Background:Strong sex disparities have been observed among patients with bladder cancer(BCa).FGFR3 is one of the most frequently mutated genes in bladder cancer,and there are inconsistencies in its frequency in male a...Background:Strong sex disparities have been observed among patients with bladder cancer(BCa).FGFR3 is one of the most frequently mutated genes in bladder cancer,and there are inconsistencies in its frequency in male and female patients.Methods:Here,we conducted a meta-analysis comparing the FGFR3 somatic mutation frequency in men and women among 7351 patients with BCa from 18 cohorts.Results:We showed that female patients had a 1.32 times higher risk of having FGFR3 somatic mutations than males.This difference was attributed to mutations occurring at the 2 most frequently mutated sites,S249 and Y375.Additionally,nonsense mutations were more likely to be found in women,whereas indel/frameshift mutations were almost exclusively found in men;however,no difference was noted for missense mutations.Conclusions:A female sex bias in FGFR3 somatic mutationswas observed in BCa.Well-powered individual participant data analyses addressing the possible confounding effects of other factors(eg,age,ethnicity,smoking status,muscle invasiveness,and molecular subtype),as well as analyses integrating omics and functional investigations,are warranted to further validate and explain the mechanisms of the current findings.展开更多
The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of GATA4 were sequenced of DNA ...The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of GATA4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms （SNPs） reported in NCBI. Bioinformatics analysis was performed to analyze the possible mechanism by which mutations were linked to VSD. Among those variants, c. 1004C〉A （p.S335X） occurred in the highly conserved domain of GATA4 and generated a termination codon, which led to the production of truncated GATA4. The seven novel heterozygous GATA4 mutations were only identified in cardiac tissues with VSD, suggesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells implies that the genetic contribution to VSD may have been underestimated.展开更多
P53 gene mutations have been known to be highly related to the majority of human cancers.The colocation of biologists and bioinformaticians have constructed many databases for cancer research.Although the relationship...P53 gene mutations have been known to be highly related to the majority of human cancers.The colocation of biologists and bioinformaticians have constructed many databases for cancer research.Although the relationship between the presence of TP53 mutation and cancers has been reported in various studies,few reports TP53 mutation distribution in different functional domains.Hence,we use 2 databases(The TP53 Mutation Database of the International Agency for the Research on Cancer and The Genomic Data Commons data portal)to compare survival rate with and without TP53 mutations in a certain cancer,as well as to find most frequent mutation sites in different functional domains of the TP53 protein.Our study shows that most somatic mutations of TP53 and high mutation rate sites are concentrated in the DNA-binding domain,and the survival of certain cancers varies with and without P53.展开更多
Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important ro...Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations （SNVs） and somatic insertions and deletions （indels） of SCZ. Methods： One Chinese family with a monozygotic （MZ） twin pair discordant for SCZ was included. Whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. Results： One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. Conclusions： This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.展开更多
BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast ...BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.展开更多
The development of rapid genome sequencing has greatly enhanced our understanding of the molecular biology underlying many malignancies.Whole exome sequencing has highlighted the individualistic nature of malignancies...The development of rapid genome sequencing has greatly enhanced our understanding of the molecular biology underlying many malignancies.Whole exome sequencing has highlighted the individualistic nature of malignancies on a patient-to-patient basis and begun to revolutionize therapeutic approaches.In recent years,whole genome sequencing of urothelial malignancies has identified a host of somatic mutations which contribute to growth,progression,and metastasis of urothelial carcinoma of the bladder and upper tract urothelial carcinoma.As genetic sequencing continues,additional targets will be identified,allowing development of novel therapeutic agents targeting cancer on a molecular level,with the goal of delivering highly individualized care based on the underlying mutational profile of the patient’s malignancy.In this review,we aim to discuss known genetic alterations of urothelial malignancy and the implications these mutations carry in terms of prognostication and development of targeted therapeutic agents.We will focus on RNA-expression profiling and genomic DNA profiling,with a focus on comprehensive whole exome and whole genome sequencing relative to selected urothelial carcinoma-associated genes and circulating tumor DNA analysis.展开更多
Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GN...Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GNAQ,GNA11,or GNB2 gene[1],leading to vascular malformations in the cutaneous forehead,cerebral cortex,and eye[1,2].Notably,~70%of pediatric patients diagnosed with SWS exhibit brain calcification(BC)[4],though the prevalence of BC ranges from only 1%in young individuals to>20%in the senior population(>60 years old)[5].Similar to the elderly,BC in pediatric SWS patients is identified as vascular calcification[6,7],whereas BC in pediatric patients with tuberous sclerosis and tumors has been previously described as dystrophic calcification[6].展开更多
Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor recepto...Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.展开更多
Energy metabolism reprogramming was recently identified as one of the cancer hallmarks.One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear ge...Energy metabolism reprogramming was recently identified as one of the cancer hallmarks.One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA(mtDNA).In the past decades,several types of somatic mtDNA alterations have been identified in gastric cancer.However,the role of these mtDNA alterations in gastric cancer progression remains unclear.In this review,we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer.The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed.We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers.The two primary mutation types(transition mutations and mononucleotide or dinucleotide repeat instability)imply potential causative factors.Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer.The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies.展开更多
We described two members in a family with gastrointestinal stromal tumors （GISTs） without cutaneous hyperpigmentation. The patients were father and son who did not have cutaneous hyperpigmentation. Histological exam...We described two members in a family with gastrointestinal stromal tumors （GISTs） without cutaneous hyperpigmentation. The patients were father and son who did not have cutaneous hyperpigmentation. Histological examination showed that these tumors were GISTs expressing CD34 and CD117. Tumor DNA extracted from paraffin-embedded specimens revealed somatic mutation with a deletion mutation at different codons in exon 11 of c-kit gene after direct sequencing analysis. No germline mutation was detected in DNA extracted from peripheral leukocytes obtained from the father and son. We propose that GISTs could be caused by sporadic somatic mutation in a family without germline mutation and hyperpigmentation.展开更多
The mutation rate is a pivotal biological characteristic,intricately governed by natural selection and historically garnering considerable attention.Recent advances in high-throughput sequencing and analytical methodo...The mutation rate is a pivotal biological characteristic,intricately governed by natural selection and historically garnering considerable attention.Recent advances in high-throughput sequencing and analytical methodologies have profoundly transformed our understanding in this domain,ushering in an unprecedented era of mutation rate research.This paper aims to provide a comprehensive overview of the key concepts and methodologies frequently employed in the study of mutation rates.It examines various types of mutations,explores the evolutionary dynamics and associated theories,and synthesizes both classical and contemporary hypotheses.Furthermore,this review comprehensively explores recent advances in understanding germline and somatic mutations in animals and offers an overview of experimental methodologies,mutational patterns,molecular mechanisms,and driving forces influencing variations in mutation rates across species and tissues.Finally,it proposes several potential research directions and pressing questions for future investigations.展开更多
Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this...Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.展开更多
Acute myeloid leukemia(AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies...Acute myeloid leukemia(AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies have described the molecular landscape of AML and identified several somatic alterations that impact overall survival. Despite all these advancement, several challenges remain in translating this information into effective therapy. Herein we will review the molecular landscape of AML and discuss the impact of the most common somatic mutations on disease biology and outcome.展开更多
BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,non-genetic disorder characterized by multiple gastrointestinal polyps,and ectodermal lesions such as alopecia,fingernail atrophy,and skin mucosal pigmentation.Unfort...BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,non-genetic disorder characterized by multiple gastrointestinal polyps,and ectodermal lesions such as alopecia,fingernail atrophy,and skin mucosal pigmentation.Unfortunately,the pathogenesis of CCS is currently unknown.CASE SUMMARY Here,we describe the case of an elderly female with diarrhea,fatigue,and hair loss,who experienced abdominal pain for over half a year and was found to have multiple gastrointestinal polyps.She was diagnosed with CCS and was treated with albumin supplementation and prednisone,and her electrolyte imbalance was corrected.Following treatment,her symptoms significantly improved.To elucidate the role of potential genetic events in the pathogenesis of CCS,we performed exome sequencing using an extract of her colorectal adenoma.CONCLUSION Our data revealed multiple somatic mutations and copy number variations.Our findings provide a novel insight into the potential mechanisms of CCS etiology.展开更多
Gastrointestinal malignancies are among the leading causes of cancer-related deaths worldwide. Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppre...Gastrointestinal malignancies are among the leading causes of cancer-related deaths worldwide. Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppressor genes or activation of oncogenes. Advances in Molecular Biology techniques have allowed for more accurate analysis of tumors’ genetic profiling using new breakthrough technologies such as next generation sequencing (NGS), leading to the development of targeted therapeutical approaches based upon biomarker-selection. During the last 10 years tremendous advances in the development of targeted therapies for patients with advanced cancer have been made, thus various targeted agents, associated with predictive biomarkers, have been developed or are in development for the treatment of patients with gastrointestinal cancer patients. This review summarizes the advances in the field of molecular biomarkers in tumors of the gastrointestinal tract, with focus on the available NGS platforms that enable comprehensive tumor molecular profile analysis.展开更多
MicroRNAs （miRNAs or miRs） are endogenous non-coding RNAs that negatively regulate gene expres- sion by binding to the 3＇ non-coding regions of target mRNAs, resulting in their cleavage or blocking their translatio...MicroRNAs （miRNAs or miRs） are endogenous non-coding RNAs that negatively regulate gene expres- sion by binding to the 3＇ non-coding regions of target mRNAs, resulting in their cleavage or blocking their translation. miRNAs may have an impact on cell differentiation, proliferation, and survival, and their deregulation can be inclined to diseases and cancers, including thyroid tumors. The purpose of this review is to summarize the existing findings of deregulated miRNAs in different types of thyroid tumors and to exhibit their potential target genes, especially to demonstrate those involved in tumor invasion and metastasis. In addition, new findings of circulating miRNA expres- sion profiles, single nucleotide polymorphism （SNP） in thyroid tumors, and the correlation of somatic mutations with deregulated miRNA expression in thyroid tumors were all included in this review.展开更多
Genome editing using the Cas9 endonuclease of Streptococcus pyogenes has demonstrated unparalleled efficacy and facility for modifying genomes in a wide variety of organisms. Caenorhabditis elegans is one of the most ...Genome editing using the Cas9 endonuclease of Streptococcus pyogenes has demonstrated unparalleled efficacy and facility for modifying genomes in a wide variety of organisms. Caenorhabditis elegans is one of the most convenient multicellular organisms for genetic analysis, and the application of this novel genome editing technique to this organism promises to revolutionize analysis of gene function in the future. CRISPR-Cas9 has been successfully used to generate imprecise insertions and deletions via non-homologous end-joining mechanisms and to create precise mutations by homology-directed repair from donor templates. Key variables are the methods used to deliver the Cas9 endonuclease and the efficiency of the single guide RNAs. CRISPR-Cas9-mediated editing appears to be highly specific in C. elegans, with no reported off-target effects. In this review, 1 briefly summarize recent progress in CRISPR-Cas9-based genome editing in C. elegans, highlighting technical improvements in mutagenesis and mutation detection, and discuss potential future appli- cations of this technique.展开更多
BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers lit...BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers little benefit to individuals.AIM To investigate the clinical outcomes of TP53 and CDH1 mutations in GC.METHODS In this study,202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected.A total of 490 genes were identified using target capture.Through t-test and Wilcoxon rank-sum test,somatic mutations,microsatellite instability,and clinical statistics,including overall survival,were detected,compared,and calculated.RESULTS The mutation rates of 32 genes,including TP53,SPEN,FAT1,and CDH1 exceeded 10%.TP53 mutations had a slightly lower overall occurrence rate(33%).The TP53 mutation rate was significantly higher in advanced stages(stage Ⅲ/Ⅳ)than that in early stages(stage Ⅰ/Ⅱ)(P<0.05).In contrast,CDH1 mutations were significantly associated with diffuse GC.TP53 is related to poor prognosis of advanced-stage tumors;nevertheless,CDH1 corresponds to a diffuse type of cancer.TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms.CONCLUSION Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.展开更多
PROTEUS syndrome is characterized by patchy and progressive overgrowth affecting multiple tissues, including bone, soft tissue, and skin, along with susceptibility to the development oftumors. It was originally descri...PROTEUS syndrome is characterized by patchy and progressive overgrowth affecting multiple tissues, including bone, soft tissue, and skin, along with susceptibility to the development oftumors. It was originally described by Cohen and Hayden in 19791 and named by Wiedmann in 1983.2 The cause of Proteus syndrome is proposed to be a somatic mutation that is lethal in non-mosaic state; cells derived from the mutated cell line carrying this mutation result in anomalies in multiple tissues.3 The clinical manifestations are variable,展开更多
BACKGROUND Tumor-to-tumor metastasis(TTM)is an uncommon condition.Only a few cases of renal cell carcinoma(RCC)as donor tumor of TTM have been reported in literature,and none of these studies have described RCC metast...BACKGROUND Tumor-to-tumor metastasis(TTM)is an uncommon condition.Only a few cases of renal cell carcinoma(RCC)as donor tumor of TTM have been reported in literature,and none of these studies have described RCC metastasizing to synchronous pheochromocytoma(PCC).CASE SUMMARY The patient was a 54-year-old woman who presented with recurrent dull abdominal pain for six months,which was further aggravated for one more month.Enhanced computed tomography revealed a tumor mass in the right kidney and another mass in the left retroperitoneum/adrenal gland.Histopathology and immunochemistry of resected specimens confirmed the diagnosis of clear cell renal cell carcinoma(CCRCC)of the right kidney,and the left retroperitoneum revealed a typical PCC with CCRCC metastasis.Whole exome sequencing revealed the presence of a c.529A>T somatic mutation of the Von Hippel Lindau(VHL)gene in the metastasized CCRCC,which was also present in the primary right kidney CCRCC,as confirmed by Sanger sequencing.No VHL mutation was detected in the PCC or in normal right kidney tissue.Fluorescence in situ hybridization revealed loss of chromosome 3p in both the primary right kidney CCRCC and CCRCC metastasized to PCC in the left kidney.CONCLUSION This is the first case showing metastasis of CCRCC to PCC,thus leading to tumorto-tumor metastasis.展开更多
基金Supported by the National Natural Science Foundation of China(no.82303057)Natural Science Foundation of Hubei Province of China(no.2023AFB521)“Chutian Scholars Program”of Hubei Province of China.
文摘Background:Strong sex disparities have been observed among patients with bladder cancer(BCa).FGFR3 is one of the most frequently mutated genes in bladder cancer,and there are inconsistencies in its frequency in male and female patients.Methods:Here,we conducted a meta-analysis comparing the FGFR3 somatic mutation frequency in men and women among 7351 patients with BCa from 18 cohorts.Results:We showed that female patients had a 1.32 times higher risk of having FGFR3 somatic mutations than males.This difference was attributed to mutations occurring at the 2 most frequently mutated sites,S249 and Y375.Additionally,nonsense mutations were more likely to be found in women,whereas indel/frameshift mutations were almost exclusively found in men;however,no difference was noted for missense mutations.Conclusions:A female sex bias in FGFR3 somatic mutationswas observed in BCa.Well-powered individual participant data analyses addressing the possible confounding effects of other factors(eg,age,ethnicity,smoking status,muscle invasiveness,and molecular subtype),as well as analyses integrating omics and functional investigations,are warranted to further validate and explain the mechanisms of the current findings.
基金supported by National Natural Science Fund of China (No.30871079)National Science Foundation of Jiangsu province (No. BK2007232)
文摘The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect （VSD）. The coding and intron-exon boundary regions of GATA4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms （SNPs） reported in NCBI. Bioinformatics analysis was performed to analyze the possible mechanism by which mutations were linked to VSD. Among those variants, c. 1004C〉A （p.S335X） occurred in the highly conserved domain of GATA4 and generated a termination codon, which led to the production of truncated GATA4. The seven novel heterozygous GATA4 mutations were only identified in cardiac tissues with VSD, suggesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells implies that the genetic contribution to VSD may have been underestimated.
文摘P53 gene mutations have been known to be highly related to the majority of human cancers.The colocation of biologists and bioinformaticians have constructed many databases for cancer research.Although the relationship between the presence of TP53 mutation and cancers has been reported in various studies,few reports TP53 mutation distribution in different functional domains.Hence,we use 2 databases(The TP53 Mutation Database of the International Agency for the Research on Cancer and The Genomic Data Commons data portal)to compare survival rate with and without TP53 mutations in a certain cancer,as well as to find most frequent mutation sites in different functional domains of the TP53 protein.Our study shows that most somatic mutations of TP53 and high mutation rate sites are concentrated in the DNA-binding domain,and the survival of certain cancers varies with and without P53.
基金a grant from the National Natural Science Foundation of China
文摘Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations （SNVs） and somatic insertions and deletions （indels） of SCZ. Methods： One Chinese family with a monozygotic （MZ） twin pair discordant for SCZ was included. Whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. Results： One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. Conclusions： This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.
文摘BACKGROUND Although chronic-phase chronic myeloid leukemia(CP-CML)is treatable and nearly curable in about 50%of patients,accelerated-phase chronic myeloid leukemia(AP-CML)shows concerning drug resistance,while blast crisis chronic myeloid leukemia(BC-CML)is highly lethal.Advances in whole exome sequencing(WES)reveal pan-cancer mutations in BC-CML,supporting mutation-guided therapies beyond Breakpoint cluster region-Abelson.Artificial intelligence(AI)and machine learning(ML)enable genomic stratification and drug repurposing,addressing overlooked actionable mutations.AIM To stratify BC-CML into molecular subtypes using WES,ML,and AI for precision drug repurposing.METHODS Included 123 CML patients(111 CP-CML,5 AP-CML,7 BC-CML).WES identified pan-cancer mutations.Variants annotated via Ensembl Variant Effect Predictor and Catalogue of Somatic Mutations in Cancer(COSMIC).ML(principal component analysis,K-means)stratified BC-CML.COSMIC signatures and PanDrugs prioritized drugs.Analysis of variance/Kruskal-Wallis validated differences(P<0.05).RESULTS In this exploratory,hypothesis-generating study of BC-CML patients(n=7),we detected over 2500 somatic mutations.ML identified three BC-CML clusters:(1)Cluster 1[breast cancer susceptibility gene 2(BRCA2),TP53];(2)Cluster 2[isocitrate dehydrogenase(IDH)1/2,ten-eleven translocation 2];and(3)Cluster 3[Janus kinase(JAK)2,colony-stimulating factor 3 receptor],with distinct COSMIC signatures.Therapies:(1)Polyadenosinediphosphate-ribose polymerase inhibitors(olaparib);(2)IDH inhibitors(ivosidenib);and(3)JAK inhibitors(ruxolitinib).Mutational burden,signatures,and targets varied significantly across clusters,supporting precision stratification.CONCLUSION This WES-AI-ML framework provides mutation-guided therapies for BC-CML,enabling real-time stratification and Food and Drug Administration-approved drug repurposing.While this exploratory study is limited by its small sample size(n=7),it establishes a methodological framework for precision oncology stratification that warrants validation in larger,multi-center cohorts.
文摘The development of rapid genome sequencing has greatly enhanced our understanding of the molecular biology underlying many malignancies.Whole exome sequencing has highlighted the individualistic nature of malignancies on a patient-to-patient basis and begun to revolutionize therapeutic approaches.In recent years,whole genome sequencing of urothelial malignancies has identified a host of somatic mutations which contribute to growth,progression,and metastasis of urothelial carcinoma of the bladder and upper tract urothelial carcinoma.As genetic sequencing continues,additional targets will be identified,allowing development of novel therapeutic agents targeting cancer on a molecular level,with the goal of delivering highly individualized care based on the underlying mutational profile of the patient’s malignancy.In this review,we aim to discuss known genetic alterations of urothelial malignancy and the implications these mutations carry in terms of prognostication and development of targeted therapeutic agents.We will focus on RNA-expression profiling and genomic DNA profiling,with a focus on comprehensive whole exome and whole genome sequencing relative to selected urothelial carcinoma-associated genes and circulating tumor DNA analysis.
基金supported by the Natural Science Foundation of Guangdong Province(2022A1515010297)the National Natural Science Foundation of China(32100765)+1 种基金the Xiamen Medical Health Science and Technology Project(3502Z20194098)the Shenzhen-Hong Kong-Macao Science and Technology Innovation Project(SGDX2020110309280100).
文摘Dear Editor,Sturge-Weber Syndrome(SWS)is a rare congenital neurocutaneous syndrome[1,2],with an estimated prevalence of 0.19 in 100,000 annually[3].It is a non-hereditary disease linked to a somatic mutation in the GNAQ,GNA11,or GNB2 gene[1],leading to vascular malformations in the cutaneous forehead,cerebral cortex,and eye[1,2].Notably,~70%of pediatric patients diagnosed with SWS exhibit brain calcification(BC)[4],though the prevalence of BC ranges from only 1%in young individuals to>20%in the senior population(>60 years old)[5].Similar to the elderly,BC in pediatric SWS patients is identified as vascular calcification[6,7],whereas BC in pediatric patients with tuberous sclerosis and tumors has been previously described as dystrophic calcification[6].
基金supported by the GIBH funds provided by the Chinese Academy of Sciences,the City of Guangzhou and Guangdong Province
文摘Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.
基金Supported by A grant from the Center of Excellence for Cancer Research at Taipei Veterans General,the Ministry of Health and Welfare,No.DOH102-TDC-111-007,Executive Yuana grant from the Ministry of Education,Aim for the Top University Planand grant from the National Science Council,No.NSC101-2320-B-010-068-MY3,Taiwan
文摘Energy metabolism reprogramming was recently identified as one of the cancer hallmarks.One of the underlying mechanisms of energy metabolism reprogramming is mitochondrial dysfunction caused by mutations in nuclear genes or mitochondrial DNA(mtDNA).In the past decades,several types of somatic mtDNA alterations have been identified in gastric cancer.However,the role of these mtDNA alterations in gastric cancer progression remains unclear.In this review,we summarize recently identified somatic mtDNA alterations in gastric cancers as well as the relationship between these alterations and the clinicopathological features of gastric cancer.The causative factors and potential roles of the somatic mtDNA alterations in cancer progression are also discussed.We suggest that point mutations and mtDNA copy number decreases are the two most common mtDNA alterations that result in mitochondrial dysfunction in gastric cancers.The two primary mutation types(transition mutations and mononucleotide or dinucleotide repeat instability)imply potential causative factors.Mitochondrial dysfunction-generated reactive oxygen species may be involved in the malignant changes of gastric cancer.The search for strategies to prevent mtDNA alterations and inhibit the mitochondrial retrograde signaling will benefit the development of novel treatments for gastric cancer and other malignancies.
文摘We described two members in a family with gastrointestinal stromal tumors （GISTs） without cutaneous hyperpigmentation. The patients were father and son who did not have cutaneous hyperpigmentation. Histological examination showed that these tumors were GISTs expressing CD34 and CD117. Tumor DNA extracted from paraffin-embedded specimens revealed somatic mutation with a deletion mutation at different codons in exon 11 of c-kit gene after direct sequencing analysis. No germline mutation was detected in DNA extracted from peripheral leukocytes obtained from the father and son. We propose that GISTs could be caused by sporadic somatic mutation in a family without germline mutation and hyperpigmentation.
文摘The mutation rate is a pivotal biological characteristic,intricately governed by natural selection and historically garnering considerable attention.Recent advances in high-throughput sequencing and analytical methodologies have profoundly transformed our understanding in this domain,ushering in an unprecedented era of mutation rate research.This paper aims to provide a comprehensive overview of the key concepts and methodologies frequently employed in the study of mutation rates.It examines various types of mutations,explores the evolutionary dynamics and associated theories,and synthesizes both classical and contemporary hypotheses.Furthermore,this review comprehensively explores recent advances in understanding germline and somatic mutations in animals and offers an overview of experimental methodologies,mutational patterns,molecular mechanisms,and driving forces influencing variations in mutation rates across species and tissues.Finally,it proposes several potential research directions and pressing questions for future investigations.
文摘Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
文摘Acute myeloid leukemia(AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies have described the molecular landscape of AML and identified several somatic alterations that impact overall survival. Despite all these advancement, several challenges remain in translating this information into effective therapy. Herein we will review the molecular landscape of AML and discuss the impact of the most common somatic mutations on disease biology and outcome.
文摘BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare,non-genetic disorder characterized by multiple gastrointestinal polyps,and ectodermal lesions such as alopecia,fingernail atrophy,and skin mucosal pigmentation.Unfortunately,the pathogenesis of CCS is currently unknown.CASE SUMMARY Here,we describe the case of an elderly female with diarrhea,fatigue,and hair loss,who experienced abdominal pain for over half a year and was found to have multiple gastrointestinal polyps.She was diagnosed with CCS and was treated with albumin supplementation and prednisone,and her electrolyte imbalance was corrected.Following treatment,her symptoms significantly improved.To elucidate the role of potential genetic events in the pathogenesis of CCS,we performed exome sequencing using an extract of her colorectal adenoma.CONCLUSION Our data revealed multiple somatic mutations and copy number variations.Our findings provide a novel insight into the potential mechanisms of CCS etiology.
文摘Gastrointestinal malignancies are among the leading causes of cancer-related deaths worldwide. Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppressor genes or activation of oncogenes. Advances in Molecular Biology techniques have allowed for more accurate analysis of tumors’ genetic profiling using new breakthrough technologies such as next generation sequencing (NGS), leading to the development of targeted therapeutical approaches based upon biomarker-selection. During the last 10 years tremendous advances in the development of targeted therapies for patients with advanced cancer have been made, thus various targeted agents, associated with predictive biomarkers, have been developed or are in development for the treatment of patients with gastrointestinal cancer patients. This review summarizes the advances in the field of molecular biomarkers in tumors of the gastrointestinal tract, with focus on the available NGS platforms that enable comprehensive tumor molecular profile analysis.
基金Project supported by thc National Natural Science Foundation of China （No. 81272935）
文摘MicroRNAs （miRNAs or miRs） are endogenous non-coding RNAs that negatively regulate gene expres- sion by binding to the 3＇ non-coding regions of target mRNAs, resulting in their cleavage or blocking their translation. miRNAs may have an impact on cell differentiation, proliferation, and survival, and their deregulation can be inclined to diseases and cancers, including thyroid tumors. The purpose of this review is to summarize the existing findings of deregulated miRNAs in different types of thyroid tumors and to exhibit their potential target genes, especially to demonstrate those involved in tumor invasion and metastasis. In addition, new findings of circulating miRNA expres- sion profiles, single nucleotide polymorphism （SNP） in thyroid tumors, and the correlation of somatic mutations with deregulated miRNA expression in thyroid tumors were all included in this review.
基金supported by National Institutes of Health (NIH grant R01 GM054657) to A.D.C
文摘Genome editing using the Cas9 endonuclease of Streptococcus pyogenes has demonstrated unparalleled efficacy and facility for modifying genomes in a wide variety of organisms. Caenorhabditis elegans is one of the most convenient multicellular organisms for genetic analysis, and the application of this novel genome editing technique to this organism promises to revolutionize analysis of gene function in the future. CRISPR-Cas9 has been successfully used to generate imprecise insertions and deletions via non-homologous end-joining mechanisms and to create precise mutations by homology-directed repair from donor templates. Key variables are the methods used to deliver the Cas9 endonuclease and the efficiency of the single guide RNAs. CRISPR-Cas9-mediated editing appears to be highly specific in C. elegans, with no reported off-target effects. In this review, 1 briefly summarize recent progress in CRISPR-Cas9-based genome editing in C. elegans, highlighting technical improvements in mutagenesis and mutation detection, and discuss potential future appli- cations of this technique.
基金Supported by Guangdong Yiyang Healthcare Charity Foundation,No.JZ2022014.
文摘BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers little benefit to individuals.AIM To investigate the clinical outcomes of TP53 and CDH1 mutations in GC.METHODS In this study,202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected.A total of 490 genes were identified using target capture.Through t-test and Wilcoxon rank-sum test,somatic mutations,microsatellite instability,and clinical statistics,including overall survival,were detected,compared,and calculated.RESULTS The mutation rates of 32 genes,including TP53,SPEN,FAT1,and CDH1 exceeded 10%.TP53 mutations had a slightly lower overall occurrence rate(33%).The TP53 mutation rate was significantly higher in advanced stages(stage Ⅲ/Ⅳ)than that in early stages(stage Ⅰ/Ⅱ)(P<0.05).In contrast,CDH1 mutations were significantly associated with diffuse GC.TP53 is related to poor prognosis of advanced-stage tumors;nevertheless,CDH1 corresponds to a diffuse type of cancer.TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms.CONCLUSION Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.
文摘PROTEUS syndrome is characterized by patchy and progressive overgrowth affecting multiple tissues, including bone, soft tissue, and skin, along with susceptibility to the development oftumors. It was originally described by Cohen and Hayden in 19791 and named by Wiedmann in 1983.2 The cause of Proteus syndrome is proposed to be a somatic mutation that is lethal in non-mosaic state; cells derived from the mutated cell line carrying this mutation result in anomalies in multiple tissues.3 The clinical manifestations are variable,
基金the National Natural Science Foundation of China,No.NSFC 81872107 and No.NSFC 81872108。
文摘BACKGROUND Tumor-to-tumor metastasis(TTM)is an uncommon condition.Only a few cases of renal cell carcinoma(RCC)as donor tumor of TTM have been reported in literature,and none of these studies have described RCC metastasizing to synchronous pheochromocytoma(PCC).CASE SUMMARY The patient was a 54-year-old woman who presented with recurrent dull abdominal pain for six months,which was further aggravated for one more month.Enhanced computed tomography revealed a tumor mass in the right kidney and another mass in the left retroperitoneum/adrenal gland.Histopathology and immunochemistry of resected specimens confirmed the diagnosis of clear cell renal cell carcinoma(CCRCC)of the right kidney,and the left retroperitoneum revealed a typical PCC with CCRCC metastasis.Whole exome sequencing revealed the presence of a c.529A>T somatic mutation of the Von Hippel Lindau(VHL)gene in the metastasized CCRCC,which was also present in the primary right kidney CCRCC,as confirmed by Sanger sequencing.No VHL mutation was detected in the PCC or in normal right kidney tissue.Fluorescence in situ hybridization revealed loss of chromosome 3p in both the primary right kidney CCRCC and CCRCC metastasized to PCC in the left kidney.CONCLUSION This is the first case showing metastasis of CCRCC to PCC,thus leading to tumorto-tumor metastasis.
