Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Exploring quantitative traits-associated copy number deletions through reanalysis of UK10K consortium whole genome sequencing cohorts.

OBJECTIVES: We performed comprehensive association analyses of common high-confidence gnomAD-reported copy number deletions (CNDs) with 60 quantitative traits from UK10K consortium WGS data. METHODS: The study made use of data generated by the UK10K Consortium. UK10K consortium WGS data consist of TwinsUK (n = 1754, middle-aged females) and ALSPAC (n = 1867, birth to adolescence) cohorts. UK10K consortium called 18,739 CNDs (hg19) with GenomeSTRiP software. After filtering out variants with minor allele frequency < 0.05 or HWE P < 1.0 × 10- 6, 1222 (TwinsUK) and 1211 (ALSPAC) CNDs remained for association analyses with 60 normalized quantitative traits. RESULTS: We identified 23 genome-wide significant associations at 13 loci, among which 2 associations reached experiment-wide significance. We found that two common deletions in chromosome 4, located between WDR1 and ZNF518B (23.3 kb, dbVar ID:nssv15888957, 4:10211262-10,234,569 and 9.8 kb, dbVar ID:nssv15888975, 4:10392422-10,402,191), were associated with uric acid levels (P = 5.23 × 10- 11 and 2.29 × 10- 8, respectively). We also discovered a novel deletion spanning chromosome 18 (823 bp, dbVar ID: nssv15841628, 8:74347187-74,348,010) associated with low HDL cholesterol levels (P = 4.15 × 10- 7). Additionally, we observed two red blood cell traits-associated loci with genome-wide significance, a 13.2 kb deletion in 7q22.1 (nssv15922542) and a 3.7 kb deletion in 12q24.12 (nssv15813226), both of which were located in regions previously reported to be associated with red blood cell traits. Two deletions in 11q11 (nssv15803200 and nssv15802240), where clusters of multiple olfactory receptor genes exist, and a deletion (nssv15929560) upstream to DOCK5 were associated with childhood obesity. Finally, when defining Trait-Associated copy number Deletions (TADs) as CNDs with phenotype associations at sub-threshold significance (P < 10- 3), we identified 157 (97.5%) out of 161 TADs in non-coding regions, with a mean size of 4 kb (range: 209 - 47,942 bp). CONCLUSION: We conducted a reanalysis of the UK10K Whole Genome Sequencing cohort, which led to the identification of multiple high confidence copy number deletions associated with quantitative traits. These deletions have standard dbVar IDs and replicate previous findings, as well as reveal novel loci that require further replication studies.

High-Performance Memristive Synapse Composed of Ferroelectric ZnVO-Based Schottky Junction.

In pursuit of realizing neuromorphic computing devices, we demonstrated the high-performance synaptic functions on the top-to-bottom Au/ZnVO/Pt two-terminal ferroelectric Schottky junction (FSJ) device architecture. The active layer of ZnVO exhibited the ferroelectric characteristics because of the broken lattice-translational symmetry, arising from the incorporation of smaller V5+ ions into smaller Zn2+ host lattice sites. The fabricated FSJ devices displayed an asymmetric hysteresis behavior attributed to the ferroelectric polarization-dependent Schottky field-emission rate difference in between positive and negative bias voltage regions. Additionally, it was observed that the magnitude of the on-state current could be systematically controlled by changing either the amplitude or the width of the applied voltage pulses. Owing to these voltage pulse-tunable multi-state memory characteristics, the device revealed diverse synaptic functions such as short-term memory, dynamic range-tunable long-term memory, and versatile rules in spike time-dependent synaptic plasticity. For the pattern-recognition simulation, furthermore, more than 95% accuracy was recorded when using the optimized experimental device parameters. These findings suggest the ZnVO-based FSJ device holds significant promise for application in next-generation brain-inspired neuromorphic computing systems.

Late-Onset Slowly Progressing Cone/Macular Dystrophy in Patients With the Biallelic Hypomorphic Variant p.Arg1933Ter in RP1.

Purpose: Homozygous hypomorphic variants of the RP1 gene, including c.5797C>T, p.Arg1933Ter, have traditionally been considered non-pathogenic. This study aimed to elucidate the clinical manifestations of late-onset, slowly progressive cone/macular dystrophy in patients homozygous for p.Arg1933Ter in the RP1 gene. Methods: Five patients with biallelic p.Arg1933Ter in RP1 were retrospectively recruited, and their clinical profiles were analyzed. Copy number variation analysis and Alu insertion assessment of genes associated with inherited retinal diseases were conducted. The results of comprehensive ophthalmological examinations, multimodal imaging, and full-field electroretinogram tests were analyzed. Results: No specific sequencing errors or structural variations associated with the clinical phenotypes were identified. Alu element insertion in RP1 was not detected. The mean ± SD age at the first visit was 62.2 ± 9.8 years, with symptoms typically starting between 45 and 50 years of age. Two patients exhibited a mild form of cone/macular dystrophy, characterized by a relatively preserved fundus appearance and blurring of the ellipsoid zone on optical coherence tomography. Three patients had late-onset cone/macular dystrophy with significant atrophy. Conclusions: To our knowledge, this study is the first to report that a homozygous hypomorphic variant of RP1, previously considered non-pathogenic, leads to cone/macular dystrophy. Translational Relevance: The study introduces novel possibilities suggesting that the homozygous hypomorphic variant of RP1 may be linked to variant pathogenicity.

Patient-Derived Organoids Recapitulate Pathological Intrinsic and Phenotypic Features of Fibrous Dysplasia.

Fibrous dysplasia (FD) is a rare bone disorder characterized by the replacement of normal bone with benign fibro-osseous tissue. Developments in our understanding of the pathophysiology and treatment options are impeded by the lack of suitable research models. In this study, we developed an in vitro organotypic model capable of recapitulating key intrinsic and phenotypic properties of FD. Initially, transcriptomic profiling of individual cells isolated from patient lesional tissues unveiled intralesional molecular and cellular heterogeneity. Leveraging these insights, we established patient-derived organoids (PDOs) using primary cells obtained from patient FD lesions. Evaluation of PDOs demonstrated preservation of fibrosis-associated constituent cell types and transcriptional signatures observed in FD lesions. Additionally, PDOs retained distinct constellations of genomic and metabolic alterations characteristic of FD. Histological evaluation further corroborated the fidelity of PDOs in recapitulating important phenotypic features of FD that underscore their pathophysiological relevance. Our findings represent meaningful progress in the field, as they open up the possibility for in vitro modeling of rare bone lesions in a three-dimensional context and may signify the first step towards creating a personalized platform for research and therapeutic studies.

Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Comprehensive RNA-sequencing analysis of colorectal cancer in a Korean cohort.

Considering the recent increase in the number of colorectal cancer (CRC) cases in South Korea, we aimed to clarify the molecular characteristics of CRC unique to the Korean population. To gain insights into the complexities of CRC and promote the exchange of critical data, RNA-sequencing analysis was performed to reveal the molecular mechanisms that drive the development and progression of CRC; this analysis is critical for developing effective treatment strategies. We performed RNA-sequencing analysis of CRC and adjacent normal tissue samples from 214 Korean participants (comprising a total of 381 including 169 normal and 212 tumor samples) to investigate differential gene expression between the groups. We identified 19,575 genes expressed in CRC and normal tissues, with 3,830 differentially expressed genes (DEGs) between the groups. Functional annotation analysis revealed that the upregulated DEGs were significantly enriched in pathways related to the cell cycle, DNA replication, and IL-17, whereas the downregulated DEGs were enriched in metabolic pathways. We also analyzed the relationship between clinical information and subtypes using the Consensus Molecular Subtype (CMS) classification. Furthermore, we compared groups clustered within our dataset to CMS groups and performed additional analysis of the methylation data between DEGs and CMS groups to provide comprehensive biological insights from various perspectives. Our study provides valuable insights into the molecular mechanisms underlying CRC in Korean patients and serves as a platform for identifying potential target genes for this disease. The raw data and processed results have been deposited in a public repository for further analysis and exploration.