NPM1 as a potential therapeutic target for atypical teratoid/rhabdoid tumors.

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets. METHODS: Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines. RESULTS: WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells. CONCLUSIONS: We propose that NPM1 is a novel therapeutic target for AT/RTs.

DeviCNV: detection and visualization of exon-level copy number variants in targeted next-generation sequencing data.

BACKGROUND: Targeted next-generation sequencing (NGS) is increasingly being adopted in clinical laboratories for genomic diagnostic tests. RESULTS: We developed a new computational method, DeviCNV, intended for the detection of exon-level copy number variants (CNVs) in targeted NGS data. DeviCNV builds linear regression models with bootstrapping for every probe to capture the relationship between read depth of an individual probe and the median of read depth values of all probes in the sample. From the regression models, it estimates the read depth ratio of the observed and predicted read depth with confidence interval for each probe which is applied to a circular binary segmentation (CBS) algorithm to obtain CNV candidates. Then, it assigns confidence scores to those candidates based on the reliability and strength of the CNV signals inferred from the read depth ratios of the probes within them. Finally, it also provides gene-centric plots with confidence levels of CNV candidates for visual inspection. We applied DeviCNV to targeted NGS data generated for newborn screening and demonstrated its ability to detect novel pathogenic CNVs from clinical samples. CONCLUSIONS: We propose a new pragmatic method for detecting CNVs in targeted NGS data with an intuitive visualization and a systematic method to assign confidence scores for candidate CNVs. Since DeviCNV was developed for use in clinical diagnosis, sensitivity is increased by the detection of exon-level CNVs.

Prevalence of Attention-Deficit/Hyperactivity Disorder and its Comorbidity among Korean Children in a Community Population.

The aim of this study was to determine the prevalence of attention deficit hyperactivity disorders (ADHD) in children according to socio-demographic factors and the distribution of ADHD subtypes in a community in Korea. A screening survey using the Korean version of ADHD Rating Scale (K-ARS) was conducted between 2007 and 2008, and clinical interviews by a pediatric psychiatrist were performed for selected children between 2009 and 2010. A total of 49,573 elementary school students, between ages of 7 and 12, constituted the target population, among which 38,365 students (77.2%) and respective parents gave consent to participate. Of the participants, 200 screened children were clinically examined to confirm the diagnosis of ADHD. We estimated the prevalence of ADHD and its comorbidity in the population, after adjusting for nonresponse and nonparticipation. The prevalence of ADHD was 11.7% in boys and 5.2% in girls, with an overall prevalence of 8.5%. The combined type of inattentive and hyperactive was the most frequent at 4.7% of the whole population. Children were more likely to have ADHD if their parents were separated and had less education. Most commonly combined comorbidity was autism spectrum disorder (ASD) (10.1%). The prevalence of ADHD in the school-aged population is an essential information for improving the quality of public health mental services for evaluation and treatment of ADHD.

Genetic Characteristics of Polycythemia Vera and Essential Thrombocythemia in Korean Patients.

BACKGROUND: Despite recent advances in the investigation of myeloproliferative neoplasms (MPN), the impact of genetic heterogeneity on its molecular pathogenesis has not been fully elucidated. Thus, in this study, we aim to characterize the genetic complexity in Korean patients with polycythemia vera (PV) and essential thrombocythemia (ET). METHODS: We conducted association studies using 84 single-nucleotide polymorphisms (SNPs) in 229 patients (96 with PV and 133 with ET) and 170 controls. Further, whole-genome sequencing was performed in six patients (two with JAK2 V617F and four with wild-type JAK2), and putative somatic mutations were validated in a further 69 ET patients. Clinical and laboratory characteristics were also analyzed. RESULTS: Several germline SNPs and the 46 haplotype were significantly associated with PV and ET. Three somatic mutations in MPDZ, IQCH, and CALR genes were selected and validated. The frequency of the CALR mutation was 58.0% (40/69) in ET patients, who did not carry JAK2/MPL mutations. Moreover, compared with JAK2 V617F-positive patients, those with CALR mutations showed lower hemoglobin and hematocrit levels (P = 0.004 and P = 0.002, respectively), higher platelet counts (P =0.008), and a lower frequency of cytoreductive therapy (P = 0.014). CONCLUSION: This study was the first comprehensive investigation of the genetic characteristics of Korean patients with PV and ET. We found that somatic mutations and the 46 haplotype contribute to PV and ET pathogenesis in Korean patients.

Investigation of the nanoviscosity effect of a G-quadruplex and single-strand DNA using fluorescence correlation spectroscopy.

Guanine (G)-quadruplexes are of interest because of their presence in the telomere sequence and the oncogene promoter region. Their diffusion and change of structure, especially in high viscosity solutions, are important for understanding their dynamics. G-quadruplexes may have less effective viscosity (nanoviscosity) when they are smaller than the solvent molecules. In this paper, we report the difference in the diffusion dynamics of the G-rich DNA sequences of single-strand DNA (ssDNA) and the G-quadruplex in aqueous, sucrose, and polyethylene glycol (PEG) solutions. From experiments with aqueous and sucrose solutions, we confirm that a simple diffusion model according to the viscosity is appropriate. In the PEG experiments, the nanoviscosity effect is observed according to PEG's molecular weight. In the PEG 200 solution, both the ssDNA and the G-quadruplex possess macroviscosity. In the PEG 10,000 solution, the G-quadruplex possesses nanoviscosity and the ssDNA possesses macroviscosity, whereas, in the PEG 35,000 solution, both ssDNA and the G-quadruplex possess nanoviscosity. The experimental results are consistent with the theoretical predictions.

Tailoring the Structure-Property Relationship of Ring-Opened Metathesis Copolymers for CO2-Selective Membranes.

In this work, we explore the use of ring-opening metathesis polymerization (ROMP) facilitated by a second-generation Grubbs catalyst (G2) for the development of advanced polymer membranes aimed at CO2 separation. By employing a novel copolymer blend incorporating 4,4'-oxidianiline (ODA), 1,6-hexanediamine (HDA), 1-adamantylamine (AA), and 3,6,9-trioxaundecylamine (TA), along with a CO2-selective poly(ethylene glycol)/poly(propylene glycol) copolymer (Jeffamine2003) and polydimethylsiloxane (PDMS) units, we have synthesized membranes under ambient conditions with exceptional CO2 separation capabilities. The strategic inclusion of PDMS, up to a 20% composition within the PEG/PPG matrix, has resulted in copolymer membranes that not only surpass the 2008 upper limit for CO2/N2 separation but also meet the commercial targets for CO2/H2 separation. Comprehensive analysis reveals that these membranes adhere to the mixing rule and exhibit percolation behavior across the entire range of compositions (0-100%), maintaining robust antiplasticization performance even under pressures up to 20 atm. Our findings underscore the potential of ROMP in creating precisely engineered membranes for efficient CO2 separation, paving the way for their application in large-scale environmental and industrial processes.

Teleworking Is Significantly Associated with Anxiety Symptoms and Sleep Disturbances among Paid Workers in the COVID-19 Era.

Due to social distancing during COVID-19, teleworking has spread in Korea. Accordingly, the effects of teleworking on physical and mental health have emerged. We aim to determine the association between teleworking and mental health, including anxiety symptoms and sleep disturbance, in paid workers. The data of paid workers from the Sixth Korean Working Conditions Survey, collected between October 2020 and April 2021, were analyzed. Gender stratification analysis and propensity score matching were performed for variables relevant to sociodemographic and occupational characteristics. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each sex were analyzed using multivariable logistic regression, adjusting for sociodemographic and occupational characteristics. Among 28,633 participants, analyses were performed for anxiety symptoms (teleworkers vs. non-teleworkers; men: 12.1% vs. 4.9%; women: 13.5% vs. 5.3%) and sleep disturbance (men: 33.6% vs. 21.3%; women: 39.7% vs. 25.3%). In male teleworkers, the AORs for anxiety symptoms and sleep disturbance were 1.86 (95% CI: 1.14-3.04) and 1.52 (95% CI: 1.10-2.11), respectively. In female teleworkers, the AORs for anxiety symptoms and sleep disturbance were 1.66 (95% CI: 1.13-2.43) and 1.65 (95% CI: 1.28-2.14), respectively. Our results emphasize the importance of mental health and the need for continuous education and care for teleworkers, given the rapid increase in teleworking.

Comparison of Homologous Recombination Repair Gene Next-Generation Sequencing Analysis in Patients With Metastatic Castration-Resistant Prostate Cancer Between Local and Central Laboratories in Korea.

Background: Following success of the phase III PROfound trial, the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib was approved by the US Food and Drug Administration in May 2020 for adult patients with deleterious homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). As locally adopted multigene panel next-generation sequencing (NGS) assays for selecting PARP inhibitor candidates have not been thoroughly evaluated, we compared the analytical performance of the FoundationOne CDx (Foundation Medicine, Inc., Cambridge, MA, USA) (central laboratory) and other NGS assays (local laboratory) with samples from the PROfound trial in Korea. Methods: One hundred PROfound samples (60 HRR mutation [HRRm] cases and 40 non-HRRm cases) were analyzed. The results of HRR gene mutation analysis were compared between the FoundationOne CDx and two other NGS assays [SureSelect Custom Design assay (Agilent Technologies, Inc., Santa Clara, CA, USA) and Oncomine Comprehensive assay (Thermo Fisher Scientific, Inc., Waltham, MA, USA)]. Results: The positive percent agreement for single nucleotide variants (SNVs) and insertion/deletions (indels) between the central laboratory and local laboratory was 98.7%-100.0%. The negative percent agreement and overall percent agreement (OPA) for SNVs and indels between central and local laboratories were both 100%. Compared with that of the FoundationOne CDx assay, the OPA for copy number variations of the Oncomine Comprehensive and SureSelect Custom assays reached 99.8%-100%. Most mCRPC patients harboring a deleterious genetic variant were successfully identified with both local laboratory assays. Conclusions: The NGS approach at a local laboratory showed comparable analytical performance for identifying HRRm status to the FoundationOne CDx assay used at the central laboratory.

Investigation of somatic mutation profiles and tumor evolution of primary oropharyngeal cancer and sequential lymph node metastases using multiregional whole-exome sequencing.

Lymph node (LN) metastasis is an important factor in determining the treatment and prognosis of oropharyngeal squamous cell carcinoma (OPSCC). Here, we compared the somatic mutational profiles and clonal evolution of primary and metastatic LNs using multiregion sequencing of human papilloma virus (HPV)-positive OPSCC and HPV-negative OPSCC. We performed high-depth whole-exome sequencing (200×) of 76 samples from 18 patients with OPSCC (10 HPV-positive and 8 HPV-negative), including 18 primary tumor samples, 40 metastatic LN samples, and 18 normal tissue samples. Among 40 metastatic LNs, 22 showed extranodal extension (ENE). Mutation profiles of HPV-positive OPSCC and HPV-negative OPSCC were similar to those reported previously. Somatic mutations in CDKN2A and TP53 were frequently detected in HPV-negative OPSCC. Somatic mutations in HPV-positive OPSCC samples showed APOBEC-related signatures. Somatic mutations from metastatic LNs showed a different pattern than the primary tumor. Somatic mutations acquired in the WNT pathway during metastasis showed a significant relationship with ENE. Clonal evolution analysis of primary and metastatic LNs showed that, in some cases, each metastatic LN originated from a different primary tumor sub-clone.

YAP1 Expression in HR+HER2- Breast Cancer: 21-Gene Recurrence Score Analysis and Public Dataset Validation.

BACKGROUND: YAP1, an oncogene in numerous cancers, is a downstream transcription factor of the Hippo pathway. This study focuses on its relationship with the Oncotype Dx (ODX) test risk score (RS) in patients with hormone-receptor-positive, HER2-negative (HR+HER2-) breast cancer. METHODS: We retrospectively analyzed 401 HR+HER2- breast cancer patients from Gangnam Severance Hospital who underwent ODX tests (May 2014-April 2020). YAP1 nuclear localization was evaluated via immunohistochemical staining and its clinical correlation with clinicopathological parameters, including RS, was analyzed. Public datasets TCGA-BRCA and METABRIC validated clinical outcomes. RESULTS: YAP1 expression negatively correlated with ODX RS (OR 0.373, p = 0.002). Elevated YAP1 mRNA levels corresponded to better clinical outcomes, specifically in ER-positive patients, with significant results in METABRIC and TCGA-BRCA datasets (p < 0.0001 OS in METABRIC, p = 0.00085 RFS in METABRIC, p = 0.040 DFS in TCGA-BRCA). In subsets with varying ESR1 mRNA expression and pronounced YAP1 expression, superior survival outcomes were consistently observed. CONCLUSION: YAP1 may be a valuable prognostic marker and potential therapeutic target in HR+HER2- breast cancer patients.

Qualitative and Quantitative Magnetic Resonance Imaging Phenotypes May Predict CDKN2A/B Homozygous Deletion Status in Isocitrate Dehydrogenase-Mutant Astrocytomas: A Multicenter Study.

OBJECTIVE: Cyclin-dependent kinase inhibitor (CDKN)2A/B homozygous deletion is a key molecular marker of isocitrate dehydrogenase (IDH)-mutant astrocytomas in the 2021 World Health Organization. We aimed to investigate whether qualitative and quantitative MRI parameters can predict CDKN2A/B homozygous deletion status in IDH-mutant astrocytomas. MATERIALS AND METHODS: Preoperative MRI data of 88 patients (mean age ± standard deviation, 42.0 ± 11.9 years; 40 females and 48 males) with IDH-mutant astrocytomas (76 without and 12 with CDKN2A/B homozygous deletion) from two institutions were included. A qualitative imaging assessment was performed. Mean apparent diffusion coefficient (ADC), 5th percentile of ADC, mean normalized cerebral blood volume (nCBV), and 95th percentile of nCBV were assessed via automatic tumor segmentation. Logistic regression was performed to determine the factors associated with CDKN2A/B homozygous deletion in all 88 patients and a subgroup of 47 patients with histological grades 3 and 4. The discrimination performance of the logistic regression models was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: In multivariable analysis of all patients, infiltrative pattern (odds ratio [OR] = 4.25, p = 0.034), maximal diameter (OR = 1.07, p = 0.013), and 95th percentile of nCBV (OR = 1.34, p = 0.049) were independent predictors of CDKN2A/B homozygous deletion. The AUC, accuracy, sensitivity, and specificity of the corresponding model were 0.83 (95% confidence interval [CI], 0.72-0.91), 90.4%, 83.3%, and 75.0%, respectively. On multivariable analysis of the subgroup with histological grades 3 and 4, infiltrative pattern (OR = 10.39, p = 0.012) and 95th percentile of nCBV (OR = 1.24, p = 0.047) were independent predictors of CDKN2A/B homozygous deletion, with an AUC accuracy, sensitivity, and specificity of the corresponding model of 0.76 (95% CI, 0.60-0.88), 87.8%, 80.0%, and 58.1%, respectively. CONCLUSION: The presence of an infiltrative pattern, larger maximal diameter, and higher 95th percentile of the nCBV may be useful MRI biomarkers for CDKN2A/B homozygous deletion in IDH-mutant astrocytomas.

Investigating the interfacial properties of halide perovskite/TiOx heterostructures for versatile photocatalytic reactions under sunlight.

Heterostructures of metal halide perovskites and TiOx are efficient photocatalytic materials owing to the combination of the advantages of each compound, specifically the high absorption coefficients and long charge-carrier lifetimes of perovskites, and efficient photocatalytic activity of TiOx. However, chemical reduction of CO2 using PNC/TiOx heterostructures without organic solvents has not been reported yet. Here, we report the first solvent-free reduction of CO2 using amorphous TiOx with embedded colloidal perovskite nanocrystals (PNCs). The combination was obtained by carrying out hydrolysis of titanium butoxide (TBOT) on the PNC surface without high-temperature calcination. We proposed a mechanism involving photoexcited electrons being transferred from PNCs to TBOT, enabling photocatalytic reactions using TiOx under visible-light excitation. We demonstrated efficient visible-light-driven photocatalytic reactions at PNC/TiOx interfaces, specifically with a CO production rate of 30.43 µmol g-1 h-1 and accelerated degradation of organic pollutants under natural sunlight. Our work has provided a simple path toward both efficient CO2 reduction and photocatalytic degradation of organic dyes.

Prediction of cancer prognosis with the genetic basis of transcriptional variations.

Phenotypes of diseases, including prognosis, are likely to have complex etiologies and be derived from interactive mechanisms, including genetic and protein interactions. Many computational methods have been used to predict survival outcomes without explicitly identifying interactive effects, such as the genetic basis for transcriptional variations. We have therefore proposed a classification method based on the interaction between genotype and transcriptional expression features (CORE-F). This method considers the overall "genetic architecture," referring to genetically based transcriptional alterations that influence prognosis. In comparing the performance of CORE-F with the ensemble tree, the best-performing method predicting patient survival, we found that CORE-F outperformed the ensemble tree (mean AUC, 0.85 vs. 0.72). Moreover, the trained associations in the CORE-F successfully identified the genetic mechanisms underlying survival outcomes at the interaction-network level.

Association between physical risk factors and sleep disturbance among workers in Korea: The 5th Korean Working Conditions Survey.

OBJECTIVE: Sleep disturbance is associated with negative effects to workers' health and productivity; hence, it is important to find which population of workers are associated with sleep disturbance. This study aimed to investigate the association between physical risk factors (vibration, noise, high, and low temperatures) and sleep disturbance in the Korean working population. METHODS: We analyzed data on 29,213 paid workers from the 5th Korean Working Conditions Survey. Individual and occupational characteristics, physical risk factors exposure, and sleep disturbance were collected using self-reported questionnaires. To assess the association between physical risk factors and sleep disturbance, the chi-square test and multivariable logistic regression models were conducted. All statistical analyses were performed in sex-based subgroups. RESULTS: We observed that all physical risk factors are associated with sleep disturbance. The adjusted odds ratios (95% confidence interval [CI]) of severe exposure to vibration, noise, high and low temperature were 1.69 (CI:1.47-1.94), 2.52 (CI:2.17-2.92), 3.09 (CI:2.69-3.56), and 1.96 (CI:1.68-2.28) in male workers and 2.27 (CI:1.89-2.72), 3.52 (CI:2.92-4.24), 3.30 (CI:2.81-3.87), and 2.87 (CI:2.44-3.38) in female workers, respectively. The prevalence of sleep disturbance increased with increased exposure to physical risk factors, indicating a dose-response relationship. CONCLUSIONS: Physical risk factors exposure in the workplace was associated with sleep disturbance of workers, indicating a dose-response relationship. Given the impact of sleep disturbance on workers' health and efficiency, it may be important to control exposure to physical risk factors in the working environment with regards to sleep conditions.

Differences in stromal component of chordoma are associated with contrast enhancement in MRI and differential gene expression in RNA sequencing.

Chordoma is a malignant bone neoplasm demonstrating notochordal differentiation and it frequently involves axial skeleton. Most of chordomas are conventional type with varying amount of myxoid stroma. Previously known prognostic factors for conventional chordoma are not specific for chordoma: old age, metastasis, tumor extent, and respectability. Here, we aimed to investigate the histologic, radiologic, and transcriptomic differences in conventional chordoma based on the stromal component. A total of 45 patients diagnosed with conventional chordoma were selected between May 2011 and March 2020 from a single institution. Electronic medical records, pathology slides, and pretreatment magnetic resonance imaging (MRI) scans were reviewed. Of the 45 patients, ten cases (4 stroma-rich and 6 stroma-poor tumor) were selected for RNA sequencing, and available cases in the remainder were used for measuring target gene mRNA expression with qPCR for validation. Differential gene expression and gene set analysis were performed. Based on histologic evaluation, there were 25 (55.6%) stroma-rich and 20 (44.4%) stroma-poor cases. No clinical differences were found between the two groups. Radiologically, stroma-rich chordomas showed significant signal enhancement on MRI (72.4% vs 27.6%, p = 0.002). Upregulated genes in stroma-rich chordomas were cartilage-, collagen/extracellular matrix-, and tumor metastasis/progression-associated genes. Contrarily, tumor suppressor genes were downregulated in stroma-rich chordomas. On survival analysis, Kaplan-Meier plot was separated that showed inferior outcome of stroma-rich group, although statistically insignificant. In conclusion, the abundant stromal component of conventional chordoma enhanced well on MRI and possibly contributed to the biological aggressiveness that supported by transcriptomic characteristics. Further extensive investigation regarding radiologic-pathologic-transcriptomic correlation in conventional chordoma in a larger cohort could verify additional clinical significance.

Surface Modification of Matrimid® 5218 Polyimide Membrane with Fluorine-Containing Diamines for Efficient Gas Separation.

Polyimide membranes have been widely investigated in gas separation applications due to their high separation abilities, excellent processability, relatively low cost, and stabilities. Unfortunately, it is extremely challenging to simultaneously achieve both improved gas permeability and selectivity due to the trade-off relationship in common polymer membranes. Diamine modification is a simple strategy to tune the separation performance of polyimide membranes, but an excessive loss in permeability is also generally observed. In the present work, we reported the effects of diamine type (i.e., non-fluorinated and fluorinated) on the physicochemical properties and the corresponding separation performance of a modified membrane using a commercial Matrimid® 5218 polyimide. Detailed spectroscopic, thermal, and surface analyses reveal that the bulky fluorine groups are responsible for the balanced chain packing modes in the resulting Matrimid membranes compared to the non-fluorinated diamines. Consequently, the modified Matrimid membranes using fluorinated diamines exhibit both higher gas permeability and selectivity than those of pristine Matrimid, making them especially effective for improving the separation performance towards H2/CH4 and CO2/CH4 pairs. The results indicate that the use of fluorinated modifiers may offer new opportunities to tune the gas transport properties of polyimide membranes.

Inference of combinatorial Boolean rules of synergistic gene sets from cancer microarray datasets.

MOTIVATION: Gene set analysis has become an important tool for the functional interpretation of high-throughput gene expression datasets. Moreover, pattern analyses based on inferred gene set activities of individual samples have shown the ability to identify more robust disease signatures than individual gene-based pattern analyses. Although a number of approaches have been proposed for gene set-based pattern analysis, the combinatorial influence of deregulated gene sets on disease phenotype classification has not been studied sufficiently. RESULTS: We propose a new approach for inferring combinatorial Boolean rules of gene sets for a better understanding of cancer transcriptome and cancer classification. To reduce the search space of the possible Boolean rules, we identify small groups of gene sets that synergistically contribute to the classification of samples into their corresponding phenotypic groups (such as normal and cancer). We then measure the significance of the candidate Boolean rules derived from each group of gene sets; the level of significance is based on the class entropy of the samples selected in accordance with the rules. By applying the present approach to publicly available prostate cancer datasets, we identified 72 significant Boolean rules. Finally, we discuss several identified Boolean rules, such as the rule of glutathione metabolism (down) and prostaglandin synthesis regulation (down), which are consistent with known prostate cancer biology. AVAILABILITY: Scripts written in Python and R are available at http://biosoft.kaist.ac.kr/~ihpark/. The refined gene sets and the full list of the identified Boolean rules are provided in the Supplementary Material. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Detection of EGFR-SEPT14 fusion in cell-free DNA of a patient with advanced gastric cancer: A case report.

BACKGROUND: Gastric cancer is the fifth most diagnosed cancer worldwide and the third most common cause of cancer-related death. In recent decades, increasing application of next-generation sequencing has enabled detection of molecular aberrations, including fusions. In cases where tissue is difficult to obtain, cell-free DNA (cfDNA) is used for detecting mutations to identify the molecular profile of cancer. Here, we report a rare case of EGFR-SEPT14 fusion detected from cfDNA analysis in a patient with gastric cancer. CASE SUMMARY: A 49-year-old female diagnosed with advanced gastric cancer in July 2019 received capecitabine and then combination chemotherapy of ramucirumab and paclitaxel, but ascites was detected. The therapy was switched to nivolumab, but disease progression was observed on a positron emission tomography/computed tomography scan in May 2020. Therapy was discontinued, and cfDNA next-generation sequencing was immediately evaluated. All genomic variants, including fusions, were analyzed from cfDNA. The following somatic alterations were detected from the patient's cfDNA: an APC frameshift mutation (NM_000038.5:c.6579del, p.V2194fs) with variant allele frequency of 0.5%, an EGFR amplification with a copy number of 17.3, and an EGFR-SEPT14 fusion with variant allele frequency of 45.3%. The site of the fusion was exon 24 of EGFR fused to exon 10 of SEPT14. The fusion was in-frame and considered to be protooncogenic. Although the patient refused to continue therapy, we suggest that EGFR-targeted therapies be tried in such future cases. CONCLUSION: The expanded applications of the cfDNA assay may open a new horizon in treatment of patients with advanced gastric cancer.

A comparison of meta-analysis results with and without adjustment for the healthy worker effect: cancer mortality among workers in the semiconductor industry.

OBJECTIVES: This study compared the results of meta-analysis with and without adjustment for the healthy worker effect on the association between working in the semiconductor industry and cancer mortality. METHODS: Six studies that reported standardized mortality ratios (SMRs) for cancers were selected for meta-analysis. Using a random-effects model, the SMR results from each study were combined for all cancers and leukemias to estimate the summary SMRs (95% confidence interval, CI). To adjust for the healthy worker effect, the relative standardized mortality ratio (rSMR=SMRx/SMRnot x) were calculated using observed and expected counts for the specific cause of interest (i.e., all cancers and leukemias) and the observed and expected counts for all other causes of mortality. Then, the rSMR results were combined to estimate the summary rSMRs (95% CIs). RESULTS: The SMRs for all causes of mortality among semiconductor industry workers ranged from 0.25 to 0.80, which reflects a significant healthy worker effect. A remarkable difference was found between the summary SMRs and the summary rSMRs. The summary SMR for all cancers was 0.70 (95% CI, 0.63 to 0.79) whereas the summary rSMR was 1.38 (95% CI, 1.20 to 1.59). The summary SMR for leukemia was 0.88 (95% CI, 0.72 to 1.07), and the summary rSMR was 1.88 (95% CI, 1.20 to 2.95). CONCLUSIONS: Our results suggest that adjustment for the healthy worker effect (i.e., rSMR) may be useful in meta-analyses of cohort studies reporting SMRs.

A Population-Based Analysis of BRCA1/2 Genes and Associated Breast and Ovarian Cancer Risk in Korean Patients: A Multicenter Cohort Study.

In this study, we performed a comprehensive analysis of BRCA1/2 variants and associated cancer risk in Korean patients considering two aspects: variants of uncertain significance (VUS) and pathogenic or likely pathogenic variants (PLPVs) in BRCA1 and BRCA2. This study included 5433 Korean participants who were tested for BRCA1/2 genes. The BRCA1/2 variants were classified following the standards/guidelines for interpretation of genetic variants and using a multifactorial probability-based approach. In Korea, 15.8% of participants had BRCA1 or BRCA2 PLPVs. To estimate the additional sample numbers needed to resolve unclassified status, we applied a simulation analysis. The simulation study for VUS showed that the smaller the number of samples, the more the posterior probability was affected by the prior probability; in addition, more samples for BRCA2 VUS than those of BRCA1 VUS were required to resolve the unclassified status, and the presence of clinical information associated with their VUS was an important factor. The cumulative lifetime breast cancer risk was 59.1% (95% CI: 44.1-73.6%) for BRCA1 and 58.3% (95% CI: 43.2-73.0%) for BRCA2 carriers. The cumulative lifetime ovarian cancer risk was estimated to be 36.9% (95% CI: 23.4-53.9%) for BRCA1 and 14.9% (95% CI: 7.4-28.5%) for BRCA2 carriers.