Hearing loss (HL) is the most common sensory disorder, affecting all age groups, ethnicities, and gen-ders. According to World Health Organization (WHO) estimates in 2005, 278 million people worldwide have moderate to...Hearing loss (HL) is the most common sensory disorder, affecting all age groups, ethnicities, and gen-ders. According to World Health Organization (WHO) estimates in 2005, 278 million people worldwide have moderate to profound HL in both ears. Results of the 2002 National Health Interview Survey indicate that nearly 31 million of all non-institutionalized adults (aged 18 and over) in the United States have trouble hearing. Epidemiological studies have estimated that approximately 50%of profound HL can be attributed to genetic causes. With over 60 genes implicated in nonsyndromic hearing loss, it is also an extremely het-erogeneous trait. Recent progress in identifying genes responsible for hearing loss enables otolaryngologists and other clinicians to apply molecular diagnosis by genetic testing. The advent of the $1000 genome has the potential to revolutionize the identification of genes and their mutations underlying genetic disorders. This is especially true for extremely heterogeneous Mendelian conditions such as deafness, where the muta-tion, and indeed the gene, may be private. The recent technological advances in target-enrichment methods and next generation sequencing offer a unique opportunity to break through the barriers of limitations im-posed by gene arrays. These approaches now allow for the complete analysis of all known deafness-causing genes and will result in a new wave of discoveries of the remaining genes for Mendelian disorders. This re-view focuses on describing genotype-phenotype correlations of the most frequent genes including GJB2, which is responsible for more than half of cases, followed by other common genes and on discussing the im-pact of genomic advances for comprehensive genetic testing and gene discovery in hereditary hearing loss.展开更多
Background Multibreed genomic prediction(MBGP)is crucial for improving prediction accuracy for breeds with small populations,for which limited data are often available.Recent studies have demonstrated that partitionin...Background Multibreed genomic prediction(MBGP)is crucial for improving prediction accuracy for breeds with small populations,for which limited data are often available.Recent studies have demonstrated that partitioning the genome into nonoverlapping blocks to model heterogeneous genetic(co)variance in multitrait models can achieve higher joint prediction accuracy.However,the block partitioning method,a key factor influencing model performance,has not been extensively explored.Results We introduce mbBayesABLD,a novel Bayesian MBGP model that partitions each chromosome into nonoverlapping blocks on the basis of linkage disequilibrium(LD)patterns.In this model,marker effects within each block are assumed to follow normal distributions with block-specific parameters.We employ simulated data as well as empirical datasets from pigs and beans to assess genomic prediction accuracy across different models using cross-validation.The results demonstrate that mbBayesABLD significantly outperforms conventional MBGP models,such as GBLUP and BayesR.For the meat marbling score trait in pigs,compared with GBLUP,which does not account for heterogeneous genetic(co)variance,mbBayesABLD improves the prediction accuracy for the small-population breed Landrace by 15.6%.Furthermore,our findings indicate that a moderate level of similarity in LD patterns between breeds(with an average correlation of 0.6)is sufficient to improve the prediction accuracy of the target breed.Conclusions This study presents a novel LD block-based approach for multibreed genomic prediction.Our work provides a practical tool for livestock breeding programs and offers new insights into leveraging genetic diversity across breeds for improved genomic prediction.展开更多
Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely unknown.By integr...Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely unknown.By integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants.We identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites.Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific.Functional annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency related.Our results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.展开更多
To the Editor： With interest we read the article by Wu et all on a 53-year male with agenesia of the right lung and left-ventricular hypertrabeculation / noncompaction （LVHT）. The paper raises the following concerns.
T-lymphoblastic lymphoma(T-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background.However,complex karyotypes were already related to this group of malignancy ...T-lymphoblastic lymphoma(T-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background.However,complex karyotypes were already related to this group of malignancy and associated with poor outcome.Here,we describe a 17-year-old female being diagnosed with T-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa(GTG)-banding.However,further analyses including high-resolution molecular approaches,array-comparative genomic hybridization(aCGH),multiplex ligation-dependent probe amplification,fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype,NUP214-ABL1 gene fusion,episomes and intra-tumor genetic heterogeneity.In addition,homozygous loss of CDKN2A,as well as amplification of oncogene TLX1(HOX11)were detected.Actually,NUP214-ABL1 fusion gene replicated autonomously in this case as episomes.Overall,highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors.As episomes are missed in standard karyotyping aCGH should be performed routinely in T-LBL to possibly detect more of such cases.展开更多
Examining age-specific heterogeneity of susceptibility to cardiovascular disease is also essential in individuals without prediabetes to determine its relative size and direction compared to those with prediabetes.Of ...Examining age-specific heterogeneity of susceptibility to cardiovascular disease is also essential in individuals without prediabetes to determine its relative size and direction compared to those with prediabetes.Of particular interest,age-specific heterogeneity in genetic susceptibility may exhibit opposite directions depending on the presence or absence of prediabetes.展开更多
Aim:Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis.The discovery of intra-tumor genetic heterogeneity(ITGH),has resulted in this ...Aim:Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis.The discovery of intra-tumor genetic heterogeneity(ITGH),has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger genes.In addition,accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype disconnects.This study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast tumors.Methods:ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes,i.e.,complex single gene variance(CSGV).Results:CSGV was identified in the androgen receptor genes in all breast tumors examined.Conclusion:Evidence of CSGV suggests that a selection-as opposed to a mutation-centric hypothesis could better explain carcinogenesis.Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo mutations.Thus,the role of selection pressures,such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols.展开更多
BACKGROUND Only a few cases of diabetes mellitus with concurrent mutations in the mitochondrial MT-TL1 and CEL genes have been reported worldwide.Racial differences may influence mutation frequency,the presentation of...BACKGROUND Only a few cases of diabetes mellitus with concurrent mutations in the mitochondrial MT-TL1 and CEL genes have been reported worldwide.Racial differences may influence mutation frequency,the presentation of symptoms,and disease progression.This case report describes the clinical features,potential genetic mechanisms,and diagnostic complexity of young-onset diabetes mellitus with concurrent m.3243A>G mutation in MT-TL1 and c.1336G>A mutation in CEL.The objective is to inform precise typing,genetic counseling,and personalized treatment of monogenic diabetes mellitus,while expanding the evidence base on rare forms of diabetes mellitus.CASE SUMMARY A 30-year-old man,diagnosed with diabetic ketoacidosis six years earlier,presented with poor response to insulin therapy(glycated hemoglobin,15.35%),marked wasting(body mass index:15.06 kg/m2),sensorineural deafness,diabetic retinopathy,and peripheral neuropathy.Whole-exome sequencing revealed concurrent mutations:Mitochondrial MT-TL1 m.3243A>G(heteroplasmy 41.76%)and CEL c.1336G>A.Family investigation identified his mother,who also had diabetes,as a carrier of the CEL mutation,and his sister as harboring both mutations without diabetes.CONCLUSION This case highlights the genetic heterogeneity of monogenic diabetes and expands the known mutational spectrum.Comprehensive genetic testing is recommended to enhance diagnostic accuracy in cases of suspected monogenic diabetes.展开更多
The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis,particularly within the underrepresented Brazilian population.Utilizing whole-exome sequencing in 27 ...The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis,particularly within the underrepresented Brazilian population.Utilizing whole-exome sequencing in 27 patients with unexplained polyposis,the researchers identified 16 candidate genes in 44.4%of cases-an impressive outcome given strict exclusion criteria.Many identified variants were linked to the Wnt/β-catenin signaling pathway,reinforcing their biological relevance.However,the study underscores key challenges in genomic medicine,especially the gap between gene discovery and clinical application.A substantial proportion of variants(60.1%)were classified as of uncertain sig-nificance,and the absence of functional validation or segregation analysis limits clinical interpretation.Notably,the potential for oligogenic inheritance com-plicates traditional monogenic models of hereditary cancer risk.The study’s focus on a genetically diverse Brazilian cohort emphasizes the need for population-specific genomic resources and interpretation guidelines.Moving forward,func-tional studies,including organoid models,loss-of-heterozygosity analyses,and genotype-phenotype correlations,are essential to validate findings.Clinically,discovering novel candidate genes may inform future screening and testing pro-tocols,though careful consideration is needed to manage uncertain results.Overall,the study represents a critical step in polyposis genetics,highlighting both progress made and the work still required for clinical translation.展开更多
Mauremys mutica(Cantor,1842)is an endangered species in China.Main phenotypic variations inbody color,body weight,body shape,clutch size,egg size,and hatchling size were revealed betweenthe southern and northern popul...Mauremys mutica(Cantor,1842)is an endangered species in China.Main phenotypic variations inbody color,body weight,body shape,clutch size,egg size,and hatchling size were revealed betweenthe southern and northern populations.Both populations have the phenomenon of'larger male'sexualsize dimorphism(SSD),especially in the southern population.Furthermore,genetic variations betweenthe two populations were analyzed by RAPD band patterns of 30 random individuals in each population.The average genetic distance was 0.299±0.108 among the samples of two populations.The average ge-netic distance between southern and northern populations was 0.305±0.046.Cluster analysis indicatedthat all the individuals from the southern and northern populations were clustered among themselves toform two distinct clades.A total of 20 population-specific RAPD fragments were scored from 16 primers,and could be used as RAPD markers for distinguishing the southern and the northern population.Basedon the nucleotide sequences of two RAPD markers,two pairs of SCAR primers(SC1-S and SC2-S)weredesigned,which could be used as SCAR markers for the southern population.According to the significantphenotypic and genetic variations,we suggested that the northern population and southern populationmight be considered as two separate taxa,the'northern taxon'and the'southern taxon',and the con-servation should be respectively conducted on the two taxa.展开更多
It is well-known that gender differences exist in the onset, progression, and prognosis of cardiovascular diseases （CVDs）, and that risk factors such as high blood pressure and lipid profiles vary between men and wo...It is well-known that gender differences exist in the onset, progression, and prognosis of cardiovascular diseases （CVDs）, and that risk factors such as high blood pressure and lipid profiles vary between men and women, Cur- rently, sex differences are stressed as important variables to take into account when examining the etiology of CVD. Genome-wide association studies of CVD have employed the sex as a covariate in their analytical models, but generally disregarded potential genetic heterogeneity （GHS） attributable to sex.展开更多
The “National Institutes of Health” genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, WN/N, WKY/N, M5...The “National Institutes of Health” genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, WN/N, WKY/N, M520/N, F344/N, ACI/N, BN/SsN and BUF/N strains) which were readily available at that time. Hansen and Spuhler [1] developed a more naturalistic, genetically heterogeneous rat stock with the aim of optimizing the distribution of genotypic frequencies and recombination and under the hypothesis that the NIH-HS stock could yield a broad-range distribution of responses (broader than commonly used laboratory rat strains) to experimental conditions, and thus serve as a base population for selection studies. Along the last decade, in a series of studies we have phenotypically characterized the NIH-HS rat stock (a colony exists at our laboratory since 2004) for their anxiety/fearfulness profiles (using a battery of both unconditioned and conditioned tests/tasks), as well as regarding their stress-induced hormonal responses, coping style under inescapable stress and spatial learning ability. We have also compared the phenotypic profiles of NIH-HS rats with those of the low anxious RHA-I and the high anxious RLA-I rat strains. The NIH-HS rat stock is, as a population, a rather anxious type of rat, with predominantly reactive/passive coping style in unlearned and learned anxiety/fear tests, and elevated stress hormone responses (as well as enhanced “depressive” symptoms in the forced swimming test). Genetic studies currently under way have thus far revealed that the genetically heterogeneous NIH-HS rat stock constitutes a unique tool for fine mapping of QTL (for multiple behavioural and biological complex traits) to megabase resolution levels, thus enabling candidate gene identification. We give some examples of this in the present paper, while also highlighting that microarray gene expression studies reveal that HPA-axis- and prolactin-related genes (among others) in the amygdala appear to be related with (or associated to) the coping style and anxiety/fearfulness responses of NIH-HS rats.展开更多
Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a...Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a lack of ancient human genomes.Here,we present 21 ancient genomes from Shandong dating from the Warring States period to the Northern Dynasties.Unlike the early Neolithic samples from Shandong,the historical samples are most closely related to post-Late Neolithic populations of the Middle Yellow River Basin,suggesting a population turnover in Shandong from the Neolithic Age to the Historical era.In addition,we detect a close genetic affinity between the historical samples in Shandong and present-day Han Chinese,showing long-term genetic stability in Han Chinese,at least since the Warring States period.展开更多
This letter provides a review of the report by Peng et al on a unique case of non-small cell lung cancer(NSCLC),specifically lung adenocarcinoma,featuring reactive oxygen species proto-oncogene 1-receptor(ROS1)co-muta...This letter provides a review of the report by Peng et al on a unique case of non-small cell lung cancer(NSCLC),specifically lung adenocarcinoma,featuring reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation.The case involves a 64-year-old patient who exhibited both epidermal growth factor receptor(EGFR)L858R mutation and ROS1 rearrangement,achieving significant disease stabilization following treatment with crizotinib.This rare EGFR/ROS1 co-mutation poses distinct challenges for clinical management and highlights the necessity of personalized treatment strategies.While third-generation EGFR tyrosine kinase inhibitors(TKIs),such as osimertinib,are commonly regarded as first-line therapies,recent studies indicate that crizotinib may offer superior disease control in certain EGFR-mutant patients,particularly those who exhibit poor responses to EGFR TKIs.The case also examines the influence of tumor cell genetic heterogeneity on treatment response,underscoring the importance of evaluating tumor characteristics.In patients with EGFR/ROS1 co-mutation,gefitinib is generally effective as a first-line treatment;however,its efficacy can be limited,whereas crizotinib has demonstrated improved disease control.Future research should focus on identifying optimal treatment strategies for patients with EGFR/ROS1 co-mutation to enhance patient outcomes.In conclusion,this case report not only illustrates the effectiveness of crizotinib in managing patients with EGFR/ROS1 co-mutation but also underscores the importance of personalized treatment approaches,offering valuable insights for improving clinical outcomes in NSCLC patients with complex genetic profiles.TO THE EDITOR I read with great interest the case report by Peng et al[1],titled“Concomitant Epidermal Growth Factor Receptor Mutation/C-ROS Oncogene 1 Rearrangement in Non-Small Cell Lung Cancer”,published in the World Journal of Clinical Oncology[1].This report presents a compelling case of the exceedingly rare epidermal growth factor receptor(EGFR)/reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation in non-small cell lung cancer(NSCLC),specifically in a patient with lung adenocarcinoma.The authors describe a 64-year-old woman with an EGFR L858R mutation and ROS1 rearrangement,who achieved notable disease stability with prolonged crizotinib treatment.This case,with its distinct clinical features and challenges inherent to EGFR/ROS1 co-mutations,provides valuable insights for the oncology community and underscores the potential efficacy of ROS1-targeted therapies in treating co-mutated NSCLC.展开更多
Metabolic engineering-driven microbial cell factories have made great progress in the efficient bioproduction of biochemical and recombinant proteins.However,the low efficiency and robustness of microbial cell factori...Metabolic engineering-driven microbial cell factories have made great progress in the efficient bioproduction of biochemical and recombinant proteins.However,the low efficiency and robustness of microbial cell factories limit their industrial applications.Harnessing microbial heterogeneity contributes to solving this.In this review,the origins of microbial heterogeneity and its effects on biosynthesis are first summarized.Synthetic biologydriven tools and strategies that can be used to improve biosynthesis by increasing and reducing microbial het-erogeneity are then systematically summarized.Next,novel single-cell technologies available for unraveling microbial heterogeneity and facilitating heterogeneity regulation are discussed.Furthermore,a combined workflow of increasing genetic heterogeneity in the strain-building step to help in screening highly productive strains-reducing heterogeneity in the production process to obtain highly robust strains(IHP-RHR)facilitated by single-cell technologies was proposed to obtain highly productive and robust strains by harnessing microbial heterogeneity.Finally,the prospects and future challenges are discussed.展开更多
In 2004, an association of genetic variation in the discs large homolog 5 （DLG5＇） gene with inflammatory bowel disease （IBD） was described in two large European study samples. The initial report of DLG5 as a nove...In 2004, an association of genetic variation in the discs large homolog 5 （DLG5＇） gene with inflammatory bowel disease （IBD） was described in two large European study samples. The initial report of DLG5 as a novel IBD susceptibility gene sparked a multitude of studies investigating its effect on CD and IBD, respectively, leading to controversial findings and ongoing discussions concerning the validity of the initial association finding and its role in the aetiology of Crohn disease. This review aims to summarize the current state of knowledge and to place the reported findings in the context of current concepts of complex diseases. This includes aspects of statistical power, phenotype differences and genetic heterogeneity between different populations as well as gene-gene and gene-environment interactions.展开更多
The genetically heterogeneous NIH-HS rat stock has been characterized by its response to anxiety- and fear-inducing situations, thus leading to the conclusion that they are a rather anxious and passive coping type of ...The genetically heterogeneous NIH-HS rat stock has been characterized by its response to anxiety- and fear-inducing situations, thus leading to the conclusion that they are a rather anxious and passive coping type of rats. Taking advantage of these profiles, and knowing that they show very poor performance in the two-way active (shuttle box) escape/avoidance task, we have tested NIH-HS rats (n = 80) in the forced swimming test (FST) as well as we have studied escape response deficits (i.e. response failures) of the same animals in the two-way shuttle box task. They were also tested for anxiety in the elevated zero-maze. The goal of such a study was that of investigating whether there are associations or relationships among helplessness-like or passive coping responses between both models of depression, i.e. the FST and the helplessness-like escape deficits in the shuttle box task. The results for the first time show associations among responses from both depression models and that selecting rats for displaying extreme (active or passive) responses in one of the models predict in a coherent manner (according to the hypothesis) their behaviour in the other model. These findings are discussed in the context of the concurrent validity of both models of depression as well as concerning the possible relevance of NIH-HS rats as a tool for future studies on this field.展开更多
The National Institutes of Health Genetically Heterogeneous Rat Stock (NIH-HS) is a unique tool for genetic studies of complex traits due to its high genetic heterogeneity and to its high level of genetic recombinants...The National Institutes of Health Genetically Heterogeneous Rat Stock (NIH-HS) is a unique tool for genetic studies of complex traits due to its high genetic heterogeneity and to its high level of genetic recombinants accumulated along many outbreeding generations. In the present study, 90 NIH-HS male rats were tested for anxiety/fearfulness in the elevated zero-maze and in the open-field test in order to investigate the associations among defensive responses from both tests and, in particular, those among open- field self-grooming and freezing. These associations were evaluated by means of a correlational-factorial approach and an analysis of differences between sub- groups displaying extreme scores in representative variables. The final factor analysis revealed a first factor with high loadings of all variables from the zero-maze (“Maze timidity/conflict” factor), and a second (independent) factor dominated by open-field crossings (-0.74), rearings (-0.62) and freezing (0.65), with lower loadings of open-field grooming (-0.39) and stretched attend postures, as well as of entries and time (loadings of -0.32 to -0.25) in the open sections of the zero-maze (“Open Behavior inhibition/ desinhibition” factor), suggesting that open-field self-grooming is a response associated to activity, in the present study, rather than to inhibition. Furthermore, the finding that grooming in the OF loaded negatively in a second factor supports a relationship between grooming and dearousal. Present results, thus, are in accordance with the usefulness of these tests for the purposes they are commonly employed and add new evidence supporting their concurrent validity, as indicated by the relationships observed among measures from both tests.展开更多
Many cancers apparently showing similar phenotypes are actually distinct at the molecular level,leading to very different responses to the same treatment.It has been recently demonstrated that pathway-based approaches...Many cancers apparently showing similar phenotypes are actually distinct at the molecular level,leading to very different responses to the same treatment.It has been recently demonstrated that pathway-based approaches are robust and reliable for genetic analysis of cancers.Nevertheless,it remains unclear whether such function-based approaches are useful in deciphering molecular heterogeneities in cancers.Therefore,we aimed to test this possibility in the present study.First,we used a NCI60 dataset to validate the ability of pathways to correctly partition samples.Next,we applied the proposed method to identify the hidden subtypes in diffuse large B-cell lymphoma （DLBCL）.Finally,the clinical significance of the identified subtypes was verified using survival analysis.For the NCI60 dataset,we achieved highly accurate partitions that best fit the clinical cancer phenotypes.Subsequently,for a DLBCL dataset,we identified three hidden subtypes that showed very different 10-year overall survival rates （90％,46％ and 20％） and were highly significantly （P =0.008） correlated with the clinical survival rate.This study demonstrated that the pathwaybased approach is promising for unveiling genetic heterogeneities in complex human diseases.展开更多
Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment.Diversifying tumor cells...Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment.Diversifying tumor cells or intra-tumor heterogeneity is essential for tumor growth,invasion,and immune evasion.However,no reliable method to classify tumor cell subtypes is yet available.In this study,we introduced the single-cell sequencing combined with copy number characteristics to identify the types of tumor cells in microsatellite stable(MSS)colorectal cancer(CRC).Methods:To characterize the somatic copy number alteration(SCNA)of MSS CRC in a single cell profile,we analyzed 26 tissue samples from 19 Korean patients(GSE132465,the Samsung Medical Center[SMC]dataset)and then verified our findings with 15 tissue samples from five Belgian patients(GSE144735,the Katholieke Universiteit Leuven 3[KUL3]dataset).The Cancer Genome Atlas(TCGA)cohort,GSE39582 cohort,and National Cancer Center(NCC)cohort(24 MSS CRC patients were enrolled in this study between March 2017 and October 2017)were used to validate the clinical features of prognostic signatures.Results:We employed single cell RNA-sequencing data to identify three types of tumor cells in MSS CRC by their SCNA characteristics.Among these three types of tumor cells,C1 and C3 had a higher SCNA burden;C1 had significant chromosome 13 and 20 amplification,whereas C3 was the polar opposite of C1,which exhibited deletion in chromosome 13 and 20.The three types of tumor cells exhibited various functions in the tumor microenvironment and harbored different mutations.C1 and C2 were linked to the immune response and hypoxia,respectively,while C3 was critical for cell adhesion activity and tumor angiogenesis.Additionally,one gene(OLFM4)was identified as epithelium-specific biomarker of better prognosis of CRC(TCGA cohort:P=0.0110;GSE39582 cohort:P=0.0098;NCC cohort:P=0.0360).Conclusions:On the basis of copy number characteristics,we illustrated tumor heterogeneity in MSS CRC and identified three types of tumor cells with distinct roles in tumor microenvironment.By understanding heterogeneity in the intricate tumor microenvironment,we gained an insight into the mechanisms of tumor evolution,which may support the development of therapeutic strategies.展开更多
文摘Hearing loss (HL) is the most common sensory disorder, affecting all age groups, ethnicities, and gen-ders. According to World Health Organization (WHO) estimates in 2005, 278 million people worldwide have moderate to profound HL in both ears. Results of the 2002 National Health Interview Survey indicate that nearly 31 million of all non-institutionalized adults (aged 18 and over) in the United States have trouble hearing. Epidemiological studies have estimated that approximately 50%of profound HL can be attributed to genetic causes. With over 60 genes implicated in nonsyndromic hearing loss, it is also an extremely het-erogeneous trait. Recent progress in identifying genes responsible for hearing loss enables otolaryngologists and other clinicians to apply molecular diagnosis by genetic testing. The advent of the $1000 genome has the potential to revolutionize the identification of genes and their mutations underlying genetic disorders. This is especially true for extremely heterogeneous Mendelian conditions such as deafness, where the muta-tion, and indeed the gene, may be private. The recent technological advances in target-enrichment methods and next generation sequencing offer a unique opportunity to break through the barriers of limitations im-posed by gene arrays. These approaches now allow for the complete analysis of all known deafness-causing genes and will result in a new wave of discoveries of the remaining genes for Mendelian disorders. This re-view focuses on describing genotype-phenotype correlations of the most frequent genes including GJB2, which is responsible for more than half of cases, followed by other common genes and on discussing the im-pact of genomic advances for comprehensive genetic testing and gene discovery in hereditary hearing loss.
基金supported by the Biological Breeding-Major Projects in National Science and Technology(No.2023ZD0404405)the Earmarked Fund for China Agriculture Research System(No.CARS-pig-35)+2 种基金the National Natural Science Foundation of China(No.3227284,32302708)the 2115 Talent Development Program of China Agricultural University,the Chinese Universities Scientific Fund(No.2023TC196)the Seed Industry Revitalization Action Project of Guangdong Province(No.2024-XPY-06-001)。
文摘Background Multibreed genomic prediction(MBGP)is crucial for improving prediction accuracy for breeds with small populations,for which limited data are often available.Recent studies have demonstrated that partitioning the genome into nonoverlapping blocks to model heterogeneous genetic(co)variance in multitrait models can achieve higher joint prediction accuracy.However,the block partitioning method,a key factor influencing model performance,has not been extensively explored.Results We introduce mbBayesABLD,a novel Bayesian MBGP model that partitions each chromosome into nonoverlapping blocks on the basis of linkage disequilibrium(LD)patterns.In this model,marker effects within each block are assumed to follow normal distributions with block-specific parameters.We employ simulated data as well as empirical datasets from pigs and beans to assess genomic prediction accuracy across different models using cross-validation.The results demonstrate that mbBayesABLD significantly outperforms conventional MBGP models,such as GBLUP and BayesR.For the meat marbling score trait in pigs,compared with GBLUP,which does not account for heterogeneous genetic(co)variance,mbBayesABLD improves the prediction accuracy for the small-population breed Landrace by 15.6%.Furthermore,our findings indicate that a moderate level of similarity in LD patterns between breeds(with an average correlation of 0.6)is sufficient to improve the prediction accuracy of the target breed.Conclusions This study presents a novel LD block-based approach for multibreed genomic prediction.Our work provides a practical tool for livestock breeding programs and offers new insights into leveraging genetic diversity across breeds for improved genomic prediction.
基金the Key International(Regional)Cooperative Research Project(No.81820108028)the National Natural Science Foundation of China(Nos.81521004,81922061,81973123,and 81803306)+2 种基金the Science Foundation for Distinguished Young Scholars of Jiangsu(No.BK20160046)the Priority Academic Program for the Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine).the National Cancer Institute,National Institutes of Health of USA through grants U01-CA063673,UM1-CA167462,and U01-CA167462.
文摘Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely unknown.By integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants.We identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites.Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific.Functional annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency related.Our results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
文摘To the Editor： With interest we read the article by Wu et all on a 53-year male with agenesia of the right lung and left-ventricular hypertrabeculation / noncompaction （LVHT）. The paper raises the following concerns.
文摘T-lymphoblastic lymphoma(T-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular background.However,complex karyotypes were already related to this group of malignancy and associated with poor outcome.Here,we describe a 17-year-old female being diagnosed with T-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa(GTG)-banding.However,further analyses including high-resolution molecular approaches,array-comparative genomic hybridization(aCGH),multiplex ligation-dependent probe amplification,fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype,NUP214-ABL1 gene fusion,episomes and intra-tumor genetic heterogeneity.In addition,homozygous loss of CDKN2A,as well as amplification of oncogene TLX1(HOX11)were detected.Actually,NUP214-ABL1 fusion gene replicated autonomously in this case as episomes.Overall,highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of T-LBL patients which accordingly could benefit from treatment with tyrosine kinase inhibitors.As episomes are missed in standard karyotyping aCGH should be performed routinely in T-LBL to possibly detect more of such cases.
基金Supported by National Research Foundation of Korea,No.2018R1A2B6004867.
文摘Examining age-specific heterogeneity of susceptibility to cardiovascular disease is also essential in individuals without prediabetes to determine its relative size and direction compared to those with prediabetes.Of particular interest,age-specific heterogeneity in genetic susceptibility may exhibit opposite directions depending on the presence or absence of prediabetes.
基金This study was supported by a grant to BG from the Weekend to End Breast Cancer Fund of the Jewish General Hospital,Montreal,Quebec,Canada.
文摘Aim:Present cancer hypotheses are almost all based on the concept that accumulation of specific driver gene mutations cause carcinogenesis.The discovery of intra-tumor genetic heterogeneity(ITGH),has resulted in this hypothesis being modified by assuming that most of these ITGH mutations are in passenger genes.In addition,accumulating ITGH data on driver gene mutations have revealed considerable genotype/phenotype disconnects.This study proposes to investigate this disconnect by examining the nature and degree of ITGH in breast tumors.Methods:ITGH was examined in tumors using next generation sequencing of up to 68,000 reads and analysis tools that allowed for identification of distinct minority variants within single genes,i.e.,complex single gene variance(CSGV).Results:CSGV was identified in the androgen receptor genes in all breast tumors examined.Conclusion:Evidence of CSGV suggests that a selection-as opposed to a mutation-centric hypothesis could better explain carcinogenesis.Our hypothesis proposes that tumors develop by the selection of preexisting de novo mutations rather than just the accumulation of de novo mutations.Thus,the role of selection pressures,such as changes in tissue microenvironments will likely be critical to our understanding of tumor resistance as well as the development of more effective treatment protocols.
基金Supported by Jilin Province Science and Technology Development Project,No.20220203018SF。
文摘BACKGROUND Only a few cases of diabetes mellitus with concurrent mutations in the mitochondrial MT-TL1 and CEL genes have been reported worldwide.Racial differences may influence mutation frequency,the presentation of symptoms,and disease progression.This case report describes the clinical features,potential genetic mechanisms,and diagnostic complexity of young-onset diabetes mellitus with concurrent m.3243A>G mutation in MT-TL1 and c.1336G>A mutation in CEL.The objective is to inform precise typing,genetic counseling,and personalized treatment of monogenic diabetes mellitus,while expanding the evidence base on rare forms of diabetes mellitus.CASE SUMMARY A 30-year-old man,diagnosed with diabetic ketoacidosis six years earlier,presented with poor response to insulin therapy(glycated hemoglobin,15.35%),marked wasting(body mass index:15.06 kg/m2),sensorineural deafness,diabetic retinopathy,and peripheral neuropathy.Whole-exome sequencing revealed concurrent mutations:Mitochondrial MT-TL1 m.3243A>G(heteroplasmy 41.76%)and CEL c.1336G>A.Family investigation identified his mother,who also had diabetes,as a carrier of the CEL mutation,and his sister as harboring both mutations without diabetes.CONCLUSION This case highlights the genetic heterogeneity of monogenic diabetes and expands the known mutational spectrum.Comprehensive genetic testing is recommended to enhance diagnostic accuracy in cases of suspected monogenic diabetes.
文摘The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis,particularly within the underrepresented Brazilian population.Utilizing whole-exome sequencing in 27 patients with unexplained polyposis,the researchers identified 16 candidate genes in 44.4%of cases-an impressive outcome given strict exclusion criteria.Many identified variants were linked to the Wnt/β-catenin signaling pathway,reinforcing their biological relevance.However,the study underscores key challenges in genomic medicine,especially the gap between gene discovery and clinical application.A substantial proportion of variants(60.1%)were classified as of uncertain sig-nificance,and the absence of functional validation or segregation analysis limits clinical interpretation.Notably,the potential for oligogenic inheritance com-plicates traditional monogenic models of hereditary cancer risk.The study’s focus on a genetically diverse Brazilian cohort emphasizes the need for population-specific genomic resources and interpretation guidelines.Moving forward,func-tional studies,including organoid models,loss-of-heterozygosity analyses,and genotype-phenotype correlations,are essential to validate findings.Clinically,discovering novel candidate genes may inform future screening and testing pro-tocols,though careful consideration is needed to manage uncertain results.Overall,the study represents a critical step in polyposis genetics,highlighting both progress made and the work still required for clinical translation.
基金the National Basic Research Program of China(No.2004CB117405)the Key Research Program of Ocean and Fishery Bureau of Guangdong province(No.2001A09)
文摘Mauremys mutica(Cantor,1842)is an endangered species in China.Main phenotypic variations inbody color,body weight,body shape,clutch size,egg size,and hatchling size were revealed betweenthe southern and northern populations.Both populations have the phenomenon of'larger male'sexualsize dimorphism(SSD),especially in the southern population.Furthermore,genetic variations betweenthe two populations were analyzed by RAPD band patterns of 30 random individuals in each population.The average genetic distance was 0.299±0.108 among the samples of two populations.The average ge-netic distance between southern and northern populations was 0.305±0.046.Cluster analysis indicatedthat all the individuals from the southern and northern populations were clustered among themselves toform two distinct clades.A total of 20 population-specific RAPD fragments were scored from 16 primers,and could be used as RAPD markers for distinguishing the southern and the northern population.Basedon the nucleotide sequences of two RAPD markers,two pairs of SCAR primers(SC1-S and SC2-S)weredesigned,which could be used as SCAR markers for the southern population.According to the significantphenotypic and genetic variations,we suggested that the northern population and southern populationmight be considered as two separate taxa,the'northern taxon'and the'southern taxon',and the con-servation should be respectively conducted on the two taxa.
文摘It is well-known that gender differences exist in the onset, progression, and prognosis of cardiovascular diseases （CVDs）, and that risk factors such as high blood pressure and lipid profiles vary between men and women, Cur- rently, sex differences are stressed as important variables to take into account when examining the etiology of CVD. Genome-wide association studies of CVD have employed the sex as a covariate in their analytical models, but generally disregarded potential genetic heterogeneity （GHS） attributable to sex.
基金grants for the MICINN (PSI2009-10532) “Fundació La Maratò TV3” (ref. 092630/31) 2009SGR-0051 and the European pro- ject/consortium “EURATRANS” (grant agreement HEALTH-F4- 2010-241504)
文摘The “National Institutes of Health” genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, WN/N, WKY/N, M520/N, F344/N, ACI/N, BN/SsN and BUF/N strains) which were readily available at that time. Hansen and Spuhler [1] developed a more naturalistic, genetically heterogeneous rat stock with the aim of optimizing the distribution of genotypic frequencies and recombination and under the hypothesis that the NIH-HS stock could yield a broad-range distribution of responses (broader than commonly used laboratory rat strains) to experimental conditions, and thus serve as a base population for selection studies. Along the last decade, in a series of studies we have phenotypically characterized the NIH-HS rat stock (a colony exists at our laboratory since 2004) for their anxiety/fearfulness profiles (using a battery of both unconditioned and conditioned tests/tasks), as well as regarding their stress-induced hormonal responses, coping style under inescapable stress and spatial learning ability. We have also compared the phenotypic profiles of NIH-HS rats with those of the low anxious RHA-I and the high anxious RLA-I rat strains. The NIH-HS rat stock is, as a population, a rather anxious type of rat, with predominantly reactive/passive coping style in unlearned and learned anxiety/fear tests, and elevated stress hormone responses (as well as enhanced “depressive” symptoms in the forced swimming test). Genetic studies currently under way have thus far revealed that the genetically heterogeneous NIH-HS rat stock constitutes a unique tool for fine mapping of QTL (for multiple behavioural and biological complex traits) to megabase resolution levels, thus enabling candidate gene identification. We give some examples of this in the present paper, while also highlighting that microarray gene expression studies reveal that HPA-axis- and prolactin-related genes (among others) in the amygdala appear to be related with (or associated to) the coping style and anxiety/fearfulness responses of NIH-HS rats.
基金funded by the Shandong Province Humanities and Social Sciences Project“Sorting and Research on Human Bones of Han Dynasty Excavated from the Medical Center Cemetery in Linzi”granted to Zhigang Wu(2022-JCLS-12)the National Key Research and Development Program(2023YFC3303701-02)+5 种基金the National Natural Science Foundation of China(32270667)the Natural Science Foundation of Fujian Province of China(2023J06013)the Major Project of the National Social Science Foundation of China granted to Chuan-Chao Wang(21&ZD285)Open Research Fund of State Key Laboratory of Genetic Engineering at Fudan University(No.SKLGE-2310)Open Research Fund of Forensic Genetics Key Laboratory of the Ministry of Public Security(2023FGKFKT07)Major Special Project of Philosophy and Social Sciences Research of the Ministry of Education(2022JZDZ023).
文摘Shandong province,located in the Lower Yellow River,is one of the birthplaces of ancient Chinese civilization.However,the comprehensive genetic histories of this region have remained largely unknown until now due to a lack of ancient human genomes.Here,we present 21 ancient genomes from Shandong dating from the Warring States period to the Northern Dynasties.Unlike the early Neolithic samples from Shandong,the historical samples are most closely related to post-Late Neolithic populations of the Middle Yellow River Basin,suggesting a population turnover in Shandong from the Neolithic Age to the Historical era.In addition,we detect a close genetic affinity between the historical samples in Shandong and present-day Han Chinese,showing long-term genetic stability in Han Chinese,at least since the Warring States period.
文摘This letter provides a review of the report by Peng et al on a unique case of non-small cell lung cancer(NSCLC),specifically lung adenocarcinoma,featuring reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation.The case involves a 64-year-old patient who exhibited both epidermal growth factor receptor(EGFR)L858R mutation and ROS1 rearrangement,achieving significant disease stabilization following treatment with crizotinib.This rare EGFR/ROS1 co-mutation poses distinct challenges for clinical management and highlights the necessity of personalized treatment strategies.While third-generation EGFR tyrosine kinase inhibitors(TKIs),such as osimertinib,are commonly regarded as first-line therapies,recent studies indicate that crizotinib may offer superior disease control in certain EGFR-mutant patients,particularly those who exhibit poor responses to EGFR TKIs.The case also examines the influence of tumor cell genetic heterogeneity on treatment response,underscoring the importance of evaluating tumor characteristics.In patients with EGFR/ROS1 co-mutation,gefitinib is generally effective as a first-line treatment;however,its efficacy can be limited,whereas crizotinib has demonstrated improved disease control.Future research should focus on identifying optimal treatment strategies for patients with EGFR/ROS1 co-mutation to enhance patient outcomes.In conclusion,this case report not only illustrates the effectiveness of crizotinib in managing patients with EGFR/ROS1 co-mutation but also underscores the importance of personalized treatment approaches,offering valuable insights for improving clinical outcomes in NSCLC patients with complex genetic profiles.TO THE EDITOR I read with great interest the case report by Peng et al[1],titled“Concomitant Epidermal Growth Factor Receptor Mutation/C-ROS Oncogene 1 Rearrangement in Non-Small Cell Lung Cancer”,published in the World Journal of Clinical Oncology[1].This report presents a compelling case of the exceedingly rare epidermal growth factor receptor(EGFR)/reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation in non-small cell lung cancer(NSCLC),specifically in a patient with lung adenocarcinoma.The authors describe a 64-year-old woman with an EGFR L858R mutation and ROS1 rearrangement,who achieved notable disease stability with prolonged crizotinib treatment.This case,with its distinct clinical features and challenges inherent to EGFR/ROS1 co-mutations,provides valuable insights for the oncology community and underscores the potential efficacy of ROS1-targeted therapies in treating co-mutated NSCLC.
基金supported by the National Science Fund for Excellent Young Scholars(32222069)the National Natural Science Foundation of China(32172349,31930085)+1 种基金the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(32021005)the Jiangsu Basic Research Center for Synthetic Biology(BK20233003).
文摘Metabolic engineering-driven microbial cell factories have made great progress in the efficient bioproduction of biochemical and recombinant proteins.However,the low efficiency and robustness of microbial cell factories limit their industrial applications.Harnessing microbial heterogeneity contributes to solving this.In this review,the origins of microbial heterogeneity and its effects on biosynthesis are first summarized.Synthetic biologydriven tools and strategies that can be used to improve biosynthesis by increasing and reducing microbial het-erogeneity are then systematically summarized.Next,novel single-cell technologies available for unraveling microbial heterogeneity and facilitating heterogeneity regulation are discussed.Furthermore,a combined workflow of increasing genetic heterogeneity in the strain-building step to help in screening highly productive strains-reducing heterogeneity in the production process to obtain highly robust strains(IHP-RHR)facilitated by single-cell technologies was proposed to obtain highly productive and robust strains by harnessing microbial heterogeneity.Finally,the prospects and future challenges are discussed.
文摘In 2004, an association of genetic variation in the discs large homolog 5 （DLG5＇） gene with inflammatory bowel disease （IBD） was described in two large European study samples. The initial report of DLG5 as a novel IBD susceptibility gene sparked a multitude of studies investigating its effect on CD and IBD, respectively, leading to controversial findings and ongoing discussions concerning the validity of the initial association finding and its role in the aetiology of Crohn disease. This review aims to summarize the current state of knowledge and to place the reported findings in the context of current concepts of complex diseases. This includes aspects of statistical power, phenotype differences and genetic heterogeneity between different populations as well as gene-gene and gene-environment interactions.
基金Supported by grants for the MICINN(SAF2009-10532),“Fundacio La Marato TV3”(ref.092630/31),2009SGR-0051EURATRANS consortium(grant agreement HEALTH-F4-2010-241504)the Welcome Trust(UK).C.M-C is recipient of a FPI(2010,MICINN)PhD fellowship.
文摘The genetically heterogeneous NIH-HS rat stock has been characterized by its response to anxiety- and fear-inducing situations, thus leading to the conclusion that they are a rather anxious and passive coping type of rats. Taking advantage of these profiles, and knowing that they show very poor performance in the two-way active (shuttle box) escape/avoidance task, we have tested NIH-HS rats (n = 80) in the forced swimming test (FST) as well as we have studied escape response deficits (i.e. response failures) of the same animals in the two-way shuttle box task. They were also tested for anxiety in the elevated zero-maze. The goal of such a study was that of investigating whether there are associations or relationships among helplessness-like or passive coping responses between both models of depression, i.e. the FST and the helplessness-like escape deficits in the shuttle box task. The results for the first time show associations among responses from both depression models and that selecting rats for displaying extreme (active or passive) responses in one of the models predict in a coherent manner (according to the hypothesis) their behaviour in the other model. These findings are discussed in the context of the concurrent validity of both models of depression as well as concerning the possible relevance of NIH-HS rats as a tool for future studies on this field.
基金CNPq(201456/2011-7)Supported by grants for the MICINN(PSI2009-10532),“Fundacio La Marato TV3”(ref.092630/31),2009SGR-0051the European project/consortium“EURATRANS”(grant agreement HEALTH-F4-2010-241504).
文摘The National Institutes of Health Genetically Heterogeneous Rat Stock (NIH-HS) is a unique tool for genetic studies of complex traits due to its high genetic heterogeneity and to its high level of genetic recombinants accumulated along many outbreeding generations. In the present study, 90 NIH-HS male rats were tested for anxiety/fearfulness in the elevated zero-maze and in the open-field test in order to investigate the associations among defensive responses from both tests and, in particular, those among open- field self-grooming and freezing. These associations were evaluated by means of a correlational-factorial approach and an analysis of differences between sub- groups displaying extreme scores in representative variables. The final factor analysis revealed a first factor with high loadings of all variables from the zero-maze (“Maze timidity/conflict” factor), and a second (independent) factor dominated by open-field crossings (-0.74), rearings (-0.62) and freezing (0.65), with lower loadings of open-field grooming (-0.39) and stretched attend postures, as well as of entries and time (loadings of -0.32 to -0.25) in the open sections of the zero-maze (“Open Behavior inhibition/ desinhibition” factor), suggesting that open-field self-grooming is a response associated to activity, in the present study, rather than to inhibition. Furthermore, the finding that grooming in the OF loaded negatively in a second factor supports a relationship between grooming and dearousal. Present results, thus, are in accordance with the usefulness of these tests for the purposes they are commonly employed and add new evidence supporting their concurrent validity, as indicated by the relationships observed among measures from both tests.
基金supported in part by the National Natural Science Foundation of China(Grant Nos.31071166 and 81373085)Natural Science Foundation of Guangdong Province,China(Grant No.8251008901000007)+2 种基金Science and Technology Planning Project of Guangdong Province(Grant No.2009A030301004)Science and Technology Project of Dongguan(Grant No.2011108101015)the funds from Guangdong Medical College(Grant Nos.XG1001,JB1214,XZ1105,STIF201122,M2011024 and M2011010)
文摘Many cancers apparently showing similar phenotypes are actually distinct at the molecular level,leading to very different responses to the same treatment.It has been recently demonstrated that pathway-based approaches are robust and reliable for genetic analysis of cancers.Nevertheless,it remains unclear whether such function-based approaches are useful in deciphering molecular heterogeneities in cancers.Therefore,we aimed to test this possibility in the present study.First,we used a NCI60 dataset to validate the ability of pathways to correctly partition samples.Next,we applied the proposed method to identify the hidden subtypes in diffuse large B-cell lymphoma （DLBCL）.Finally,the clinical significance of the identified subtypes was verified using survival analysis.For the NCI60 dataset,we achieved highly accurate partitions that best fit the clinical cancer phenotypes.Subsequently,for a DLBCL dataset,we identified three hidden subtypes that showed very different 10-year overall survival rates （90％,46％ and 20％） and were highly significantly （P =0.008） correlated with the clinical survival rate.This study demonstrated that the pathwaybased approach is promising for unveiling genetic heterogeneities in complex human diseases.
文摘Background:With functionally heterogeneous cells,tumors comprise a complex ecosystem to promote tumor adaptability and evolution under strong selective pressure from the given microenvironment.Diversifying tumor cells or intra-tumor heterogeneity is essential for tumor growth,invasion,and immune evasion.However,no reliable method to classify tumor cell subtypes is yet available.In this study,we introduced the single-cell sequencing combined with copy number characteristics to identify the types of tumor cells in microsatellite stable(MSS)colorectal cancer(CRC).Methods:To characterize the somatic copy number alteration(SCNA)of MSS CRC in a single cell profile,we analyzed 26 tissue samples from 19 Korean patients(GSE132465,the Samsung Medical Center[SMC]dataset)and then verified our findings with 15 tissue samples from five Belgian patients(GSE144735,the Katholieke Universiteit Leuven 3[KUL3]dataset).The Cancer Genome Atlas(TCGA)cohort,GSE39582 cohort,and National Cancer Center(NCC)cohort(24 MSS CRC patients were enrolled in this study between March 2017 and October 2017)were used to validate the clinical features of prognostic signatures.Results:We employed single cell RNA-sequencing data to identify three types of tumor cells in MSS CRC by their SCNA characteristics.Among these three types of tumor cells,C1 and C3 had a higher SCNA burden;C1 had significant chromosome 13 and 20 amplification,whereas C3 was the polar opposite of C1,which exhibited deletion in chromosome 13 and 20.The three types of tumor cells exhibited various functions in the tumor microenvironment and harbored different mutations.C1 and C2 were linked to the immune response and hypoxia,respectively,while C3 was critical for cell adhesion activity and tumor angiogenesis.Additionally,one gene(OLFM4)was identified as epithelium-specific biomarker of better prognosis of CRC(TCGA cohort:P=0.0110;GSE39582 cohort:P=0.0098;NCC cohort:P=0.0360).Conclusions:On the basis of copy number characteristics,we illustrated tumor heterogeneity in MSS CRC and identified three types of tumor cells with distinct roles in tumor microenvironment.By understanding heterogeneity in the intricate tumor microenvironment,we gained an insight into the mechanisms of tumor evolution,which may support the development of therapeutic strategies.
