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Over 200,000 individuals are diagnosed with lung cancer in the U.S. every year, with a growing proportion of cases, especially lung adenocarcinoma, occurring in individuals who have never smoked. Women over the age of 50 comprise the largest affected demographic. To understand the genomic drivers of lung adenocarcinoma and therapeutic response in this population, we performed whole genome and/or whole exome sequencing on 73 matched lung tumor/normal pairs from post-menopausal women who participated in the Women's Health Initiative. Somatic copy number alterations showed little variation by smoking status, suggesting that aneuploidy may be a general characteristic of lung cancer regardless of smoke exposure. Similarly, clock-like and APOBEC mutation signatures were prevalent but did not differ in tumors from smokers and never-smokers. However, mutations in both EGFR and KRAS showed unique allelic differences determined by smoking status that are known to alter tumor response to targeted therapy. Mutations in the MYC-network member MGA were more prevalent in tumors from smokers. Fusion events in ALK, RET, and ROS1 were absent, likely due to age-related differences in fusion prevalence. Our work underscores the profound impact of smoking status, age, and sex on the tumor mutational landscape and identifies areas of unmet medical need.
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Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors. Algorithms were scored on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance substantially more than tumor features but purity-adjusted read depth, copy-number state and read mappability were associated with the performance of most algorithms on most tasks. No single algorithm was a top performer for all seven tasks and existing ensemble strategies were unable to outperform the best individual methods, highlighting a key research need. All containerized methods, evaluation code and datasets are available to support further assessment of the determinants of subclonal reconstruction accuracy and development of improved methods to understand tumor evolution.
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We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) for small cell lung cancer (SCLC). In SCLC, differential activation of transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. We designed a targeted capture panel that identifies chromatin organization signatures at 1535 TF binding sites and 13,240 gene transcription start sites and detects exonic mutations in 842 genes. Sequencing of cfDNA from SCLC patient-derived xenograft models captured TF activity and gene expression and revealed individual highly informative loci. Prediction models of ASCL1 and NEUROD1 activity using informative loci achieved areas under the receiver operating characteristic curve (AUCs) from 0.84 to 0.88 in patients with SCLC. As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types.
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Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Secuencias Reguladoras de Ácidos Nucleicos , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: North Korean defectors (NKDs) have often been exposed to traumatic events. However, there have been few studies of neural alterations in NKDs with post-traumatic stress disorder (PTSD) and complex PTSD (cPTSD). AIMS: To investigate neural alterations in NKDs with PTSD and cPTSD, with a specific focus on alterations in resting-state functional connectivity networks, including the default mode network (DMN). METHOD: Resting-state functional connectivity was assessed using brain functional magnetic resonance imaging in three groups of NKDs: without PTSD, with PTSD and with cPTSD. Statistical tests were performed, including region of interest (ROI)-to-ROI and ROI-to-voxel analysis, followed by post hoc correlation analysis. RESULTS: In the ROI-to-ROI analysis, differences in functional connectivity were found among the components of the DMN, as well as in the thalamus and the basal ganglia. Right hippocampus-left pallidum and right amygdala-left lingual gyrus connectivity differed between groups in the ROI-to-voxel analysis, as did connectivity involving the basal ganglia. The post hoc analysis revealed negative correlations between Coping and Adaptation Processing Scale (CAPS) score and left posterior cingulate cortex-right pallidum connectivity and between CAPS score and right putamen-left angular gyrus connectivity in the control group, which were not observed in other groups. CONCLUSIONS: The results suggest that there are alterations in the functional connectivity of the DMN and the limbic system in NKDs with PTSD and cPTSD, and that these alterations involve the basal ganglia. The lower correlations of CAPS score with right basal ganglia-DMN functional connectivity in patients compared with controls further implies that these connectivities are potential targets for treatment of PTSD and cPTSD.
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Persistent damage to liver cells leads to liver fibrosis, which is characterized by the accumulation of scar tissue in the liver, ultimately leading to cirrhosis and serious complications. Because it is difficult to reverse cirrhosis once it has progressed, the primary focus has been on preventing the progression of liver fibrosis. However, studies on therapeutic agents for liver fibrosis are still lacking. Here, we investigated that the natural dipeptide cyclic histidine-proline (CHP, also known as diketopiperazine) shows promising potential as a therapeutic agent in models of liver injury by inhibiting the progression of fibrosis through activation of the Nrf2 pathway. To elucidate the underlying biological mechanism of CHP, we used the Cellular Thermal Shift Assay (CETSA)-LC-MS/MS, a label-free compound-based target identification platform. Chloride intracellular channel protein 1 (CLIC1) was identified as a target whose thermal stability is increased by CHP treatment. We analyzed the direct interaction of CHP with CLIC1 which revealed a potential interaction between CHP and the E228 residue of CLIC1. Biological validation experiments showed that knockdown of CLIC1 mimicked the antioxidant effect of CHP. Further investigation using a mouse model of CCl4-induced liver fibrosis in wild-type and CLIC1 KO mice revealed the critical involvement of CLIC1 in mediating the effects of CHP. Taken together, our results provide evidence that CHP exerts its anti-fibrotic effects through specific binding to CLIC1. These insights into the mechanism of action of CHP may pave the way for the development of novel therapeutic strategies for fibrosis-related diseases.
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Cloruros , Factor 2 Relacionado con NF-E2 , Humanos , Canales de Cloruro/metabolismo , Cloruros/metabolismo , Cromatografía Liquida , Cirrosis Hepática/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Fenotipo , Espectrometría de Masas en TándemRESUMEN
In recent years, extracellular vesicles (EVs) have gained attention for their potential as biomarkers for the early diagnosis and treatment of various diseases. Traditionally, EV isolation has relied exclusively on ultracentrifugation. However, alternative enrichment methods such as size-exclusion chromatography (SEC) and polyethylene glycol-based precipitation have been introduced. This study utilized SEC as a characterization tool to assess the efficiency of EV isolation. Urinary EVs isolated from human urine using centrifugation (40,000 × g) were analyzed using an SEC column with a pore size of 1000 Å, an inner diameter of 7.8 mm, and a length of 300 mm. The EVs were detected sequentially using UV (280 nm) and fluorescence (λex/em = 550 nm/565 nm); the EVs were observed at approximately 6 min, while the proteins were observed at approximately 12 min. The repeated centrifugation enrichment steps resulted in an increase in EV peaks and a decrease in protein peaks. SEC analysis of the enriched EV samples confirmed that a four-cycle repetition of centrifugation is necessary for successful EV enrichment and removal of non-EV proteins from 40 mL of human urine.
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Vesículas Extracelulares , Humanos , Cromatografía en Gel , CentrifugaciónRESUMEN
Color matching experiments were conducted for 11 pairs of displays, using 7 displays with different spectral characteristics. The color matching results between the LCD display and displays that have a narrowband spectrum, such as a laser projector, QLED, or OLED, demonstrated a significant color difference between two matched colors. The maximum difference was 18.52 ΔE00, which indicates the white color difference between the LCD and laser projector. There was also a clear observer variability of 2.27 ΔE00. The new cone fundamental function derived from 757 metameric pairs showed good performance compared to CIE standard observers reducing the display color mismatching significantly. This function also demonstrated a better performance when evaluating color matching in color chart image.
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Lung cancer in never-smokers disproportionately affects older women. To understand the mutational landscape of this cohort, we performed detailed genome characterization of 73 lung adenocarcinomas from participants of the Womenâ™s Health Initiative (WHI). We find enrichment of EGFR mutations in never-/light-smokers and KRAS mutations in heavy smokers as expected, but we also show that the specific variants of these genes differ by smoking status, with important therapeutic implications. Mutational signature analysis revealed signatures of clock, APOBEC, and DNA repair deficiency in never-/light-smokers; however, the mutational load of these signatures did not differ significantly from those found in smokers. Last, tumors from both smokers and never-/light-smokers shared copy number subtypes, with no significant differences in aneuploidy. Thus, the genomic landscape of lung cancer in never-/light-smokers and smokers is predominantly differentiated by somatic mutations and not copy number alterations.
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Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.
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Carcinoma Basocelular , Neoplasias de la Próstata , Neoplasias Cutáneas , Masculino , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Próstata/patología , Carcinoma Basocelular/genética , Carcinoma Basocelular/patología , Neoplasias Cutáneas/patología , Genómica , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores , Factores de Intercambio de Guanina NucleótidoRESUMEN
Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. SIGNIFICANCE: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517.
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ADN Tumoral Circulante , Neoplasias de la Próstata , Masculino , Humanos , ADN Tumoral Circulante/genética , Nucleosomas/genética , Medicina de Precisión , Neoplasias de la Próstata/patología , Regulación Neoplásica de la Expresión Génica , FenotipoRESUMEN
Cell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we develop Griffin, a framework for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing data. Griffin employs a GC correction procedure tailored to variable cfDNA fragment sizes, which generates a better representation of chromatin accessibility and improves the accuracy of cancer detection and tumor subtype classification. We demonstrate estrogen receptor subtyping from cfDNA in metastatic breast cancer. We predict estrogen receptor subtype in 139 patients with at least 5% detectable circulating tumor DNA with an area under the receive operator characteristic curve (AUC) of 0.89 and validate performance in independent cohorts (AUC = 0.96). In summary, Griffin is a framework for accurate tumor subtyping and can be generalizable to other cancer types for precision oncology applications.
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Ácidos Nucleicos Libres de Células , Neoplasias , Humanos , Ácidos Nucleicos Libres de Células/genética , Nucleosomas/genética , Neoplasias/diagnóstico , Neoplasias/genética , Receptores de Estrógenos , Medicina de PrecisiónRESUMEN
Background: The International Trauma Questionnaire (ITQ) is a self-report assessment focused on the core features of Post-Traumatic Stress Disorder (PTSD) and complex Post-Traumatic Stress Disorder (CPTSD). It is consistent with the organizing principles of the 11th revision to the WHO's International Classification of Diseases (ICD-11). Since the 1990s, the number of North Korean defectors (NKD) entering South Korea to escape human rights violations has been increasing rapidly, with 33,815 NKD settled by 2021. The South Korean government faces an important challenge in supporting NKD to successfully adapt and settle in South Korean society. NKD experience various traumatic events during the process of defecting and repatriation. Therefore, it is essential to understand the psychological disorders of NKD, especially PTSD and CPTSD. Objective: This study aimed to test the validity of the ITQ assessment and explore the differences in symptoms and quality of life between PTSD and CPTSD. Method: The study sample comprised 503 trauma-exposed NKD. Confirmatory factor analysis (CFA) and latent class analysis (LCA) were used to evaluate the validity of ITQ. One-way analysis of variances and post-hoc analyses revealed the difference in the Depression and Somatic Symptoms Scale (DSSS) and WHOQOL-BREF results among PTSD and CPTSD symptom LCA classes. Results: The CFA and LCA results supported the ICD-11 conceptualization of PTSD and CPTSD in NKD. The CFA results confirmed that both the first- and second-order models were statistically fit, but for community-dwelling NKD the first-order model had better model fit than the second-order model. The LCA findings revealed a four-class model with 'PTSD', 'CPTSD', 'DSO', and 'low symptom' classes. Compared to the PTSD class, CPTSD class had higher levels of depression and somatic symptoms and a lower quality of life. Conclusion: This study provided evidence that ITQ is a valid tool to assess PTSD or CPTSD in community-dwelling NKD.
Antecedentes: El Cuestionario Internacional de Trauma (ITQ en su sigla en inglés) es una evaluación de autoreporte focalizado en las características principales del Trastorno de Estrés Postraumático (TEPT) y del Trastorno de Estrés Postraumático complejo (TEPT-C). Es consistente con los principios organizadores de la onceava revisión de la Clasificación International de las Enfermedades (CIE-11) de la OMS. Desde 1990, ha aumentado rápidamente el número de desertores de Corea del Norte (NKD en su sigla en inglés) que han entrado a Corea del Sur para escapar de las violaciones a los derechos humanos, con 33,815 NKD instalados hasta 2021. El gobierno de Corea del Sur enfrenta un desafío importante en apoyar a los NKD para adaptarse e instalarse en la sociedad de Corea del Sur. Los NKD experimentan varios eventos traumáticos durante el proceso de deserción y repatriación. Por lo tanto, es esencial entender los trastornos psicológicos de NKD, especialmente TEPT y TEPT-C.Objetivo: Este estudio busca evaluar la validez de la evaluación ITQ y explorar las diferencias en los síntomas y la calidad de vida entre TEPT y TEPT-C.Método: La muestra del estudio estuvo compuesta de 503 NKD expuesto a trauma. Se usaron el análisis factorial confirmatorio (CFA en su sigla en inglés) y análisis de clases latentes (LCA en su sigla en inglés) para evaluar la validez de ITQ. Los análisis de una vía de las varianzas y los análisis post-hoc revelaron la diferencia en los resultados de la Escala de los Síntomas somáticos y Depresión (DSSS en su sigla en inglés) y WHOQOL-BREF entre los síntomas TEPT y TEPT-C de las clases de los LCA.Resultados: Los resultados de CFA y LCA apoyan la conceptualización del TEPT y TEPT-C de la CIE-11 en NKD. Los resultados del CFA confirmaron que tanto los modelos de primer y de segundo orden fueron estadísticamente adecuados, pero para los NKD viviendo en residencias comunitarias, el modelo de primer orden tuvo un mejor ajuste que el modelo de segundo orden. Los hallazgos del LCA revelaron un modelo de cuatro clases con las clases 'TEPT', 'TEPT-C', 'DSO', y 'baja sintomatología'. En comparación con la clase TEPT, la clase TEPT-C tuvo niveles más altos de síntomas somáticos y depresión y una calidad de vida más baja.Conclusión: Este estudio proporciona evidencia que el ITQ es una herramienta válida para evaluar TEPT o TEPT-C en NKD viviendo en residencias comunitarias.
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Síntomas sin Explicación Médica , Trastornos por Estrés Postraumático , República Popular Democrática de Corea , Humanos , Clasificación Internacional de Enfermedades , Calidad de Vida , Trastornos por Estrés Postraumático/diagnóstico , Encuestas y CuestionariosRESUMEN
Direct identification of the proteins targeted by small molecules can provide clues for disease diagnosis, prevention, and drug development. Despite concentrated attempts, there are still technical limitations associated with the elucidation of direct interactors. Herein, we report a target-ID system called proximity-based compound-binding protein identification (PROCID), which combines our direct analysis workflow of proximity-labeled proteins (Spot-ID) with the HaloTag system to efficiently identify the dynamic proteomic landscape of drug-binding proteins. We successfully identified well-known dasatinib-binding proteins (ABL1, ABL2) and confirmed the unapproved dasatinib-binding kinases (e.g., BTK and CSK) in a live chronic myeloid leukemia cell line. PROCID also identified the DNA helicase protein SMARCA2 as a dasatinib-binding protein, and the ATPase domain was confirmed to be the binding site of dasatinib using a proximity ligation assay (PLA) and in cellulo biotinylation assay. PROCID thus provides a robust method to identify unknown drug-interacting proteins in live cells that expedites the mode of action of the drug.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Proteómica , Humanos , Dasatinib/farmacología , Proteínas Portadoras , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , BiotinilaciónRESUMEN
Gut microbiomes are well recognized to serve a variety of roles in health and disease, even though their functions are not yet completely understood. Previous studies have demonstrated that the microbiomes of juvenile and adult dogs have significantly different compositions and characteristics. However, there is still a scarcity of basic microbiome research in dogs. In this study, we aimed to advance our understanding by confirming the difference in fecal microbiome between young and adult dogs by analyzing the feces of 4-month and 16-month-old Jindo dogs, a domestic Korean breed. Microbiome data were generated and examined for the two age groups using 16S rRNA analysis. Comparison results revealed that the 16-month-old group presented a relatively high distribution of Bacteroides, whereas the 4-month-old group presented a comparatively high distribution of the Lactobacillus genus. Microbial function prediction analyses confirmed the relative abundance of lipid metabolism in 4-month-old dogs. In 16-month-old dogs, glucose metabolism was determined using microbial function prediction analyses. This implies that the functional microbiome changes similarly to the latter in adults compared with childhood. Overall, we discovered compositional and functional variations between genes of the gut microbial population in juveniles and adults. These microbial community profiles can be used as references for future research on the microbiome associated with health and development in the canine population.
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The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 531 localized and 143 metastatic prostate cancers profiled by whole genome sequencing, 125 metastatic samples of which were also profiled via whole transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined 9 subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
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Neoplasias de la Próstata Resistentes a la Castración , Genómica , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Secuenciación Completa del GenomaRESUMEN
Lymphoma is one of the most prevalent hematological cancers, accounting for 15-20 % of new cancer diagnoses in dogs. Therefore, this study aims to explore the important genes and pathways involved in canine lymphoma progression and understand the underlying molecular mechanisms using RNA sequencing. In this study, RNAs acquired from seven pairs of lymphoma and non-lymphoma blood samples were sequenced from different breeds of dogs. Sequencing reads were preprocessed, aligned with the reference genome, assembled and expressions were estimated through bioinformatics approaches. At a false discovery rate (FDR) < 0.05 and fold change (FC) ≥ 1.5, a total of 625 differentially expressed genes (DEGs) were identified between lymphoma and non-lymphoma samples, including 347 up-regulated DEGs such as SLC38A11, SCN3A, ZIC5 etc. and 278 down-regulated DEGs such as LOC475937, CSMD1, KRT14 etc. GO enrichment analysis showed that these DEGs were highly enriched for molecular function of ATP binding and calcium ion binding, cellular process of focal adhesion, and biological process of immune response, and defense response to virus. Similarly, KEGG pathways analysis revealed 11 significantly enriched pathways such as ECM-receptor interaction, cell cycle, PI3K-Akt signaling pathway, ABC transporters etc. In the protein-protein interaction (PPI) network, CDK1 was found to be a top hub gene with highest degree of connectivity. Three modules selected from the PPI network showed that canine lymphoma was highly associated with cell cycle, ECM-receptor interaction, hypertrophic cardiomyopathy, dilated cardiomyopathy and RIG-I-like receptor signaling pathway. Overall, our findings highlighted new candidate therapeutic targets for further testing in canine lymphoma and facilitate the understanding of molecular mechanism of lymphoma's progression in dogs.
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Regulación Neoplásica de la Expresión Génica , Fosfatidilinositol 3-Quinasas , Animales , Biología Computacional , Perros , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Fosfatidilinositol 3-Quinasas/genética , Mapas de Interacción de Proteínas/genética , Transducción de Señal/genética , TranscriptomaRESUMEN
Genomic evolution of patient-derived xenografts (PDXs) may lead to their gradual divergence away of their tumors of origin. We previously reported the genomic evolution of the copy number (CN) landscapes of PDXs during their engraftment and passaging1. However, whether PDX models are highly stable throughout passaging2, or can evolve CNAs rapidly1,3, remains controversial. Here, we reassess the genomic evolution of PDXs using DNA-based CN profiles. We find strong evidence for genomic evolution in the DNA-based PDX data: a median of ~10% of the genome is differentially altered between matched primary tumors (PTs) and PDXs across cohorts (range, 0% to 73% across all models). In 24% of the matched PT-PDX samples, over a quarter of the genome is differentially affected by CN alterations. Moreover, in matched analyses of PTs and their derived PDXs at multiple passages, later-passage PDXs are significantly less similar to their parental PTs than earlier-passage PDXs, indicative of genomic divergence. We conclude that PDX models indeed evolve throughout their derivation and propagation, and that the phenotypic consequences of this evolution ought to be assessed in order to determine its relevance to the proper application of these valuable cancer models.
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As a companion and hunting dog, height, length, length to height ratio (LHR) and body-weight are the vital economic traits for Jindo dog. Human selection and targeted breeding have produced an extraordinary diversity in these traits. Therefore, the identification of causative markers, genes and pathways that help us to understand the genetic basis of this variability is essential for their selection purposes. Here, we performed a genome-wide association study (GWAS) combined with enrichment analysis on 757 dogs using 118,879 SNPs. The genomic heritability (h2) was 0.33 for height and 0.28 for weight trait in Jindo. At p-value < 5 × 10-5, ten, six, thirteen and eleven SNPs on different chromosomes were significantly associated with height, length, LHR and body-weight traits, respectively. Based on our results, HHIP, LCORL and NCAPG for height, IGFI and FGFR3 for length, DLK1 and EFEMP1 for LHR and PTPN2, IGFI and RASAL2 for weight can be the potential candidate genes because of the significant SNPs located in their intronic or upstream regions. The gene-set enrichment analysis highlighted here nine and seven overlapping significant (p < 0.05) gene ontology (GO) terms and pathways among traits. Interestingly, the highlighted pathways were related to hormone synthesis, secretion and signalling were generally involved in the metabolism, growth and development process. Our data provide an insight into the significant genes and pathways if verified further, which will have a significant effect on the breeding of the Jindo dog's population.