cell lung cancer (NSCLC) patients, 10 early stage and 5 advanced stage.MethodsDNA extracted from normal lung tissue of the 15 NSCLC patients was subjected to whole genome amplification and sequencing and analyzed for the occurrence of SNPs. The association of SNPs with the risk of lung cancer and survival was surveyed using the OncoArray study dataset of 85,716 patients (29,266 cases and 56,450 cancer-free controls) and the Prostate, Lung, Colorectal and Ovarian study subset of 1,175 lung cancer patients.ResultsWe identified 4 SNPs exclusive to the 5 patients with advanced stage NSCLC: rs10420388 and rs10418574 in the CLPP gene, and rs11126435 and rs2021725 in the M1AP gene. The variant alleles G of SNP rs10420388 and A of SNP rs10418574 in the CLPP gene were associated with increased risk of squamous cell carcinoma (OR = 1.07 and 1.07; P = 0.013 and 0.016, respectively). The variant allele T of SNP rs11126435 in the M1AP gene was associated with decreased risk of adenocarcinoma (OR = 0.95; P = 0.027). There was no significant association of these SNPs with the overall survival of lung cancer patients (P > 0.05).ConclusionsSNPs identified in the CLPP and M1AP genes may be useful in risk prediction models for lung cancer. The previously established association of the CLPP gene with cancer progression lends relevance to our findings.

Background: Seventeen loci have been found to be associated with bladder cancer risk by genome-wide association studies (GWAS) in European population. However, little is known about contribution of low-frequency and rare variants to bladder cancer susceptibility, especially in Eastern population.Methods: We performed a three-stage case-control study including 3,399 bladder cancer patients and 4,647 controls to identify low-frequency and rare variants associated with bladder cancer risk in Han Chinese. We examined exome-array data in 1,019 bladder cancer patients and 1,008 controls in discovery stage. Two replication stages were included to validate variants identified. Bonferroni adjustment was performed to define statistical significance. Logistic regression was conducted to evaluate single marker association with bladder cancer risk. We used SKAT-O method to perform gene level-based analysis. We also conduct additional experiments to explore the underlying mechanism of filtered gene(s).Results: We identified a novel rare coding variant (rs35356162 in UHRF1BP1: G > T, OR = 4.332, P = 3.62E-07 < 7.93E-07, Bonferroni cutoff) that increased bladder cancer risk in Han Chinese. Gene-level analysis showed a significant association of UHRF1BP1 (P = 4.47E-03) with bladder cancer risk. Experiments indicated down-regulation of UHRF1BP1 promoted migration and invasion through epithelial-mesenchymal transition in bladder cancer cell lines.Conclusion: The rare variant of UHRF1BP1, rs35356162, increases bladder cancer risk in Han Chinese and UHRF1BP1 might act as a tumor suppressor in bladder cancer development and progression.Summary: Little is known about potential contribution of low-frequency and rare variants to bladder cancer susceptibility. We performed a three-stage case-control study and identified a new rare variant, rs35356162 in UHRF1BP1, which increased bladder cancer risk in Han Chinese.

Background/Aims: Prognostic value of germline BRCA1 or BRCA2 (gBRCA1/2) mutations in epithelial ovarian cancer (EOC) remains controversial, especially in the estimation of long-term survival. We previously reported the largest study of gBRCA1/2 mutation prevalence in Chinese EOC patients. The aim of this study is to further illustrate the correlation of residual disease and survival in BRCA-associated EOC in China. Methods: In the current cohort consisting of 615 cases from the Chinese EOC genome-wide association study, we evaluated the association between gBRCA1/2 mutation and clinical outcomes. Results: Overall, we did not find any significant difference between gBRCA1/2 mutation carriers and non-carriers in both progression-free survival (PFS) and overall survival (OS) (19.3 vs. 18.1 months and 77.2 vs. 73.2 months, P=0.528 and 0.147, HR 0.93 and 0.79, 95%CI 0.74-1.17 and 0.57-1.09, respectively). However, within three years after diagnosis, mutation carriers showed a longer OS than non-carriers (P=0.018, HR 0.53, 95%CI 0.31-0.90). Such a survival advantage decreased along with the extension of follow-up time. Quite interestingly, in the subgroup of patients with gross residual disease, mutation carriers had a longer survival than non-carriers (18.5 vs. 15.1 months and 68.5 vs. 54.3 months, P=0.046 and 0.038, HR 0.74 and 0.65, 95% CI 0.55-1.00 and 0.43-0.98, for PFS and OS respectively). Conclusions: Our findings provided the evidence that gBRCA1/2 mutation was not associated with survival in Chinese EOC patients, which possibly attributed to more than 37% of the patients without gross residual disease. Survival benefit of gBRCA1/2 mutation was prominent in ovarian cancer patients with gross residual disease.

Objective: The DNA repair capacity (DRC) of tumor cells is an important contributor to resistance to radiation and platinum-based drugs. Because DRC may be affected by tumor cell metabolism, we measured DRC in lymphocytes from patients with non–small-cell lung cancer (NSCLC) and compared the findings with the maximum standardized uptake value (SUVmax) on18F-fluorodeoxyglucose positron emission tomography (FDG PET) after (chemo)radiation therapy. Methods: This study included 151 patients with stage IA-IV NSCLC who had FDG PET at a single institution and donated blood samples before chemotherapy. We assessed the correlation of DRC, measured in peripheral T lymphocytes by a host-cell reactivation assay with SUVmax and their associations with overall survival (OS) time by hazards ratios calculated with a Cox proportional hazards regression model. Results: SUVmax of the primary tumor at diagnosis was inversely associated with lymphocyte DRC (r = −0.175, P = 0.032), particularly among patients with advanced disease (r = −0.218, P = 0.015). However, ΔSUVmax of primary tumor was not significantly associated with DRC (r = 0.005, P = 0.968). SUVmax of regional lymph nodes at diagnosis (r = −0.307, P = 0.0008) and after (chemo)radiation treatment (r = −0.329, P = 0.034) and SUVmax of the primary tumor after (chemo)radiation treatment (r = −0.253, P = 0.045) were also inversely associated with OS time. Conclusion: DRC was inversely associated with primary tumor SUVmax before treatment but not with ΔSUVmax after (chemo)radiation. Keywords: DNA repair capacity, Standardized uptake value, 18F-fluorodeoxyglucose positron emission tomography, Outcome, Non–small-cell lung cancer

Abstract 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

The JNK and P38α pathways play an important role in the sensitivity and outcomes of chemotherapy. We hypothesize that functional single nucleotide polymorphisms (SNPs) of genes of these pathways modulate outcomes of patients with advanced non–small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy (PBC). We selectively genotyped 11 independent, potentially functional SNPs of 9 genes in the JNK and P38α pathways first in a discovery group of 355 patients with advanced NSCLC treated with PBC, and we evaluated their associations with progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards regression analysis. Then, resultant significant SNPs were further validated in a replication group of 355 patients. In both discovery and validation groups as well as their combined analysis, the MAPK14 rs3804451GA/AA genotypes showed a strong association with a reduced PFS (adjusted hazards ratio [HR] = 1.39; 95% confidence interval [CI] = 1.16–1.66; P = .0003) and OS (adjusted HR = 1.41; 95% CI = 1.11-1.80; P = .005) compared with the wild-type GG genotype. In contrast, patients with or without the MAPK14 rs3804451A allele had no significant difference in OS in response to tyrosine-kinase inhibitor treatment (adjusted HR = 0.86; 95% CI = 0.56-1.33; P = .505). The present study provides evidence that the MAPK14 rs3804451 G>A variant may modulate survival outcomes in patients with advanced NSCLC treated with PBC. Larger studies of additional patient populations are needed to validate our findings.