miR-622 Increases miR-30a Expression through Inhibition of Hypoxia-Inducible Factor 1α to Improve Metastasis and Chemoresistance in Human Invasive Breast Cancer Cells.

Hypoxia-inducible factor 1α (HIF-1α) plays a pivotal role in the survival, metastasis, and response to treatment of solid tumors. Autophagy serves as a mechanism for tumor cells to eliminate misfolded proteins and damaged organelles, thus promoting invasiveness, metastasis, and resistance to treatment under hypoxic conditions. MicroRNA (miRNA) research underscores the significance of these non-coding molecules in regulating cancer-related protein synthesis across diverse contexts. However, there is limited reporting on miRNA-mediated gene expression studies, especially with respect to epithelial-mesenchymal transition (EMT) and autophagy in the context of hypoxic breast cancer. Our study reveals decreased levels of miRNA-622 (miR-622) and miRNA-30a (miR-30a) in invasive breast cancer cells compared to their non-invasive counterparts. Inducing miR-622 suppresses HIF-1α protein expression, subsequently activating miR-30a transcription. This cascade results in reduced invasiveness and migration of breast cancer cells by inhibiting EMT markers, such as Snail, Slug, and vimentin. Furthermore, miR-30a negatively regulates beclin 1, ATG5, and LC3-II and inhibits Akt protein phosphorylation. Consequently, this improves the sensitivity of invasive MDA-MB-231 cells to docetaxel treatment. In conclusion, our study highlights the therapeutic potential of inducing miR-622 to promote miR-30a expression and thus disrupt HIF-1α-associated EMT and autophagy pathways. This innovative strategy presents a promising approach to the treatment of aggressive breast cancer.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Body mass index and type 2 diabetes and breast cancer survival: a Mendelian randomization study.

The causal relationship between body mass index (BMI) and type 2 diabetes (T2D) and breast cancer prognosis is still ambiguous. The aim of this study was to investigate the prognostic effect of BMI and T2D on breast cancer disease-free survival (DFS) among Asian individuals. In this two-sample Mendelian randomization (MR) study, the instrumental variables (IVs) were identified using a genome-wide association study (GWAS) among 24,000 participants in the Taiwan Biobank. Importantly, the validity of these IVs was confirmed with a previous large-scale GWAS (Biobank Japan Project, BBJ). In this study, we found that a genetic predisposition toward higher BMI (as indicated by BMI IVs, F = 86.88) was associated with poor breast cancer DFS (hazard ratio [HR] = 6.11; P < 0.001). Furthermore, higher level of genetically predicted T2D (as indicated by T2D IVs) was associated with an increased risk of recurrence of and mortality from breast cancer (HR = 1.43; P < 0.001). Sensitivity analyses, including the weighted-median approach, MR-Egger regression, Radial regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) supported the consistency of our findings. Finally, the causal relationship between BMI and poor breast cancer prognosis was confirmed in a prospective cohort study. Our MR analyses demonstrated the causal relationship between the genetic prediction of elevated BMI and a greater risk of T2D with poor breast cancer prognosis. BMI and T2D have important clinical implications and may be used as prognostic indicators of breast cancer.

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

MiR-139 Modulates Cancer Stem Cell Function of Human Breast Cancer through Targeting CXCR4.

Elevated expression of C-X-C motif chemokine receptor 4 (CXCR4) correlates with chemotaxis, invasion, and cancer stem cell (CSC) properties within several solid-tumor malignancies. Recent studies reported that microRNA (miRNA) modulates the stemness of embryonic stem cells. We aimed to investigate the role of miRNA, via CXCR4-modulation, on CSC properties in breast cancer using cell lines and xenotransplantation mouse model and evaluated miR-193 levels in 191 patients with invasive ductal carcinoma. We validated miR-139 directly targets the 3'-untranslated region of CXCR4. Hoechst 33342 fluorescence-activated cell sorting (FACS) and sphere-forming assay were used to identify CSCs. MiR-139 suppressed breast CSCs with mesenchymal traits; led to decreased migration and invasion abilities through down-regulating CXCR4/p-Akt signaling. In lung cancer xenograft model of nude mice transplanted with human miR-139-carrying MDA-MB-231 cells, metastatic lung nodules were suppressed. Clinically, microdissected breast tumor tissues showed miR-139 reduction, compared to adjacent non-tumor tissues, that was significantly associated with worse clinicopathological features, including larger tumor size, advanced tumor stage and lymph node metastasis; moreover, reduced miR-139 level was predominately occurred in late-stage HER2-oreexpression tumors. Collectively, our findings highlight miR-139-mediated suppression of CXCR4/p-Akt signaling and thereby affected mesenchymal stem-cell genesis, indicating its potential as a therapeutic target for invasive breast cancer.

Rare variants discovery by extensive whole-genome sequencing of the Han Chinese population in Taiwan: Applications to cardiovascular medicine.

Introduction: A population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan. Objectives: We report the first whole genome sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine. Methods: Whole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2. Results: We identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online SCN5A (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes (CYP2C9 and VKORC1) involved in drug metabolism and blood clotting. Conclusion: This research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.

Quantifying the association of low-intensity and late initiation of tobacco smoking with total and cause-specific mortality in Asia.

BACKGROUND: Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts. METHODS: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis. FINDINGS: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence. CONCLUSIONS: Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice.

Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations. AIMS: To explore genetic variants associated with chronic HBV infection. METHODS: The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole-genome genotyping by Axiom-Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method. RESULTS: Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10-35 ) was significantly associated with HBV chronicity (Pcorrected  < 8.6 × 10-8 ). Imputation analyses showed that HLA-DPA1*02:02 and HLA-DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09-1.89) and 1.61 (1.29-2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA-DRB1*13:02, HLA-DQA1* 01:02 and HLA-DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17-0.58), 0.70 (0.56-0.87) and 0.33 (0.18-0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein. CONCLUSIONS: HLA class II variants are relevant for chronicity after HBV acquisition.

Blood multiomics reveal insights into population clusters with low prevalence of diabetes, dyslipidemia and hypertension.

Diabetes, dyslipidemia and hypertension are important metabolic diseases that impose a great burden on many populations worldwide. However, certain population strata have reduced prevalence for all three diseases, but the underlying mechanisms are poorly understood. We sought to identify the phenotypic, genomic and metabolomic characteristics of the low-prevalence population to gain insights into possible innate non-susceptibility against metabolic diseases. We performed k-means cluster analysis of 16,792 subjects using anthropometric and clinical biochemistry data collected by the Taiwan Biobank. Nuclear magnetic resonance spectra-based metabolome analysis was carried out for 217 subjects with normal body mass index, good exercise habits and healthy lifestyles. We found that the gene APOA5 was significantly associated with reduced prevalence of disease, and lesser associations included the genes HIF1A, LIMA1, LPL, MLXIPL, and TRPC4. Blood plasma of subjects belonging to the low disease prevalence cluster exhibited lowered levels of the GlycA inflammation marker, very low-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, valine and leucine compared to controls. Literature mining revealed that these genes and metabolites are biochemically linked, with the linkage between lipoprotein metabolism and inflammation being particularly prominent. The combination of phenomic, genomic and metabolomic analysis may also be applied towards the study of metabolic disease prevalence in other populations.

A high-resolution HLA imputation system for the Taiwanese population: a study of the Taiwan Biobank.

An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB1*03:01, DRB1*04:05, DQA1*03:03, and DQB1*04:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.

The Causal Relationship of Circulating Triglyceride and Glycated Hemoglobin: A Mendelian Randomization Study.

CONTEXT: The association between circulating triglyceride (TG) and glycated hemoglobin A1c (HbA1c), a biomarker for type 2 diabetes, has been widely addressed, but the causal direction of the relationship is still ambiguous. OBJECTIVE: To confirm the causal relationship between TG and HbA1c by using bidirectional and 2-step Mendelian randomization (MR) approaches. METHODS: We carried out a bidirectional MR approach using the summarized results from the public database to examine any potential causal effects between serum TG and HbA1c in 16 000 individuals of the Taiwan Biobank cohort. We used the MR estimate and the MR inverse variance-weighted method to reveal that relationship between TG and HbA1c. To further determine whether the DNA methylation at specific sequences mediate the causal pathway between TG and HbA1c, using the 2-step MR approach. RESULTS: We identified that a single-unit increase in TG measured via log transformation of mg/dL data was associated with a significant increase of 10 units of HbA1c (95% CI = 1.05-18.95, P = 0.029). In contrast, the genetic determinants of HbA1c do not contribute to the amount of circulating TG (beta = 1.75, 95% CI = -11.50 to 14.90). Sensitivity analyses, included the weighted-median approach and MR-Egger regression, were performed to confirm no pleiotropic effect among these instrumental variables. Furthermore, we identified the genetic variant, rs1823200, is associated with both methylation of the CpG site adjacent to CADPS gene and HbA1c level. CONCLUSION: Our study suggests that higher circulating TG can have an affect on genomic methylation status, ultimately causing elevated level of circulating HbA1c.

The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium.

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

Association of Diabetes With All-Cause and Cause-Specific Mortality in Asia: A Pooled Analysis of More Than 1 Million Participants.

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations. Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status. Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018. Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction < .001) and more evident among adults aged 30 to 49 years (HR, 2.43; 95% CI, 2.08-2.84) than among adults aged 70 years and older (HR, 1.51; 95% CI, 1.40-1.62) (P for interaction < .001). A similar pattern of association was found between diabetes and cause-specific mortality, with significant variations noted by sex and age. Conclusions and Relevance: This study found that diabetes was associated with increased risk of death from several diseases among Asian populations. Development and implementation of diabetes management programs are urgently needed to reduce the burden of diabetes in Asia.

Increased Cellular Levels of MicroRNA-9 and MicroRNA-221 Correlate with Cancer Stemness and Predict Poor Outcome in Human Breast Cancer.

Background /Aims: Recent studies of microRNA (miRNA) involvement in tumorigenesis have indicated the critical role of these non-coding small RNAs in malignant transformation, but the prognostic role, if any, of miRNAs in breast cancer remains undetermined. Therefore, we assessed the prognostic significance of microRNA-9 (miR-9) and miR-221 in breast cancer toward the goal of understanding the contribution(s) of these miRNAs to cancer cell stemness. METHODS: The level of each of miR-9 and miR-221 in 206 paired laser capture microdissected tumor cells and non-tumor cells was determined by quantitative reverse transcription-PCR (qRT-PCR). The relationship between the miRNA signature and clinicopathological data and prognosis of breast cancer was assessed. Identification of a stem cell-enriched side population was achieved with fluorescence-activated cell sorting and a sphere-forming assay. Wound healing, Boyden chamber assays, and western blotting were used to study the contribution of each miRNA to tumor cell migration and invasion. RESULTS: We found that induction of miR-9 and miR-221 mimics conferred side-population cells to form spheroidal tumor colonies in suspension culture that maintained the mesenchymal stem-cell potential in non-invasive MCF-7 breast cancer cells. In contrast, knockdown of both miR-9 and miR-221 in invasive MDA-MB-231 breast cancer cells dramatically decreased the number of side-population colonies with stem cell-like potency, which reduced the capacity for tumor-cell renewal, invasion, and migration. Clinically, the mean proportion of miR-9- or miR-221-overexpressing cells was significantly greater in tumor cells compared with non-tumor cells (P < 0.05). Increased levels of miR-9 and miR-221 in breast tissue portended a significantly elevated risk of progression to malignancy with respect to larger tumor size, poor differentiation, late-stage evolution, lymph-node metastasis (P < 0.05), and lower overall survival (Ptrend = 0.017; eight-year follow-up). CONCLUSION: Our findings provide strong evidence that miR-9 and miR-221 can enhance the generation of cancer stem cells to yield an invasive phenotype and that overexpression of these miRNAs predicts a poor outcome for breast cancer patients.

SUMOylation of XRCC1 activated by poly (ADP-ribosyl)ation regulates DNA repair.

XRCC1 is an essential scaffold protein for base excision repair (BER) and helps to maintain genomic stability. XRCC1 has been indicated as a substrate for small ubiquitin-like modifier modification (SUMOylation); however, how XRCC1 SUMOylation is regulated in cells and how SUMOylated XRCC1 regulates BER activity are not well understood. Here, we show that SUMOylation of XRCC1 is regulated in cells under methyl-methanesulfonate (MMS) treatment and facilitates BER. Poly(ADP-ribose) polymerase 1 (PARP1) is activated by MMS immediately and synthesizes poly(ADP-ribose) (PAR), which in turn promotes recruitment of SUMO E3 TOPORS to XRCC1 and facilitates XRCC1 SUMOylation. A SUMOylation-defective mutant of XRCC1 had lower binding activity for DNA polymerase beta (POLB) and was linked to a lower capacity for repair of MMS-induced DNA damages. Our study therefore identified a pathway in which DNA damage-induced poly(ADP-ribosyl)ation (PARylation) promotes SUMOylation of XRCC1, which leads to more efficient recruitment of POLB to complete BER.

Genetic Evidence for the Association between Schizophrenia and Breast Cancer.

OBJECTIVE: To estimate the potential effect of schizophrenia on breast cancer risk in women, we performed a two-sample Mendelian randomization (MR) study. METHODS: The instrumental variables comprised 170 uncorrelated and non-pleiotropic single nucleotide polymorphisms (SNPs) that are significantly associated with schizophrenia risk in genome-wide association studies in 105,000 European descent individuals of the Psychiatric Genomics Consortium (http://www.med.unc.edu/pgc/) and the United Kingdom Clozapine Clinic. The association between these SNPs determined schizophrenia and breast cancer risk was estimated in approximately 229,000 European descent females from the Breast Cancer Association Consortium using the inverse-variance weighted and the weighted median MR methods. RESULTS: We found that the genetically-predicted risk of schizophrenia was associated with increased breast cancer risk (under a random-effects model: odds ratio per 1 unit increase in log odds of schizophrenia = 1.04, 95% confidence interval: 1.02-1.06, p = 5.6 × 10-5). Similar significant associations were observed in analyses using a weighted median model and sensitivity analysis excluding six SNPs with genotype imputation score of less than 0.8, as well as analyses stratified by estrogen receptor status of breast cancer. CONCLUSION: Our findings implicate a modest increased risk for breast cancer in genetically determined schizophrenic females.

Population structure of Han Chinese in the modern Taiwanese population based on 10,000 participants in the Taiwan Biobank project.

The Taiwan Biobank (TWB) aims to build a nationwide research database that integrates genomic/epigenomic profiles, lifestyle patterns, dietary habits, environmental exposure history and long-term health outcomes of 300,000 residents of Taiwan. We describe here an investigation of the population structure of Han Chinese on this Pacific island using genotype data of 591,048 SNPs in an initial freeze of 10,801 unrelated TWB participants. In addition to the North-South cline reported in other Han Chinese populations, we find the Taiwanese Han Chinese clustered into three cline groups: 5% were of northern Han Chinese ancestry, 79.9% were of southern Han Chinese ancestry, and 14.5% belonged to a third (T) group. We also find that this T group is genetically distinct from neighbouring Southeast Asians and Austronesian tribes but similar to other southern Han Chinese. Interestingly, high degree of LD between HLA haplotype A*33:03-B*58:01, an MHC allele being of pathological relevance, and SNPs across the MHC region was observed in subjects with T origin, but not in other Han Chinese. This suggested the T group individuals may have experienced evolutionary events independent from the other southern Han Chinese. Based on the newly-discovered population structure, we detect different loci susceptible to type II diabetes in individuals with southern and northern Han Chinese ancestries. Finally, as one of the largest dataset currently available for the Chinese population, genome-wide statistics for the 10,810 subjects are made publicly accessible through Taiwan View (https://taiwanview.twbiobank.org.tw/index; date last accessed October 14, 2016) to encourage future genetic research and collaborations with the island Taiwan.

Fanconi anemia genes in lung adenocarcinoma- a pathway-wide study on cancer susceptibility.

BACKGROUND: Carcinogens in cigarette smoke can induce the formation of DNA-DNA cross-links, which are repaired by the Fanconi anemia (FA) pathway, and it is tempting to speculate that this pathway is involved in lung tumorigenesis. This study is to determine whether genetic polymorphism of the FA genes is associated with an elevated risk of lung adenocarcinoma, and whether the association between genotypes and risk is modified by exposure to cigarette smoke. METHODS: This case-control study genotyped 53 single-nucleotide polymorphisms (SNPs) in FA genes in 709 patients (354 males and 355 females) with lung adenocarcinoma and in 726 cancer-free individuals (339 males and 387 females). Genotypic frequencies of SNPs were compared between cases and controls to identify important FA genes associated with cancer susceptibility. Joint effects in determining cancer risk contributed by genes and smoking-related risk factors and by multiple genes involved in different FA subpathways were evaluated by multivariate regression analysis and stratified analysis. All analyses were performed on males and females separately, and the comparison of results was considered a way of examining the validity of study findings. RESULTS: Lung adenocarcinomas in both male and female patients were associated with (a) genotypic polymorphisms of FANCC and FANCD1; (b) a combined effect of harboring a higher number of high-risk genotypes and smoking/passive smoking; (c) specific interactions of multiple genes, proteins encoded by which have been known to work jointly within the FA pathway. CONCLUSIONS: Genetic polymorphism of the FA genes is associated with inter-individual susceptibility to lung adenocarcinoma.

Foxo3a-mediated overexpression of microRNA-622 suppresses tumor metastasis by repressing hypoxia-inducible factor-1α in ERK-responsive lung cancer.

Metastatic spread of cancer cells portends a poor prognosis and mortality for lung cancer patients. Hypoxia-inducible factor-1α (HIF-1α) enhances tumor cell motility by activating the epithelial-to-mesenchymal transition (EMT), which is considered a prerequisite for metastasis. Recent studies of microRNA involvement in cancer invasion and metastasis have highlighted the role of such RNAs in tumor development. However, little work has been done to identify tumor suppressor microRNAs that target HIF-1α to down-modulate the EMT and thereby counteract the aggressiveness and metastasis of lung cancer cells. Here, we identified the 3'-untranslated region of HIF-1α mRNA as a target of miR-622 and established that miR-622-mediated down-modulation of HIF-1α correlates with decreased levels of mesenchymal proteins, including Snail, ß-catenin, and vimentin. Functional analyses revealed that increased miR-622 expression inhibited lung cancer cell migration and invasion in vitro. miR-622 also inhibited the genesis of metastatic lung nodules as demonstrated in a lung cancer xenograft model in which nude mice were transplanted with A549 cells expressing miR-622. Mechanistic analyses showed that overexpression of EGF decreased the miR-622 level in A549 cells, and this reduction could be rescued by administrating U0126, an inhibitor of ERK. Moreover, miR-622 overexpression mediated by the transcription factor FOXO3a decreased the invasiveness of lung tumor cells by inhibiting HIF-1α via inactivation of ERK signaling in U0126-treated A549 cells. These findings highlight the pivotal role of the FOXO3a/miR-622 axis in inhibiting HIF-1α to interfere with tumor metastasis, and this information may contribute to development of novel therapeutic strategies for treating aggressive lung cancer.

Functional variants at the 21q22.3 locus involved in breast cancer progression identified by screening of genome-wide estrogen response elements.

INTRODUCTION: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen-responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor-regulatory sequence interaction, resulting in altered expression of target genes. This study explored the association between single-nucleotide polymorphisms (SNPs) within the ERE-associated sequences and breast cancer progression. METHODS: The ERE-associated sequences throughout the whole genome that have been demonstrated to bind ERα in vivo were blasted against online information from SNP data sets and 54 SNPs located adjacent to estrogen-responsive genes were selected for genotyping in two independent cohorts of breast cancer patients: 779 patients in the initial screening stage and another 888 in the validation stage. Deaths due to breast cancer or recurrence of breast cancer were defined as the respective events of interest, and the hazard ratios of individual SNPs were estimated based on the Cox proportional hazards model. Furthermore, functional assays were performed, and information from publicly available genomic data and bioinformatics platforms were used to provide additional evidence for the associations identified in the association analyses. RESULTS: The SNPs at 21q22.3 ERE were significantly associated with overall survival and disease-free survival of patients. Furthermore, these 21q22.3 SNPs (rs2839494 and rs1078272) could affect the binding of this ERE-associated sequence to ERα or Rad21 (an ERα coactivator), respectively, which resulted in a difference in ERα-activated expression of the reporter gene. CONCLUSION: These findings support the idea that functional variants in the ERα-regulating sequence at 21q22.3 are important in determining breast cancer progression.