Search

Because of the cancer incidence increase and population aging in Taiwan, we aimed to assess the cancer prevalence, to summarize the comorbidities of older patients with the five most common cancers (i.e., breast, colorectal, liver, lung, and oral), and to develop a Taiwan cancer comorbidity index (TCCI) for studying their actual prognosis. The linkage of the Taiwan Cancer Registry, Cause of Death Database, and National Health Insurance Research Database was used. We followed the standard statistical learning steps to obtain a survival model with good discriminatory accuracy in predicting death due to noncancer causes, from which we obtained the TCCI and defined comorbidity levels. We reported the actual prognosis by age, stage, and comorbidity level. In Taiwan, cancer prevalence nearly doubled in 2004–2014, and comorbidities were common among older patients. Stage was the major predictor of patients' actual prognoses. For localized and regional breast, colorectal, and oral cancers, comorbidities correlated with noncancer-related deaths. Compared with the US, the chances of dying from comorbidities in Taiwan were lower and the chances of dying from cancer were higher for breast, colorectal, and male lung cancers. These actual prognoses could help clinicians and patients in treatment decision-making and help policymakers in resource planning.

MRE11, the nuclease component of RAD50/MRE11/NBS1 DNA repair complex which is essential for repair of DNA double-strand-breaks in normal cells, has recently garnered attention as a critical factor in solid tumor development. Herein we report the crucial role of MRE11 in oral cancer progression in a nuclease-independent manner and delineate its key downstream effectors including CXCR4. MRE11 expression in oral cancer samples was positively associated with tumor size, cancer stage and lymph node metastasis, and was predictive of poorer patient survival and radiotherapy resistance. MRE11 promoted cell proliferation/migration/invasion in a nuclease-independent manner but enhanced radioresistance via a nuclease-dependent pathway. The nuclease independent promotion of EMT and metastasis was mediated by RUNX2, CXCR4, AKT, and FOXA2, while CXCR4 neutralizing antibody mitigated these effects in vitro and in vivo. Collectively, MRE11 may serve as a crucial prognostic factor and therapeutic target in oral cancer, displaying dual nuclease dependent and independent roles that permit separate targeting of tumor vulnerabilities in oral cancer treatment.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Type III Nasopharyngeal carcinoma (NPC) is characterized by Epstein-Barr virus (EBV) infection and immune infiltration. M2 macrophages in the NPC microenvironment are considered to associate with poorer prognosis and promote disease progression. How the tumor-derived EBV or viral products regulate macrophage polarization within NPC microenvironment remains to be explored. We demonstrated that EBV products can be transferred to uninfected cancer cells or stromal cells via exosomes. The exosome-mediated intercellular communications between EBV+-NPC cells and macrophages were further investigated. Results of mass spectrometry and western blotting showed that NPC cells deposited EBV-encoded latent protein 1 (LMP1) into exosomes. The uptake of these exosomes by human monocyte-derived macrophages led to a M2-dominant polarization. Specifically, multiple properties of M2 macrophages, including higher levels of CD206, CD163, CD209, and VEGF, as well as a reduced expression of iNOS were found in macrophages stimulated with LMP1-containing exosomes (LMP1_exosomes), compared to those treated with exosomes derived from EBV-negative NPC cells. The LMP1_exosome-treated macrophages also exhibited a reduced cytotoxicity towards primary cancer cells. RNA sequencing data revealed that LMP1_exosomes suppressed the function of antigen presentation while activating the macrophage stimulating 1 receptor (MST1R)-STAT3 signaling in macrophages. Results of mechanistic studies showed that LMP1-CTAR2 domain contributed to the activation of MST1R. Additionally, treating macrophages with LMP1_exosomes activated yes-associated protein 1 (YAP1), the LMP1-mediated M2 phenotype and MST1R expression were partially suppressed by treating cells with the YAP1 inhibitor (verteporfin). It appears that YAP1 acts as a key regulator of MST1R. Clinically, higher expressions of MST1R and nuclear YAP1 were correlated with disease progression of NPC (p < 0.001). The role of LMP1_exosomes in regulating macrophage immune responses was further investigated using single-cell RNA sequencing (scRNA-seq) technique. Results showed that treating primary macrophages isolated from human head and neck tumors with LMP1_exosomes resulted in an increase in M2 proportion. Results of gene set variation analysis (GSVA) demonstrated enhanced signatures in IL10 and VEGF signalings. Collectively, our data suggest that LMP1-containing exosomes facilitate M2 macrophage polarization, which may assist cancer immune evasion in the NPC microenvironment. Citation Format: Tzu-Tung Liu, Yun-Hua Sui, Fang-Yu Tsai, Shih-Sheng Jiang, Kai-Ping Chang, Chen-Han Huang, Shu-Chen Liu. EBV positive NPC-derived exosomes promote macrophage M2 polarization via activating MST1R and YAP1 signalings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2500.

Background Morphological evaluation of oral mucosal biopsy is sometimes inconclusive, which may delay the diagnosis and treatment of oral squamous malignancy. Immunohistochemical biomarkers denoting oral squamous malignancy would be clinically helpful in such scenario. Methods We first studied the expression patterns of four potential biomarkers (cytokeratin 13, cytokeratin 17, Ki-67 and laminin 5 gamma 2 chain) in an exploratory cohort containing 54 surgical specimens from confirmed oral squamous malignancies. A pattern score was assigned to each specific expression pattern of these four biomarkers. A total score from each specimen was then calculated by summing up the four pattern scores. A cut-off value of total score denoting oral squamous malignancy was then determined. Another 34 oral squamous malignancies that were misdiagnosed as non-malignant lesions on their pre-treatment biopsies were used as a validation cohort to test the clinical utility of this scoring system. Results In the exploratory cohort, fifty-two (96%) of the 54 confirmed oral squamous malignancies had a total score of 9 and above. In the validation cohort, thirty-one (91%) of the 34 pre-treatment oral biopsy specimens also had a total score of 9 or above, supporting the feasibility of using this scoring system to predict immediate risk of oral squamous malignancy. Conclusions Our four-biomarker “oral squamous malignancy scoring system” provides reliable prediction for immediate risk of oral squamous malignancy on pre-treatment oral biopsies.

Background Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic neoplasm with high metastatic potential and poor clinical outcome. Like other solid tumors, PDAC in the early stages is often asymptomatic, and grows very slowly under a distinct acidic pHe (extracellular pH) microenvironment. However, most previous studies have only reported the fate of cancerous cells upon cursory exposure to acidic pHe conditions. Little is known about how solid tumors—such as the lethal PDAC originating within the pancreatic duct-acinar system that secretes alkaline fluids—evolve to withstand and adapt to the prolonged acidotic microenvironmental stress. Methods Representative PDAC cells were exposed to various biologically relevant periods of extracellular acidity. The time effects of acidic pHe stress were determined with respect to tumor cell proliferation, phenotypic regulation, autophagic control, metabolic plasticity, mitochondrial network dynamics, and metastatic potentials. Results Unlike previous short-term analyses, we found that the acidosis-mediated autophagy occurred mainly as an early stress response but not for later adaptation to microenvironmental acidification. Rather, PDAC cells use a distinct and lengthy process of reversible adaptive plasticity centered on the early fast and later slow mitochondrial network dynamics and metabolic adjustment. This regulates their acute responses and chronic adaptations to the acidic pHe microenvironment. A more malignant state with increased migratory and invasive potentials in long-term acidosis-adapted PDAC cells was obtained with key regulatory molecules being closely related to overall patient survival. Finally, the identification of 34 acidic pHe-related genes could be potential targets for the development of diagnosis and treatment against PDAC. Conclusions Our study offers a novel mechanism of early rapid response and late reversible adaptation of PDAC cells to the stress of extracellular acidosis. The presence of this distinctive yet slow mode of machinery fills an important knowledge gap in how solid tumor cells sense, respond, reprogram, and ultimately adapt to the persistent microenvironmental acidification.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria. Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case–control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2). Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660–0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95–5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04–36.28) had risk higher than 0.0151. Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention. Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear. Methods: The protein expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition in vitro and in vivo. The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2. Results: NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC. Conclusions: Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer.

Introduction In high-income countries, advances in early diagnosis and treatment have improved cancer survival. However, socioeconomic inequalities in survival have persisted or increased for some adult cancers. Materials and methods We assessed net survival for the 20 most common adult cancers in Taiwan. They were stratified into six age groups and three socioeconomic groups. Results Out of 120 cancer site and age group combinations, 49 showed improvements in 5-year net survival from 2000–2004 to 2005–2010. Only cervix uteri cancer in the 35–49-year age group showed a deterioration. During 2000–2010, 13 of the 20 cancer cases experienced socioeconomic inequalities for all age groups combined, and the deprivation gaps varied with cancer site and age at diagnosis. For the five most common cancers – liver, colon and rectum, lung, breast, and oral – there were socioeconomic inequalities, and 5-year net survival improved for most or all of the six age groups from 2000–2004 to 2005–2010. Conclusion Reducing socioeconomic inequality in survival may lead to improvements in survival overall. We should focus on the age groups with large deprivation gaps. Our results are useful for prioritizing cancer sites and age groups for in-depth socioeconomic disparity studies and for proposing interventions for health disparity reductions and net cancer survival improvements.

The early onset breast cancer patients (age ≤ 40) often display higher incidence of axillary lymph node metastasis, and poorer five-year survival than the late-onset patients. To identify the genes and molecules associated with poor prognosis of early onset breast cancer, we examined gene expression profiles from paired breast normal/tumor tissues, and coupled with Gene Ontology and public data base analysis. Our data showed that the expression of GAS7b gene was lower in the early onset breast cancer patients as compared to the elder patients. We found that GAS7 was associated with CYFIP1 and WAVE2 complex to suppress breast cancer metastasis via blocking CYFIP1 and Rac1 protein interaction, actin polymerization, and β1-integrin/FAK/Src signaling. We further demonstrated that p53 directly regulated GAS7 gene expression, which was inversely correlated with p53 mutations in breast cancer specimens. Our study uncover a novel regulatory mechanism of p53 in early onset breast cancer progression through GAS7–CYFIP1-mediated signaling pathways.

In an effort to understand the underlying mechanisms of lymph node metastasis in oral squamous cell carcinoma (OSCC), through in vivo selection, LN1-1 cells were previously established from OEC-M1 cells and showed enhanced lymphangiogenesis and lymphatic metastasis capabilities. In the current study, we use a stable isotope labeling with amino acids in cell culture (SILAC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic platform to compare LN1-1 to OEC-M1 cells. Interferon-stimulated gene 15 (ISG15) was found highly expressed in LN1-1 cells. Immunohistochemical analysis and meta-analysis of publicly available microarray datasets revealed that the ISG15 level was increased in human OSCC tissues and associated with poor disease outcome. Knockdown of ISG15 had minimal effects on tumor growth but did decrease tumor lymphangiogenesis and lymphatic metastasis of LN1-1 cells. Consistent with the in vivo assay, ISG15 knockdown did not impair cell growth but diminished cell migration, invasion, and transendothelial migration in vitro. ISG15-induced cell migration was independent of ISGylation and associated with membrane protrusion. Ectopic expression of ISG15 increased Rac1 activity and knockdown of Rac1 impaired ISG15-enhanced migration. Furthermore, Rac1 colocalized with ISG15 to a region of membrane protrusion and ISG15 coimmunoprecipitated with Rac1, especially with the Rac1-GDP form. Importantly, as shown by proximity ligation assays, ISG15 and Rac1 physically interacted with each other. Our results indicated that ISG15 affects cell migration by interacting with Rac1 and regulating Rac1 activity and contributes to lymphatic metastasis in OSCC.

Introduction: The association between estrogen receptor (ER) gene polymorphism and lung cancer risk is rarely studied. This study aimed to explore the ER gene polymorphisms associated with the lung adenocarcinoma risk in never-smoking women. Methods: This study evaluated 532 never-smoking female patients with lung adenocarcinoma and 532 healthy controls. The ESR1 and ESR2 single nucleotide polymorphism (SNP) data were retrieved from a genome-wide association study. Using a multivariate-adjusted logistic regression assay, the associations of ESR1 and ESR2 SNPs with the lung adenocarcinoma risk were estimated. Expression quantitative trait loci analysis was performed to investigate the possible functional roles of ER gene SNPs. Results: For ESR1, seven tagged SNPs were identified. Among them, rs7753153 and rs985192 were associated with lung adenocarcinoma risk (rs7753153: odds ratios [OR], 1.509; 95% confidence intervals [CI], 1.168–1.950; rs985192: OR, 1.309; 95% CI, 1.001–1.712). For ESR2, only rs3020450 was associated with lung adenocarcinoma risk (OR, 2.110; 95% CI, 1.007–4.422). Subjects without hormone replacement therapy (HRT) use carrying at-risk genotypes had a significantly higher lung adenocarcinoma risk than subjects with HRT carrying no at-risk genotypes (rs7753153 GG: OR, 2.133; 95% CI, 1.415–3.216; rs985192 AA/AC, OR: 1.752, 95% CI: 1.109–2.768; rs3020450 AG/GG, OR: 7.162, 95% CI: 1.608–31.90). Risk genotypes of rs7753153 ( p = 0.0248) and rs9479122 ( p = 0.0251) were associated with decreased ESR1 expression. Conclusions: ER gene SNPs are associated with lung adenocarcinoma risk in never-smoking women. The joint effects of ER gene SNPs and HRT use on lung adenocarcinoma risk highlight the importance of the gene–environment interaction in lung carcinogenesis.

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene–HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30 % increased risk of lung cancer (OR 1.3, 95 % CI 1.0–1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.

CISD2 is a redox-sensitive gene critical for normal development and mitochondrial integrity. CISD2 was known to have aberrant expression in several types of human cancers. However, its relation with lung cancer is still not clear. In this study we found CISD2 mRNA was significantly upregulated in lung adenocarcinoma (ADC) samples, compared with their adjacent normal counterparts, and was correlated with tumor stage, grade, and prognosis based on analysis of clinical specimens-derived expression data in public domain and our validation assay. Cell based assay indicated that CISD2 expression regulated accumulation of reactive oxygen species (ROS), polarization of mitochondrial membrane potential, as well as cell viability, apoptosis, invasiveness, and tumorigenicity. In addition, CISD2 expression was found significantly correlated with stress response/redox signaling genes such as EGR1 and GPX3, while such correlations were also found valid in many public domain data. Taken together, upregulation of CISD2 is involved in an increased antioxidant capacity in response to elevated ROS levels during the formation and progression of lung ADC. The molecular mechanism underlying how CISD2 regulates ROS homeostasis and augments malignancy of lung cancer warrants further investigations.

SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells.

Recent studies compared the age effects and birth cohort effects on female invasive breast cancer (FIBC) incidence in Asian populations with those in the US white population. They were based on age–period–cohort model extrapolation and estimated annual percentage change (EAPC) in the age‐standardized incidence rates (ASR). It is of interest to examine these results based on cohort‐specific annual percentage change in rate (APCR) by age and without age–period–cohort model extrapolation. FIBC data (1991–2010) were obtained from the Taiwan Cancer Registry and the U.S. SEER 9 registries. APCR based on smoothed Lexis diagrams were constructed to study the age, period, and cohort effects on FIBC incidence. The patterns of age‐specific rates by birth cohort are similar between Taiwan and the US. Given any age‐at‐diagnosis group, cohort‐specific rates increased overtime in Taiwan but not in the US; cohort‐specific APCR by age decreased with birth year in both Taiwan and the US but was always positive and large in Taiwan. Given a diagnosis year, APCR decreased as birth year increased in Taiwan but not in the US. In Taiwan, the proportion of APCR attributable to cohort effect was substantial and that due to case ascertainment was becoming smaller. Although our study shows that incidence rates of FIBC have increased rapidly in Taiwan, thereby confirming previous results, the rate of increase over time is slowing. Continued monitoring of APCR and further investigation of the cause of the APCR decrease in Taiwan are warranted.

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.

Aging is associated with bone loss and degenerative joint diseases, in which the aging of bone marrow-derived mesenchymal stem cell (bmMSC)[1] may play an important role. In this study, we analyzed the gene expression profiles of bmMSC from 14 donors between 36 and 74 years old, and obtained age-associated genes (in the background of osteoarthritis) and osteoarthritis-associated genes (in the background of old age). Pathway analysis of these genes suggests that alterations in glycobiology might play an important role in the aging of human bmMSC. On the other hand, antigen presentation and signaling of immune cells were the top pathways enriched by osteoarthritis-associated genes, suggesting that alteration in immunology of bmMSC might be involved in the pathogenesis of osteoarthritis. Most intriguingly, we found significant age-associated differential expression of HEXA, HEXB, CTSK, SULF1, ADAMTS5, SPP1, COL8A2, GPNMB, TNFAIP6, and RPL29; those genes have been implicated in the bone loss and the pathology of osteoporosis and osteoarthritis in aging. Collectively, our results suggest a pathological role of bmMSC in aging-related skeletal diseases, and suggest the possibility that alteration in the immunology of bmMSC might also play an important role in the etiology of adult-onset osteoarthritis.

Background/PurposeRespiratory Syncytial Virus (RSV) is the leading cause of hospitalization in young children. The population-based burden of RSV hospitalization and the effect of potential risk factors on the severity of illness were evaluated in Taiwanese children.MethodsWe analyzed the annual population-based incidence, underlying diseases and characteristics of hospitalizations due to RSV in Taiwanese children under 5 years of age from 2004 to 2007 by using Taiwan's National Health Insurance database.ResultsA total of 11,081 children with RSV-associated hospitalization were studied. Average annual population-based hospitalization incidence was 1,077 and 232 per 100,000 children-year in children under 6 months and under 5 years of age, respectively. The peak incidence occurred between 1 and 2 months of age. The male-to-female incidence risk ratio was 1.4:1 (p < 0.001). There was a significant seasonal distribution with consistent peaks in the spring and autumn every year (p < 0.001). A total of 373 patients (3.3%) had repeated RSV infection. The 943 children (8.5%) with underlying diseases were older (p = 0.001), required longer intensive care unit (ICU) stays (p < 0.001), had a higher rate of endotracheal intubation (p < 0.05), and incurred higher medical costs (p < 0.001). A total of 888 patients (8%) required ICU care. Younger age (p < 0.001), prematurity (p < 0.001), cerebral palsy (p < 0.001) and congenital heart disease (p < 0.001) were independent predictors of requiring ICU care.ConclusionRSV infection occurs biennially with peaks in spring and fall in Taiwan. Patients with underlying diseases need longer hospital and ICU stays and incur higher medical costs. Younger age, prematurity, congenital heart disease and cerebral palsy are predictors of ICU care.

Background Few studies have investigated the epidemiology and disease burden of childhood pneumonia in Taiwan, a middle-income country. Methods Using Taiwan's National Health Insurance database, we analyzed the annual population-based incidence and mortality rate of hospitalizations due to pneumonia in children under 18 years old from 1997 to 2004 in Taiwan. Results The average annual incidence of hospitalized pneumonia was 1,240 episodes per 100,000 children in those below 18 years old. For children under 5 years old and for infants, the incidence was 3,965 and 4,984 out of 100,000, respectively. Boys were more likely to be affected than girls (male to female risk ratio 1.27, P

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells.

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P

RNA interference (RNAi) is an endogenous cellular process in which small double-stranded RNAs lead to the destruction of mRNAs with complementary nucleoside sequence. With the production of RNAi libraries, large-scale RNAi screening in human cells can be conducted to identify unknown genes involved in a biological pathway. One challenge researchers face is how to deal with the multiple testing issue and the related false positive rate (FDR) and false negative rate (FNR). This paper proposes a Bayesian hierarchical measurement error model for the analysis of data from a two-channel RNAi high-throughput experiment with replicates, in which both the activity of a particular biological pathway and cell viability are monitored and the goal is to identify short hair-pin RNAs (shRNAs) that affect the pathway activity without affecting cell activity. Simulation studies demonstrate the flexibility and robustness of the Bayesian method and the benefits of having replicates in the experiment. This method is illustrated through analyzing the data from a RNAi high-throughput screening that searches for cellular factors affecting HCV replication without affecting cell viability; comparisons of the results from this HCV study and some of those reported in the literature are included., Published in at http://dx.doi.org/10.1214/11-AOAS496 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Background Cancer-related genes show racial differences. Therefore, identification and characterization of DNA copy number alteration regions in different racial groups helps to dissect the mechanism of tumorigenesis. Methods Array-comparative genomic hybridization (array-CGH) was analyzed for DNA copy number profile in 40 Asian and 20 Caucasian lung cancer patients. Three methods including MetaCore analysis for disease and pathway correlations, concordance analysis between array-CGH database and the expression array database, and literature search for copy number variation genes were performed to select novel lung cancer candidate genes. Four candidate oncogenes were validated for DNA copy number and mRNA and protein expression by quantitative polymerase chain reaction (qPCR), chromogenic in situ hybridization (CISH), reverse transcriptase-qPCR (RT-qPCR), and immunohistochemistry (IHC) in more patients. Results We identified 20 chromosomal imbalance regions harboring 459 genes for Caucasian and 17 regions containing 476 genes for Asian lung cancer patients. Seven common chromosomal imbalance regions harboring 117 genes, included gain on 3p13-14, 6p22.1, 9q21.13, 13q14.1, and 17p13.3; and loss on 3p22.2-22.3 and 13q13.3 were found both in Asian and Caucasian patients. Gene validation for four genes including ARHGAP19 (10q24.1) functioning in Rho activity control, FRAT2 (10q24.1) involved in Wnt signaling, PAFAH1B1 (17p13.3) functioning in motility control, and ZNF322A (6p22.1) involved in MAPK signaling was performed using qPCR and RT-qPCR. Mean gene dosage and mRNA expression level of the four candidate genes in tumor tissues were significantly higher than the corresponding normal tissues (PP=0.06). In addition, CISH analysis of patients indicated that copy number amplification indeed occurred for ARHGAP19 and ZNF322A genes in lung cancer patients. IHC analysis of paraffin blocks from Asian Caucasian patients demonstrated that the frequency of PAFAH1B1 protein overexpression was 68% in Asian and 70% in Caucasian. Conclusions Our study provides an invaluable database revealing common and differential imbalance regions at specific chromosomes among Asian and Caucasian lung cancer patients. Four validation methods confirmed our database, which would help in further studies on the mechanism of lung tumorigenesis.

Background Varicella has an important impact on public health. Starting in 2004 in Taiwan, nationwide free varicella vaccinations were given to 1-year-old children. Methods Our study investigated the epidemiological characteristics of varicella from 2000 to 2008, and assessed the change of varicella epidemiology after the mass varicella immunization. ICD-9-CM codes related to varicella or chickenpox (052, 052.1, 052.2, 052.7, 052.8, 052.9) were analyzed for all young people under 20 years of age through the National Health Insurance database of Taiwan from 2000 to 2008. Results Case numbers of varicella or chickenpox significantly declined after the nationwide immunization in 2004. Winter, particularly January, was the epidemic season of varicella. We found a significant post-vaccination decrease in incidence among preschool children, especially 3 to 6 year-old children-- the peak incidence was 66 per thousand for 4 and 5 year-old children before the nationwide immunization (2000 to 2003), and the peak incidence was 23 per thousand for 6 year-old children in 2008 (p < 0.001). Varicella-related hospitalization also significantly decreased in children younger than 6 years after the nationwide immunization. Conclusion The varicella annual incidence and varicella-related hospitalization markedly declined in preschool children after nationwide varicella immunization in 2004.

We performed this nationwide retrospective investigation among the recipients of varicella vaccine to evaluate the breakthrough varicella infection rate, factors associated with breakthrough infection and the vaccine effectiveness. The recipients of these vaccinations were identified through Taiwan's National Immunization Information System and data on breakthrough infections among these recipients were collected by using Taiwan's National Health Insurance Claims Database. From 2000 to 2007, 1,057,345 persons received varicella vaccinations in Taiwan. Varicella breakthrough infection occurred among 22,640 (2.1%) vaccinees and 170 (0.016%) required hospitalization for varicella disease. Annual breakthrough infection rates ranged from 0.12% to 2.04%. The mean age of vaccination was 1.6 years (median 1.3 years) and the mean age at breakthrough infection was 3.9 years. The mean interval between vaccination and the breakthrough infection was 2.3 years. The rate was significantly lower in regions where free varicella vaccinations were available than in regions where they were not (P

Herpes zoster, a common disease, has an important impact on the health of adults, particularly the elderly, and the health system. This study evaluated the disease burden and epidemiological characteristics of herpes zoster in Taiwan. Using herpes zoster-related ICD-9-CM codes used on Taiwan's National Health Insurance claims, we analyzed overall and age group differences in incidence, complications, utilization of healthcare facilities, lengths of stay, and cost of their medical care in Taiwan's population from 2000 to 2005. The overall annual incidence of zoster was 4.97 cases per 1000 people, with women having a significantly higher incidence than men (5.20 per 1000 vs. 4.72 per 1000, p

Varicella has an important impact on public health, especially before the introduction of the varicella vaccine. This study investigated the epidemiological characteristics and disease burden of varicella during the introduction of the varicella vaccine for mass vaccination in Taiwan.The International Classification of Diseases, 9th Revision, Clinical Modification codes related to varicella (052, 052.1, 052.2, 052.7, 052.8, 052.9) were analyzed for the population of Taiwan from 2000 to 2005 through the National Health Insurance database.Most of the patients with varicella were younger than 10 years. The overall age-specific annual incidence peaked in 4- and 5-year-old children (60.5 and 60.2/1000 children, respectively). A significant decrease in incidence among 3- to 6-year-old children was observed in areas with free varicella vaccination (p0.001). Winter was the season for epidemic varicella, particularly January. The varicella-related hospital admission rate was 60/1000 patients (95% confidence interval [CI], 48.5-71.5/1000 patients). Infants younger than 1 year, and adults aged from 19 to 38 years and older than 75 years had the highest hospital admission rates. The mean duration of hospital stay was 5.05 days (95%CI, 4.98-5.12 days). The complication rate among patients admitted to hospital was 39.1%, and the most common complication was lower respiratory tract infection (22.1% among patients admitted to hospital). Twenty nine patients with varicella died; 52% had underlying disease and 72% had complications related to varicella. The annual varicella-related medical expense was highest in 2000 (NT$118.6 million/year) and declined after 2002.Most patients with varicella were younger than 10 years, and the incidence peaked among children aged 4 to 5 years. The incidence of varicella among 3- to 6-year-old children was significantly lower in the areas with a free public vaccination policy. The hospital admission rates were highest for infants and elderly people.

Pneumococcal/lobar pneumonia and empyema have an important impact on the health of children worldwide. There has been no epidemiological study of pneumococcal/lobar pneumonia and empyema in Taiwan, a middle-income Asian population. Using Taiwan’s National Health Insurance database, we collected and analyzed data obtain from medical care claims related to pneumococcal/lobar pneumonia and empyema for children below the 18 years old from 1997 to 2004. We found the annual population-based incidence to have significant year to year increases and the average annual incidences of pneumococcal/lobar pneumonia and empyema in children under five to be 44.9 and 10.5 episodes per 100,000 children-year, respectively. About 64% of children with pneumococcal/lobar pneumonia and empyema were under 5 years old. Children 4 to 5 years old had the highest incidences of both pneumococcal/lobar pneumonia and empyema. Incidence was the highest each spring. The odds ratio of the case fatality among pneumococcal/lobar pneumonia patients complicated with empyema to those without was 118 (95% confidence interval 28–492). In conclusion, the population-based incidences of pneumococcal/lobar pneumonia and empyema among children under five in Taiwan were 44.9 and 10.5 episodes per 100,000 children-year, respectively, and 4- to 5-year-old children had the highest incidences of both pneumococcal/lobar pneumonia and empyema. This population might benefit from a universal pneumococcal vaccination program which might cover about 70% of invasive pneumococcal diseases in Taiwanese children under 5 years old.

BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.