The mechanism of interactions between flavan-3-ols against a-glucosidase and their in vivo antihyperglycemic effects.

Catechin and epicatechin are flavan-3-ols, with (+)-catechin (C) and (-)-epicatechin (EC) being the most common optical isomers found in nature. In this study, we found that C and EC showed notable inhibitory activity against a-glucosidase (AGH), and that both inhibition activities reversible and competitive. Additionally, we observed that C and EC quenched the intrinsic fluorescence of AGH through a static quenching mechanism, and that the electrostatic force was the predominant driving factor in the binding reaction. Molecular docking studies indicated that the benzene-ring-4'-hydroxyphenyl construct on flavan-3-ol plays an important role in AGH inhibition, and that the inhibition increases along with increased binding of amino acid residues at this site. Furthermore, C and EC inhibited glucose absorption in everted intestine sleeves in vitro and suppressed increases in postprandial blood glucose levels in vivo. Our results suggest that C and EC are useful to protect against hyperglycemia through inhibiting the activity of a-glucosidase.

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.

EGFR exon 19 in-frame deletion and polymorphisms of DNA repair genes in never-smoking female lung adenocarcinoma patients.

We explored potential associations between genetic polymorphisms in genes related to DNA repair and detoxification metabolism and epidermal growth factor receptor (EGFR) mutations in a cohort of 410 never-smoking patients with lung adenocarcinoma. Multivariate-adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CI) of EGFR mutation status in association with the genotypes of DNA repair and detoxification metabolism genes were evaluated using logistic regression analysis. We found an association between in-frame deletion in EGFR exon 19 and a single nucleotide polymorphism (SNP) rs1800566C/T located in NQO1 (aOR, 2.2 with 95% CI, 1.0-4.8) in female never-smokers. The SNP rs744154C/G in ERCC4 was also associated with the EGFR exon 19 in-frame deletion both in never-smokers (aOR, 1.7 with 95% CI, 1.0-3.0) and female never-smokers (aOR, 1.9 with 95% CI, 1.0-3.6). Although the association was marginally significant in multivariate logistic regression analysis, the A/A genotype of rs1047840 in EXO1 was associated with a 7.6-fold increase in the occurrence of the EGFR exon 19 in-frame deletion in female never-smokers. Moreover, risk alleles in NQO1, ERCC4 and EXO1 were associated with an increasing aOR of the EGFR exon 19 in-frame deletion both in never-smokers (p = 0.007 for trend) and female never-smokers (p = 0.002 for trend). Our findings suggest that the in-frame deletion in EGFR exon 19 is associated with polymorphisms in DNA repair and detoxification metabolism genes in never-smoking lung adenocarcinoma patients, especially in females.

MAP3K1 expression is associated with progression and poor prognosis of hormone receptor-positive, HER2-negative early-stage breast cancer.

PURPOSE: In this study, we assessed whether the overexpression of MAP3K1 promotes the proliferation, migration, and invasion of breast cancer cells, which affect the prognosis of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early stage breast cancer. METHODS: Two HR-positive, HER2-negative breast cancer cell lines (MCF7 and T-47D) overexpressing MAP3K1 were transfected with two MAP3K1 short hairpin RNA plasmids (shMAP3K1 [#3] and shMAP3K1 [#5]). The proliferation, migration, and invasion of these cells were then examined. We assessed whether shMAP3K1 affects the cell cycle, levels of downstream signaling molecules (ERK, JNK, p38 MAPK, and NF-κB), and sensitivity to chemotherapeutic and hormonal agents. To assess the anti-tumor effect of MAP3K1 knockdown in the breast cancer orthotopic model, MCF7 and T-47D cells treated with or without shMAP3K1 (#3) and shMAP3K1 (#5) were inoculated into the mammary fat pads of mice. In total, 182 patients with HR-positive, HER2-negative T1 and T2 breast cancer and 0-3 nodal metastases were included. Additionally, 73 patients with T1 and T2 breast cancer and negative nodes who received adjuvant endocrine therapy alone were selected as an independent validation cohort. RESULTS: In both cell lines, shMAP3K1 (#3) and shMAP3K1 (#5) significantly reduced cell growth, migration, and invasion by downregulating MMP-9 and by blocking the G2/M phase of the cell cycle and its regulatory molecule cyclin B1. Moreover, both shMAP3K1 (#3) and shMAP3K1 (#5) downregulated ERK-, JNK-, p38 MAPK-, and NF-κB-dependent gene transcription and enhanced the sensitivity of both cell lines to doxorubicin, docetaxel, and tamoxifen. We observed that both shMAP3K1 (#3) and shMAP3K1 (#5) inhibited tumor growth compared with that in the scrambled group of MCF7 and T-47D cell orthotopic tumors. Patients with MAP3K1 overexpression exhibited significantly poorer 10-year disease-free survival (DFS) (70.4% vs. 88.6%, p = 0.003) and overall survival (OS) (81.9% vs. 96.3%, p = 0.001) than those without MAP3K1 overexpression. Furthermore, phospho-ERK (p < 0.001) and phospho-JNK (p < 0.001) expressions were significantly associated with MAP3K1 expression, and both phospho-ERK and phospho-JNK expressions were significantly correlated with poor 10-year DFS and OS. These biological findings, including a significant association between DFS and OS, and the expressions of MAP3K1, phospho-ERK, and phospho-JNK were further validated in an independent cohort. Multivariate analysis identified MAP3K1 expression as an independent poor prognostic factor for DFS and OS. CONCLUSION: Our results indicate that the overexpression of MAP3K1 plays a major role in the poor prognosis of HR-positive, HER2-negative early stage breast cancer.

Viral contamination on the surfaces of the personal protective equipment among health care professionals working in COVID-19 wards: A single-center prospective, observational study.

OBJECTIVE: To evaluate potential viral contamination on the surfaces of personal protective equipment (PPE) in COVID-19 wards. METHODS: Face shields, gloves, the chest area of PPE and shoe soles were sampled at different time points. The samples were tested for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by PCR, and the cycle threshold (CT) values were recorded. RESULTS: The positive rate was 74.7% (239/320) for all PPE specimens. The CT values of the samples were ranked in the following order: face shields > chests > gloves > shoe soles (37.08±1.38, 35.48±2.02, 34.17±1.91 and 33.52±3.16, respectively; P for trend < .001). After disinfection, the CT values of shoe soles decreased compared with before disinfection (32.78±3.47 vs. 34.3±2.61, P = .037), whereas no significant effect of disinfection on the CT values of face shields, chests and gloves was observed. After disinfection, the CT values of specimens collected from shoe soles gradually increased; before disinfection, the CT values of shoe sole specimens were all less than 35. CONCLUSIONS: SARS-CoV-2 can attach to the surfaces of the PPE of healthcare professionals in COVID-19 wards, especially the shoe soles and undisinfected gloves. Shoe soles had the highest SARS-CoV-2 loads among all tested PPE items.

Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer.

INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.

Genetic variants in DNA repair predicts the survival of patients with esophageal cancer.

OBJECTIVE: To investigate the association of the genetic variants in excision repair cross-complementation group 2 (ERCC2) R156R and ERCC4 rs3136038 with survival duration for patients with esophageal cancer. BACKGROUND: ERCC2 and ERCC4 are important molecules participating nucleotide excision repair system. The clinical relevance of the genetic variants of these genes is largely unknown currently. PATIENTS AND METHODS: A total of 400 patients with a diagnosis of esophageal cancer were included. The genetic variants in the promoter regions of ERCC2 on R156R and ERCC4 on rs3136038 were analyzed with the TaqMan assay from leukocyte DNA collected before treatment and correlated to survival of the patients. RESULTS: Presence with ERCC2 R156R C/C or ERCC4 rs3136038 C/T genotype of the patients could additively increase risk of death and disease progression. Under multivariate analysis, T, N staging and simultaneous presentation of these unfavorable genotypes were found significant for prognosis (P < 0.05). Accumulation of each unfavorable genotype would associate with adjusted HRs [95% CI] of 1.35 [1.10-1.65] and 1.37 [1.12-1.68] (P ≤ 0.05) for death and disease progression respectively. The prognostic impact of these genotypes were more evident in the subgroup of patients with early disease status including T staging (II or less), free from lymph node metastasis or being able to undergo surgical resection (P < 0.05 for both overall and disease progression-free survival duration, respectively). CONCLUSION: Genetic variants in ERCC2 and ERCC4 may provide further survival prediction in addition to TNM staging system of esophageal cancer, which is more evident in the patients with early disease status.

Polymorphism in epidermal growth factor receptor intron 1 predicts prognosis of patients with esophageal cancer after chemoradiation and surgery.

BACKGROUND: The EGFR gene has been demonstrated to be an important factor influencing treatment response for various cancers, and its expression has been shown to be modified by the polymorphic CA repeat length at the 5'-regulatory sequence in intron 1. We investigated whether this EGFR polymorphism is associated with prognosis in patients with esophageal cancer after concurrent chemoradiotherapy (CCRT) and esophagectomy. METHODS: A cohort of 148 patients with esophageal cancer received cisplatin-based CCRT (concurrently combined with 40 Gy irradiation) and subsequent esophagectomy. Their EGFR genotypes were determined by polymerase chain reaction from leukocyte DNA, which was obtained before treatment and was correlated with patient survival. RESULTS: Patients with the homozygous short allele (<20 CA) of the EGFR gene in intron 1 were more likely to have a shorter duration of survival after CCRT and surgery than those with the homozygous long allele [adjusted hazard ratio (HR) (95% confidence interval [CI]) of death: 1.88 (1.02-3.49); P = 0.045]. This unfavorable prognostic effect of EGFR homozygous short CA repeat was mainly manifested in patients with good response to CCRT [adjusted HR (95% CI) of death 3.40 (1.06-10.89); P = 0.039]; it was less evident in those with poor response to CCRT [adjusted HR (95% CI) 1.40 (0.65-3.02); P = 0.384]. CONCLUSIONS: The EGFR CA repeat genetic polymorphism may act as a valuable molecular predictor of clinical outcome of esophageal cancer after CCRT and esophagectomy, especially in those with good response to CCRT.

Hierarchical NiCo2S4@Nickel-Cobalt Layered Double Hydroxide Nanotube Arrays on Metallic Cotton Yarns for Flexible Supercapacitors.

Constructing high capacitance active materials and three-dimensional (3D) conductive networks inside textile yarn frames is a promising strategy to synthesize yarn supercapacitor electrodes. In this study, growing NiCo2S4@Ni-Co layered double hydroxide (LDH) nanotube arrays on Au-metalized cotton yarns yields a novel yarn supercapacitor electrode material. The resulting yarn electrode possesses numerous merits, including high electrical conductivity from NiCo2S4 and Au-metalized cotton yarns, high capacitance of Ni-Co LDH nanosheets, and the 3D hierarchical electrode structure. The unique electrode structure leads to excellent electrochemical properties including high capacitance (5680 mF cm-2), excellent rate performance, and stable cycling performance. A two-ply symmetric yarn supercapacitor assembled from the NiCo2S4/Ni-Co LDH/Au/cotton yarn electrode reaches an areal energy density of 3.5 µW h cm-2.

Flexible hybrid yarn-shaped supercapacitors based on porous nickel cobalt sulfide nanosheet array layers on gold metalized cotton yarns.

A high-performance yarn-shaped supercapacitor electrode material with light weight, small volume, flexibility and low cost, is highly desirable for the development of flexible energy storage devices. Herein, a cotton/Au/nickel cobalt sulfide hybrid yarn electrode was designed and synthesized by electrodepositing nickel cobalt sulfide nanosheet arrays on the Au metalized cotton yarn. The metalized cotton yarn as a conductive substrate ensures rapid electron transportation. The porous layer which constructed by CoNi2S4 nanosheet arrays significantly enlarges the interface between the electrolyte ions and electrode materials, providing large electroactive surface area for the faradic redox reactions. The hierarchically porous structure of entire yarn electrode shortens the electrolyte diffusion path. A synergistic effect caused by the unique electrode structure greatly increases the electrochemical performance. This hybrid yarn electrode exhibits high specific capacitance of 1323 F/g at 1 A/g, good electrochemical stability and high flexibility with performance well maintained under the mechanical bending condition. An assembled two-ply structured all-solid-state symmetric supercapacitor device delivers an energy density of 40.9 Wh/kg at a power density of 1.43 kW/kg.

Polymorphisms of ESR1, UGT1A1, HCN1, MAP3K1 and CYP2B6 are associated with the prognosis of hormone receptor-positive early breast cancer.

In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10.6 years, 363 patients were alive, and 51 (12.3%) had died. Multiple-adjusted hazard ratios (aHRs) and the corresponding 95% confidence intervals for distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS) in association with the genotypes of 34 SNPs from the above-mentioned 16 genes were evaluated, using the stepwise selection Cox model. We found that the SNP, ESR1-codon325 rs1801132 (G/G+G/C), was associated with a longer DDFS, whereas UGT1A1 rs4148323 (A/A+A/G), and HCN1 rs981782 (A/A+A/C) were significantly associated with poorer DDFS. MAP3K1 rs889312 (C/C) and CYP2B6 rs3211371 (T/C) were significantly associated with poor DFS, DDFS and OS. Among premenopausal women, MAP3K1 rs889312 (C/C), CYP2B6 rs3211371 (T/C), CYP2B6 rs4802101 (T/T), ABCB1 rs2032582 (C/C), and ALDH3A1 rs2231142 (G/G) were significantly associated with poor DDFS, DFS, or OS. Our results provide additional evidence that genetic polymorphisms observed in SNPs are associated with the prognoses of patients with HR-positive breast cancers; this may indicate different treatment strategies for these patients.

Polymorphism of T-cell receptor gamma short tandem repeats as a susceptibility risk factor of hepatocellular carcinoma.

BACKGROUND: T-cells play a critical role in the immunological surveillance network against cancer formation. The activation of T-cells is initiated by binding of T-cell receptors (TCR) with antigen epitopes. Polymorphisms of TCR-gamma microsatellite (short tandem repeats, STR) marker has been associated with early-onset colorectal cancer. The aim of this study was to test the relationship of TCR-gamma STR genetic polymorphisms and hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 225 chronic hepatitis B- or C-related HCC and liver cirrhosis patients were enrolled in this study. The other 225 sex-matched cirrhotic patients without HCC were recruited as controls. Their TCR-ygammaSTR polymorphisms at loci D7S1818 and D7S2206 were measured by polymerase chain reaction. Dietary habits and other possible risk factors for HCC were also assessed by a structured questionnaire. RESULTS: Compared to controls, the HCC patients were older in age (64.9 +/- 10.3 vs. 53.5 +/- 10.1 years, p < 0.001) and had a higher percentage of family history of HCC (13.3% vs. 7.6%, p = 0.045) and habitual alcohol use (23.1% vs. 15.6%, p= 0.042). A total of 20 genotypes of TCR-gamma D7S1818 STR were detected. Of these, the genotype 16 (13/14 of repeat number of GA A) had a higher percentage in the HCC groups than in the controls (13.8% vs. 6.7%, p = 0.013). After adjustment for age, family history of HCC and habitual alcohol use, the TCR-gamma genotype 16 remained a significant risk factor for HCC (OR: 2.18, 95% CI: 1.02-4.65, p= 0.045). CONCLUSION: The TCR-gamma STR polymorphism may be associated with HCC susceptibility.

Association of GSTP1 polymorphism and survival for esophageal cancer.

PURPOSE: Activity of glutathione S-transferase (GST) is associated with detoxification of xenobiotics and the maintenance of cell viability. Genetically variant GSTs produce different enzymatic activities. The clinical significance of this variation is still puzzling. We investigated whether genetic polymorphisms of GST including GSTP1, GSTM1, and GSTT1 affect survival among esophageal cancer patients. EXPERIMENTAL DESIGN: From 1996 to 2002, 233 patients with pathologically proven esophageal cancer were recruited from the Department of Surgery, National Taiwan University Hospital. GST genotypes, including GSTT1, GSTM1, and GSTP1, were determined by PCR or PCR-RFLP. The influence of the genetic polymorphisms on patient survival was estimated using the method of Kaplan-Meier survival function and Cox proportional hazards models. RESULTS: The mean survival times (months) of the GSTP1 Ile/Ile, Ile/Val, and Val/Val were 11, 10, and 7, respectively (P < 0.05). The more the patients carried GSTP1 variant Val alleles, the poorer the survival rate (adjusted hazard ratio, 1.36; 95% confidence interval, 1.01-1.84; Ptrend = 0.045). In contrast, no association of GSTT1 or GSTM1 genotypes with survival rate was noted. CONCLUSION: The presence of the GSTP1 variant allele (Val) is associated with a poorer prognosis of esophageal cancer.

The associations of p53 overexpression with p53 codon 72 genetic polymorphism in esophageal cancer.

Variations in p53 codon 72 have been identified as significant predisposing factors for various cancers, but molecular mechanisms remain unclear. We investigated associations of p53 overexpression with codon 72 variants and other factors with esophageal cancer. Status of p53 overexpression was determined by immunohistochemical staining. Codon 72 polymorphisms and mutation of p53 was identified by PCR-RFLP and direct sequencing from exons 4 to 9, respectively. We evaluated 126 patients who underwent esophagectomy in the National Taiwan University Hospital, and found that the status of p53 overexpression was significantly influenced by presence of codon 72 polymorphisms. After adjustment for other possible confounders, the incidence of p53 overexpression was significantly decreased in patients with Pro/Pro genotype with an odds ratio (OR) of 0.21 (95% CI: 0.067-0.64) (p = 0.0065) compared with incidence in patients with Arg/Arg genotype. The incidence of p53 overexpression was additively increased with environmental exposure to cigarette smoke, alcohol, and areca quid. When compared with individuals exposed to only one of these environmental risk factors, patients who had exposure to two or three risk factors had ORs of 6.11 (95% CI: 1.80-20.75) and 6.22 (95% CI: 1.81-21.34) for p53 overexpression, respectively. Elderly patients (age >70 years) were also more likely to have p53 overexpression, with an OR of 5.63 (95% CI: 1.53-20.64) compared with overexpression among patients aged less than 55 years. Forty-one patients received further evaluation of p53 mutation. There was also a higher incidence of, but without reaching a statistical significance, p53 mutation in patients with p53 overexpression (OR[95% CI]: 2.18 [0.52-9.6]) and codon 72 Arg/Arg genotype (OR [95% CI] of 0.8 [0.13-4.2], comparing genotypes of Pro/Pro and Arg/Pro with Arg/Arg). Our data provide the first observations that the presence of p53 codon 72 variants can be a significant factor influencing p53 overexpression in esophageal cancer, with overexpression also influenced by combined or prolonged environmental exposures.

Association of cytokine and DNA repair gene polymorphisms with hepatitis B-related hepatocellular carcinoma.

BACKGROUND: Hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) mainly by causing chronic necroinflammatory hepatic disease. We investigated the mechanisms underlying the inflammatory hepatocarcinogenesis by examining whether genetic variations in cytokines, antioxidant enzymes, and DNA repair genes affect the HCC risk. METHODS: We analyzed 10 polymorphisms in the genes for interleukin-1beta (IL-1B), interleukin-1-receptor antagonist (IL-1RN), tumor necrosis factor-alpha (TNF-A), glutathione S-transferase, XRCC1, hMLH1, and XPD in 577 HBV carriers with HCC and 389 HBV carrier controls. RESULTS: Overall, only the hMLH1-93*A allele significantly increased HCC risk. We identified polymorphism combinations associated with HCC. In the presence of the IL-1RN*2 allele, adjusted odds ratios (ORs) for HCC associated with C/C, T/C, and T/T genotypes of the IL-1B-31 polymorphism were 1.00, 2.93 [95% confidence interval (95% CI) 1.07-8.07], and 5.76 (95% CI 1.79-18.53), respectively. There was a dose-dependent association between the number of putative high-risk genotypes in the IL-1B, TNF-A, hMLH1, and XRCC1 genes and HCC. The adjusted OR for HBV carriers with > or = 3 putative high-risk genotypes was 9.29 (95% CI 2.90-29.75) compared with those with none or only one of the high-risk genotypes. These associations were not observed among HBV carriers without the IL-1RN*2 allele. Smoking modified the combined effect of multiple loci in the IL-1RN, IL-1B, TNF-A, hMLH1, and XRCC1 genes; a high-risk multilocus genotype only significantly increased the risk in smokers (adjusted OR 4.84; 95% CI 1.69-13.92). CONCLUSIONS: Genetic variations in cytokine and DNA repair genes contribute to susceptibility to HBV-related HCC. Smoking increased such genetic susceptibility.

R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability.

PURPOSE: Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS: Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS: YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION: These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.

Exploring the associations between genetic variants in genes encoding for subunits of calcium channel and subtypes of bipolar disorder.

BACKGROUND: Associations of two voltage-gated calcium channel (Cav) genes, CACNA1C and CACNB2, were identified for bipolar disorder (BP) in different ethnic groups in recent genome-wide association studies. The current study aimed to evaluate the associations of several Cav genes and subtypes of BP in genetically more homogeneous Taiwanese samples. Additionally, we tested interaction effects among genes that encode for α1, ß and γ-subunits of calcium channel. METHODS: 8 Cav genes were selected based on evidence in prior association studies and significant linkage regions for BP. 280 BP patients and 200 controls were recruited. Multifactor dimensionality reduction was performed for interaction testing in these discovery samples. Replication was conducted for two markers using additional 495 Taiwanese cases and 1341 controls. RESULTS: Weak associations for CACNA1C (rs10848635), CACNA1E (rs10848635), CACNB2 (rs11013860), and CACNG2 (rs2284018) genes were observed. Joint analysis of four markers revealed higher accumulative risk with increasing numbers of risk genotypes an individual endorsed for BP-I (Ptrend=0.006) and BP-II (Ptrend=0.017) disorders. Combined analysis with independent replication samples further supported the association of rs11013860 in CACNB2 with BP subtype I (P=1×10(-6)). Suggestive interactions were found between genes encoded for different subunits of calcium channel (α1, ß, and γ). LIMITATIONS: Moderate sample size and incomplete markers coverage for the chosen Cav genes. CONCLUSIONS: Our results support the involvement of different calcium channel genes in bipolar illness, in particular the beta-subunit in the Asian population. Further investigation of functional property of these genes can contribute on understanding the etiological mechanisms of bipolar illness.

CYP19 genetic polymorphism haplotype AASA is associated with a poor prognosis in premenopausal women with lymph node-negative, hormone receptor-positive breast cancer.

Given the critical role of CYP19 in estrogen synthesis, we investigated the influence of CYP19 gene polymorphisms on the clinical outcome of lymph node- (LN-) negative, hormone receptor- (HR-) positive early breast cancers. Genotyping for the CYP19 polymorphisms rs4646 (A/C), rs1065779 (A/C), CYP19 (TTTA)n (short allele/long (S/L) allele using the 7 TTTA repeat polymorphism as the cut-off), and rs1870050 (A/C) was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes of CYP19 and distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Patients were divided into the 6 subhaplotypes of CCLA (41.1%), AASA (17.1%), CASA (11.9%), CCLC (8.9%), CCSA (7.5%), AASC (8.9%), and others (4.6%). In premenopausal patients, haplotype AASA was significantly associated with a poor DDFS (adjusted hazard ratio (aHR), 3.3; P = 0.001), DFS (aHR, 2.5; P = 0.0008), and OS (aHR, 2.9; P = 0.0004) after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotype AASA remained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5; P = 0.0005), DFS (HR, 3.2; P = 0.003), and OS (HR, 6.4; P = 0.0009). However, in postmenopausal patients, haplotype AASA was not associated with a poor prognosis, whereas the AASC haplotype was significantly associated with a poor DFS (aHR, 3.1; P = 0.03) and OS (aHR, 4.4; P = 0.01). Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotype AASA is associated with poor survival of premenopausal women but does not affect survival of postmenopausal women.

EGFR L858R mutation and polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients.

PURPOSE: To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations. EXPERIMENTAL DESIGN: We studied 617 patients with lung adenocarcinoma, including 302 never-smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERα, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis. RESULTS: In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)(n) repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2-5.7 for 1 or 2 alleles with (TTTA)(n) repeats >7 compared with both alleles with (TTTA)(n) repeats ≤ 7), and the rs2234693 in ERα (OR, 2.1; 95% CI, 1.1-4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERα was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1-8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1-7.6) and other mutations (OR, 4.3; 95% CI, 1.3-14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0-3.2) and 3.6 (1.1-11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERα, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend). CONCLUSIONS: The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients.