Renal cell carcinoma (RCC) is the most common type of kidney cancer, but its genetic architecture has not been fully characterized, particularly in Asian populations. Here, we perform a multi-ancestry meta-analysis of 33,712 RCC cases and 845,786 controls, including individuals of East Asian (5,313 cases and 96,912 controls), European (25,890 cases and 743,585 controls), African American (897 cases and 3,109 controls), and Latin American ancestry (1,612 cases and 2,180 controls), which unveils 10 novel RCC-associated loci and a Chinese-specific locus at 12p13.33. Leveraging genome-wide association study (GWAS) data and cross-ancestry expression quantitative trait loci (eQTLs) mapping from 266 kidney tissues, we refine the identification of putative causal variants and genes implicated in RCC. These findings are substantiated through CRISPR-based screenings and multiplexed single-cell perturbations. Additionally, we functionally validate a novel association between rs28684409 and the oncogene RPL4 at the complex genetic locus 15q22.31. This comprehensive genetic investigation underscores the utility of integrating cross-ancestry GWASs, QTLs, and functional screens to elucidate the genetic underpinnings of complex diseases.

Metabolic-epigenetic crosstalk accelerates breast cancer (BC) progression; however, the conduit linking glycolytic flux to chromatin remodeling remains incompletely defined. Here, we delineate a kinase-metabolism-epigenetic axis centered on the Mitogen-Activated Protein Kinase Associated Protein 1 (MAPKAP1, also known as SIN1). Single-cell transcriptomic profiling of highly invasive tumors identifies SIN1 as a central node co-enriched with epithelial-mesenchymal transition and proliferation programs. Biochemical mapping and mass spectrometry demonstrate that SIN1 scaffolds TTK to promote phosphorylation of lactate dehydrogenase A (LDHA) at Tyr239 (p-LDHA^239), thereby amplifying glycolysis and lactate production. The resulting lactate accumulation increases histone H3K18 lactylation (H3K18la), which, as shown by ChIP-seq, is enriched at the Solute Carrier Family 2 Member 3 (SLC2A3, also known as GLUT3) promoter, upregulating GLUT3 and enhancing glucose uptake, thus establishing a self-reinforcing SIN1/TTK/LDHA-H3K18la-GLUT3 feed-forward loop. Structure-function analyses using domain truncations, molecular docking, and high-throughput virtual screening nominate LR-90 as a small-molecule inhibitor of the SIN1/TTK/LDHA complex. LR-90 reduces p-LDHA^239, lactate levels, H3K18la occupancy at the GLUT3 promoter, glucose uptake, invasion, and tumor growth, and it synergizes with standard chemotherapy in patient-derived organoids and mouse xenografts. Clinically, elevated SIN1 expression is associated with adverse pathological features and inferior overall survival. Collectively, these findings link SIN1-mediated recruitment of TTK for LDHA phosphorylation to histone lactylation and GLUT3-driven metabolic reprogramming, and suggest that pharmacological disruption of this axis with LR-90, alone or in combination with standard chemotherapy, may offer a therapeutic strategy for high-glycolytic, high-lactate breast cancer.

The genetic architecture of renal cell carcinoma (RCC) has not been fully characterized, particularly in Asian populations. Here, we conducted a genome-wide association study (GWAS) of 4, 692 RCC patients and 10, 116 controls of Chinese ancestry, extending to a multi-ancestry cohort totaling 879, 498 participants. Our approach unveiled 10 novel RCC-associated loci and a Chinese-specific locus at 12p13.33 with genome-wide significance. Utilizing GWAS results and cross-ancestry expression quantitative trait loci (eQTLs), we achieved a refined identification of RCC-related candidate causal variants and genes. These findings were substantiated through CRISPR-based screenings and multiplexed single-cell perturbations. Functionally, we established a novel association between rs28684409 and the oncogene RPL4 at the complex genetic locus 15q22.31. This top-down genetic study of RCC underscores the utility of integrating cross-ancestry GWASs, QTLs, and functional screens to deeply elucidate complex diseases and identify potential therapeutic targets. Hongji Dai, Xinlei Chu, Han Du, Shutong Yang, Yanxin Yao, Xinru Yu, Yanrui Zhao, Zhangyan Lyu, Wei Wang, Chao Sheng, Hong Zheng, Fangfang Song, Fengju Song, Mulin Jun Li, Kexin Chen. Genetic landscape and functional exploration of kidney cancer predisposition in cross-ancestral populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1018.

BACKGROUND:Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS:PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS:The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS:Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

DNA methylation plays a crucial role in the development and progression of cancer and has been utilized for subtyping various tumors. This study focused on classifying epithelial ovarian cancer (EOC) based on DNA methylation and characterizing the subtypes through an integrated analysis of genomic, transcriptomic, and clinical data. We performed genome-wide DNA methylation profiling on 137 EOC tumor tissues using Infinium MethylationEPIC array and four methylation subtypes (MS1-MS4) were identified by non-negative matrix factorization (NMF) approach, showing significant differences in prognosis (P = 2.413 × 10⁻⁹). The MS1 group showed the best prognosis and the most favorable response to paclitaxel in combination with platinum-based chemotherapy. MS2 exhibited a gene expression pattern of relatively high immune cell infiltration and MS3 had a gene expression pattern associated with metabolic related pathway with a moderate prognosis. In contrast, MS4 had the poorest prognosis and was marked by the highest methylation levels among the four subtypes. A four-differential methylation position (DMP) signature was constructed for prognosis prediction and nomogram was also developed for enhancing clinical utility. Together, this study identified a novel molecular subtype for EOC, elucidating the heterogeneity of EOC from an epigenetic perspective and providing a new strategy for personalized treatment options for EOC patients.

Abstract Background The association between tea consumption and ovarian cancer (OC) risk has been reported in several epidemiology studies. However, the results were inconsistent and the causal relationship remains unclear. To explore the causal relationship between tea consumption and OC risk, we performed a two-sample Mendelian randomization (MR) analysis. Methods MR analysis was conducted using two published genome wide association studies (GWASs) (25,509 cases and 40,941 controls of European population and 3,238 cases and 4,083 controls of East Asian population) and in house GWAS (2,147 OC cases and 3,179 controls of Chinese population) by inverse variance-weighted, weighted median, and MR-Egger methods. Genetic instruments of 233 single nucleotide polymorphisms (SNPs) for European population, 382 SNPs for East Asian population, and 172 SNPs for Chinese population were created. Results We identified that tea consumption has protective effect against overall OC in European population (OR = 0.95, 95%CI: 0.90–0.99, P = 2.65E-02) and Chinese population (OR = 0.96, 95%CI: 0.92-1.00, P = 3.63E-02). When stratified by histological subtype, we found that tea consumption was significantly associated with the risk of Serous OC in European (OR = 0.92, 95%CI: 0.88–0.98, P = 4.86E-03), East Asian (OR = 0.96, 95%CI: 0.92–0.99, P = 9.87E-03), and Chinese (OR = 0.94, 95%CI: 0.90–0.99, P = 1.69E-02) population. In European population, there was a reduced risk of ovarian tumors of low malignant potential (OR = 0.90, 95%CI: 0.81-1.00, P = 4.59E-02), but an increased risk of Endometrioid OC (OR = 1.14, 95%CI: 1.03–1.27, P = 1.12E-02). Conclusion Our study suggested that there might be a causal relationship between tea consumption and OC risk in both European and East Asian populations and also may provide the evidence for cancer prevention and control.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset ( n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Supplementary Tables 1-2 from Genomic and Molecular Characterization of Malignant Peripheral Nerve Sheath Tumor Identifies the IGF1R Pathway as a Primary Target for Treatment

Abstract Background ABO blood groups has been associated with risk of several cancers; however, the results for an association with ovarian cancer are inconsistent and little is known about the expression of histo‐blood group (ABH) antigens and ABO gene in ovarian tumor tissues. Methods To assess the impact of genotype‐derived ABO blood types on the risk of EOC, we conducted a case–control study in 1,870 EOC and 4,829 controls. Expression of A and B antigen in 70 pairs of ovarian tumor tissues and adjacent normal tissues were detected by immunohistochemistry. Gene expression and DNA methylation profiling was conducted in ovarian tumor tissues. Results We identified that blood group A was associated with increased risk for EOC compared to blood group O (OR = 1.18, 95% CI = 1.03–1.36, p = 0.019). Increased frequency of aberrant expression of histo‐blood group antigens was observed in patients with blood group A (76.5%) compared to patients with blood group O (21.1%) and B (5.0%) by immunohistochemistry (p < 0.001). ABO gene expression was down‐regulated in ovarian tumor tissues compared with paired adjacent normal tissues (p = 0.027). In addition, ABO gene expression was positively correlated with NFYB (r = 0.38, p < 0.001) and inversely correlated with DNA methylation level of four CpG sites on ABO gene (cg11879188, r = − 0.3, p = 0.002; cg22535403, r = − 0.30, p = 0.002; cg13506600, r = − 0.22, p = 0.025; cg07241568, r = − 0.21, p = 0.049) in ovarian tumor tissues. Conclusion We identified blood group A was associated with increased EOC risk in Chinese women and provided the clues of the possible molecular mechanisms of blood group A related to ovarian cancer risk.

Abstract Aims To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. Methods and results Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43–3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20–80%) PRS. Conclusion The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.

The comprehensive regulation effect of eRNA on tumor immune cell infiltration and the outcome remains obscure. We comprehensively identify the eRNA-mediated immune infiltration patterns of gastric cancer (GC) samples. We creatively proposed a random forest machine-learning (ML) algorithm to map eRNA to mRNA expression patterns. The eRNA score was constructed using principal component analysis algorithms and validated in an independent cohort. Three subtypes with distinct eRNA expression patterns were determined in GC. There were significant differences between the three subtypes in the overall survival rate, immune cell infiltration characteristics, and immunotherapy response indicators. The patients in the high eRNA score group have a higher overall survival rate and might benefit from immunotherapy. This work revealed that eRNA regulation might be a new prognostic index and might offer a potential biomarker in the response of immunotherapy. Evaluating the eRNA regulation manner of GC will contribute to guiding more effective immunotherapy strategies.

Background Perfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population. Methods Participants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer. Results Perfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (OR ER+ = 1.47, 95% CI: 1.19, 1.80; OR PR+ = 1.36, 95% CI: 1.09, 1.69; OR HER2 = 1.62, 95% CI: 1.19, 2.21). Conclusions Overall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

Knowledge is limited on attendance and involvement of perceived participation of children with long-term health conditions.To evaluate the perceived participation of children with long-term health conditions and to compare their participation with that of healthy peers.A cross-sectional comparative study was designed using self-reported data from 65 children with long-term health conditions and from 65 healthy peers, utilising the simplified Chinese version of Picture My Participation (PMP-C; Simplified).The frequency scores of children with long-term health conditions were significantly lower than those of healthy peers in terms of attendance for the total domain and for 13 activity items. The involvement scores of children with long-term health conditions were significantly lower than those of healthy children in 3 items. There was a strong correlation between rank orders of the most important activities for the two groups (r = 0.83).Children with long-term health conditions participated less in activities compared to healthy children. Further studies are required to investigate factors of the participation of children.The PMP-C (Simplified) offered an opportunity for children to express their own perspectives of participation based on their individual experience of the activity.

ObjectiveTo investigate the CT characteristics of hepatitis B cirrhosis, and to predict the risk of bleeding by establishing a predictive model for upper gastrointestinal bleeding in liver cirrhosis. MethodsA retrospective analysis was performed for the clinical data of 101 patients with hepatitis B cirrhosis who were admitted to Tianjin First Central Hospital from January 2015 to June 2021, and these patients were divided into upper gastrointestinal bleeding group and non-bleeding group. The two groups were compared in terms of laboratory findings and CT values in plain scan, arterial phase, portal vein phase, and venous phase measured by contrast-enhanced CT, and the changes in CT values (ΔCT) across different phases were calculated. The t-test or the Mann-Whitney U rank sum test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. Logistic regression analysis was used to predict the related risk factors; The discrimination of the model was evaluated by calculating the area under the working characteristic curve of the subjects, and the model calibration criteria were determined by Hosmer-lemeshow. Based on the results of multivariate logistic regression analysis, Rstudio4.1.2 R package was used to establish a predictive model, and draws the corresponding ROC curve, calibration curve and clinical decision curve. ResultsThere were significant differences in serum TBil, WBC and PLT levels between the non-bleeding group and the bleeding group (all P＜0.05). There were significant differences in liver-plain, spleen-P-plain and spleen- P-A ΔCT(all P＜0.05). The univariate logistic analysis showed that there were significant differences in leukocytes (odds ratio ［OR］=0.770, 95% confidence interval ［CI］: 0.624-0.952, P=0.016), platelets (OR=0.979, 95%CI: 0965-0.994, P=0.006), liver plain scan (OR=1.142, 95%CI: 1058-1.233, P=0.001), ΔCT value of the spleen from portal vein phase to plain scan (OR=0.979, 95%CI: 0.959-1.000, P=0.050), and ΔCT value of the spleen from portal vein phase to arterial phase (OR=0.979, 95% CI: 0.944-0.994, P=0.015) between the hepatitis B cirrhosis patients with upper gastrointestinal bleeding and those without bleeding. The multivariate logistic analysis showed that platelets (OR=0.968, 95%CI: 0.944-0.993, P=0.011), liver plain phase (OR=1.148, 95%CI: 1.047-1.259, P=0.003), and ΔCT value of the spleen from portal vein phase to arterial phase (OR=0.951, 95%CI: 0.908-0.995, P=0.030) were independent risk factors for upper gastrointestinal bleeding. A predictive model for upper gastrointestinal bleeding in hepatitis B cirrhosis was established based on the results of the multivariate logistic analysis, and a calibration curve was plotted. This model had an area under the receiver operating characteristic curve of 0.801 at the cut-off value of 0.433, with a sensitivity of 81.4% and a specificity of 77.6%. The calibration curve of the model fitted well with the ideal curve. ConclusionThere are special ΔCT changes in hepatitis B cirrhosis, and the predictive model based on ΔCT has a good predictive ability for upper gastrointestinal bleeding in patients with hepatitis B cirrhosis.

High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR=1.79, 95% CI: 1.17-2.75, P=0.008) and OS in post-menopausal women (HR=1.35, 95% CI: 1.04-1.74, P=0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation (“L-shaped” and “U-shaped”, respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a “U-shaped” relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.

目的 调查本科护生心理弹性及专业适应性水平,探讨护生心理弹性与专业适应性相关性.方法 2019-12,选取天津医科大学护理学专业2016-2019级20个班级在校404名学生作为调查对象,均完成青少年心理弹性量表与大学生专业适应性量表的填写.结果 共发放问卷404份,剔除无效问卷后收回有效问卷392份.各年级护生之间心理弹性总分(F=3.394,P=0.018)、情绪控制维度(F=3.892,P=0.009)和人际协助维度(F=3.153,P=0.025)得分比较,差异均有统计学意义.专业适应性量表中,专业承诺、专业学习动力、专业学习行为及专业自我效能平均得分分别为(29.37±4.539)、(25.86±3.706)、(35.32±5.392)和(16.06±2.971)分.各年级间学生专业适应性总分(F=6.740,P＜0.001)、专业承诺维度(F=8.594,P＜0.001)、专业学习动力维度(F=11.526,P＜0.001)及专业学习行为维度(F=3.684,P=0.012)得分比较,差异均有统计学意义;父母不同文化程度的护生在专业适应性总分(F=2.760,P=0.042)、专业学习行为维度(F=3.851,P=0.010)及专业自我效能维度(F=4.005,P=0.008)得分,差异有统计学意义.相关性分析结果显示,除了心理弹性量表中的家庭支持、人际协助维度与专业适应性量表中的专业自我效能维度无相关关系外,护生的心理弹性各维度与专业适应性各维度之间呈正相关关系,均P＜0.05.多因素分析结果显示,学生所在年级(t=-3.32,P=0.001)、心理弹性中情绪控制(t=2.718,P=0.007)和目标专注因子(t=7.808,P＜0.001)是专业适应性的影响因素.结论 本科护生心理弹性与专业适应性现状较好,学生心理弹性与专业适应性受学生年级及家庭背景因素影响较大,护生的心理弹性是影响其专业适应性的主要因素.

Single nucleotide polymorphisms (SNPs) within microRNA binding sites can affect the binding of microRNA to mRNA and regulate gene expression, thereby contributing to cancer prognosis. Here we performed a two-stage study of 2647 breast cancer patients to explore the association between SNPs within microRNA binding sites and breast cancer prognosis. In stage I, we genotyped 192 SNPs within microRNA binding sites using the Illumina Goldengate platform. In stage II, we validated SNPs associated with breast cancer prognosis in another dataset using the TaqMan platform. We identified 8 SNPs significantly associated with breast cancer prognosis in stage I (P<0.05), and only rs10878441 was statistically significant in stage II (AA vs CC, HR=2.21, 95% CI: 1.11-4.42, P=0.024). We combined the data from stage I and stage II, and found that, compared with rs10878441 AA genotype, CC genotype was associated with poor survival of breast cancer (HR=2.19, 95% CI: 1.30-3.70, P=0.003). Stratified analyses demonstrated that rs10878441 was related to breast cancer prognosis in grade II and lymph node-negative patients (P<0.05). The Leucine-rich repeat kinase 2 (LRRK2) rs10878441 CC genotype is associated with poor prognosis of breast cancer in a Chinese population and may be used as a potential prognostic biomarker for breast cancer. • The LRRK2 rs10878441 CC genotype is associated with poor prognosis of breast cancer in a Chinese population. • Stratified analyses demonstrated that rs10878441 was related to breast cancer prognosis in grade II patients and lymph node-negative patients.

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.

Background: Inflammatory markers have been reported to be predictors for the presence of epithelial ovarian cancer (EOC), however, the cut-off value of each marker remains unclear and predictive capability of the markers in different histology types of EOC is still unknown. Methods: A total of 207 patients with benign ovarian masses and 887 EOC patients who underwent surgical resection, and were pathologically diagnosed were included. We compared the difference of preoperative inflammatory markers between benign ovarian masses and EOC patients. Stratified analysis by histology subtype was further conducted. Logistic regression analyses and receiver operating characteristic (ROC) curves was used to evaluate the predictive capability of the markers. Results: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were significantly associated with all stages and subtypes of EOC (P<0.001). The optimal cut-off points based on ROC curve analyses for NLR, PLR, and LMR were found to be 2.139 (AUC=0.749, P<0.001), 182.698 (AUC=0.730, P<0.001), and 3.619 (AUC = 0.709, P<0.001), respectively. In low CA125 level patients, high level of NLR and PLR increase the risk of endometrioid EOC, while low level of LMR were significantly associated with an increased risk of serous EOC. Conclusions: In addition to CA125, NLR, PLR, and LMR could be used as predictors of EOC and preoperative inflammatory markers may be used as a potential biomarker for predicting different histotypes of EOC.