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Identification of novel mutations in and in a family with craniofacial microsomia: evidence of digenic

《医学前沿（英文）》   页码 1006-1009 doi: 10.1007/s11684-023-1000-3

摘要： Identification of novel mutations in and in a family with craniofacial microsomia: evidence of digenic inheritance

关键词： family craniofacial microsomia     Identification novel mutations    

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Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future

《医学前沿（英文）》 2023年 第17卷 第1期   页码 18-42 doi: 10.1007/s11684-022-0976-4

摘要： With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.

关键词： non-small cell lung cancer     driver mutations     treatment strategy     resistant mechanism     immune-checkpoint inhibitors    

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Characteristics of compensatory mutations in the

Shengfen Wang, Yang Zhou, Bing Zhao, Xichao Ou, Hui Xia, Yang Zheng, Yuanyuan Song, Qian Cheng, Xinyang Wang, Yanlin Zhao

《医学前沿（英文）》 2020年 第14卷 第1期   页码 51-59 doi: 10.1007/s11684-019-0720-x

摘要： The aim of this study was to characterize gene mutations in (MTB) and investigate the factors associated with mutations and the relation between mutations and tuberculosis (TB) transmission. A total of 245 MTB clinical isolates from patients with TB in six provinces and two municipalities in China were characterized based on gene mutations through DNA sequencing of and genes, phenotyping via standard drug susceptibility testing, and genotypic profiling by mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing. Approximately 36.4% of the rifampin-resistant isolates harbored nonsynonymous mutations in the gene. Twenty-nine nonsynonymous single mutations and three double mutations were identified. The mutations at locus 483 (11.3%) were predominant, and the mutations at V483G, W484G, I491V, L516P, L566R, N698K, and A788E accounted for 54.5% of the total detected mutations. Fifteen new mutations in the gene were identified. Rifampin resistance and mutations at locus 531 were significantly associated with mutations. MIRU-VNTR genotype results indicated that 18.4% of the studied isolates were clustered, and the mutations were not significantly associated with MIRU-VNTR clusters. A large proportion of mutation was observed in the rifampicin-resistant MTB isolates. However, the findings of this study do not support the association of mutation with compensated transmissibility.

关键词： tuberculosis     drug resistance     compensatory mutations     transmission    

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122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations

null

《医学前沿（英文）》 2014年 第8卷 第2期   页码 217-226 doi: 10.1007/s11684-014-0326-2

摘要：

This study was designed to investigate the contribution of miRNA-122-binding site polymorphism at the IL-1A gene and its multiplicative interactions with hepatitis B virus (HBV) mutations in the risk of hepatocellular carcinoma (HCC). A total of 1021 healthy controls, 302 HBV surface antigen (HBsAg) seroclearance subjects, and 2011 HBsAg-positive subjects (including 1021 HCC patients) were enrolled in this study. Quantitative PCR was used to genotype rs3783553. HBV mutations were determined by direct sequencing. Multivariate logistic regression analyses were performed to test the associations of rs3783553, mutations, and their interactions with the risk of HCC. No significant association was found between rs3783553 and the risk of HCC among healthy controls, HBsAg seroclearance subjects, HBsAg-positive subjects without HCC, and all controls. Additionally, rs3783553 was not significantly associated with chronic HBV infection, liver cirrhosis, HBV e antigen seroconversion, abnormal alanine aminotransferase, and high viral load (>104 copies/ml). However, the TTCA insertion allele of rs3783553 was significantly associated with an increased frequency of HBV C7A mutation compared with homozygous TTCA deletion carriers [(del/ins+ ins/ins) vs. del/del, adjusted odds ratio (OR)=1.48, 95% confidence interval (CI)=1.09-2.02, P=0.013]. Multiplicative interaction of rs3783553 with HBV preS deletion significantly reduced the risk of HCC in males, with an adjusted OR of 0.64 (95% CI=0.42-0.98; P=0.041) after age and HBV genotype were adjusted. Although rs3783553 did not significantly affect genetic susceptibility to HBV-related HCC, its variant allele may predispose the host to selecting HBV C7A mutation during evolution and significantly reduce the risk of HCC caused by HBV preS deletion. This study provides an insight into the complex host-virus interaction in HBV-induced hepatocarcinogenesis and is helpful in determining HBsAg-positive subjects who are likely to develop HCC.

关键词： hepatocellular carcinoma (HCC)     interaction     miRNA-122-binding site     IL-1A     rs3783553     hepatitis B virus (HBV) mutations    

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Distinct gene expression pattern of mutations coordinated by target repression and promoter hypermethylation

《医学前沿（英文）》 2022年 第16卷 第4期   页码 627-636 doi: 10.1007/s11684-020-0815-4

摘要： Runt-related transcription factor 1 (RUNX1) is an essential regulator of normal hematopoiesis. Its dysfunction, caused by either fusions or mutations, is frequently reported in acute myeloid leukemia (AML). However, RUNX1 mutations have been largely under-explored compared with RUNX1 fusions mainly due to their elusive genetic characteristics. Here, based on 1741 patients with AML, we report a unique expression pattern associated with RUNX1 mutations in AML. This expression pattern was coordinated by target repression and promoter hypermethylation. We first reanalyzed a joint AML cohort that consisted of three public cohorts and found that RUNX1 mutations were mainly distributed in the Runt domain and almost mutually exclusive with NPM1 mutations. Then, based on RNA-seq data from The Cancer Genome Atlas AML cohort, we developed a 300-gene signature that significantly distinguished the patients with RUNX1 mutations from those with other AML subtypes. Furthermore, we explored the mechanisms underlying this signature from the transcriptional and epigenetic levels. Using chromatin immunoprecipitation sequencing data, we found that RUNX1 target genes tended to be repressed in patients with RUNX1 mutations. Through the integration of DNA methylation array data, we illustrated that hypermethylation on the promoter regions of RUNX1-regulated genes also contributed to dysregulation in RUNX1-mutated AML. This study revealed the distinct gene expression pattern of RUNX1 mutations and the underlying mechanisms in AML development.

关键词： RUNX1     gene mutation     acute myeloid leukemia     transcriptional repression     DNA methylation    

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宿主微生物组内的基因组突变——适应性进化或净化选择 Review

张家超, Rob Knight

《工程（英文）》 2023年 第20卷 第1期   页码 96-102 doi: 10.1016/j.eng.2021.11.018

摘要：

二代测序技术转变了人们评估宿主相关微生物区系和微生物组的分类组成功能的能力。未来10 年将会开展更多的人类微生物组研究，特别是那些探索微生物组内基因组突变的研究。本文聚焦于微生物组内菌株之间的共同进化，塑造了宿主肠道微生物种内和种间的菌株水平多样性。还探讨了微生物基因组突变与常见代谢疾病之间的关联，以及病原体和益生菌在入侵和定植过程中的适应性进化。最后，讨论了注释和分析微生物基因组突变方法和算法的研究进展。

关键词： 肠道菌群     基因组突变     适应性进化     净化选择     单核苷酸变异    

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Association of novel mutations and heplotypes in the preS region of hepatitis B virus with hepatocellular

Jia-Xin XIE, Jian-Hua YIN, Qi ZHANG, Rui PU, Wen-Ying LU, Hong-Wei ZHANG, Guang-Wen CAO, Jun ZHAO, Hong-Yang WANG,

《医学前沿（英文）》 2010年 第4卷 第4期   页码 419-429 doi: 10.1007/s11684-010-0160-0

摘要： The association of viral mutations and haplotypic carriages with mutations in the preS region of hepatitis B virus (HBV) genotypes B and C with hepatocellular carcinoma (HCC) is of great significance for the prediction of this malignancy, but it remains obscure. We analyzed the preS sequences of HBV genotypes B and C from 1172 HBV-infected subjects including 231 patients with HCC. As compared with the HBV-infected subjects without HCC, C2875T, G2946C, A3054C, C3060A, T3066C, C3116T, A3120C, G3191A, A1C, C7A, C10A, A31C, C76T, G105C, and G147C in both genotypes were significantly associated with increased risks of HCC. C2875A, G2950A, G2951A, A3054T, C3060T, T3066A, T3069G, A3120T, and G3191C were significantly associated with increased risks of HCC in genotype C, whereas these mutations were inversely associated with HCC in genotype B. Multivariate regression analyses showed that C76A/T was a novel factor independently associated with an increased risk of HCC, as compared with those without HCC. The frequencies of haplotypes 2964A-3116T-preS2 start codon wild-type-7C, 2964C-3116T-7A-76C, and 2964A-3116T-7C-76A/T were significantly higher in the patients with HCC (<0.001), whereas a haplotypic carriage with a single mutation and another three wild-types were inversely associated with HCC. Conclusively, the association of HBV mutations in the preS region with HCC depends on HBV genotype and haplotypic carriage with two or more mutations that are each associated with an increased risk of HCC independently.

关键词： hepatitis B virus     hepatocellular carcinoma     mutation     genotype     haplotype    

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Molecular pathogenesis of acute myeloid leukemia: A diverse disease with new perspectives

Felicitas THOL, Arnold GANSER

《医学前沿（英文）》 2010年 第4卷 第4期   页码 356-362 doi: 10.1007/s11684-010-0220-5

摘要： Acute myeloid leukemia (AML) is a very heterogeneous neoplasm of the hematopoietic stem cell. Despite important achievements in the treatment of AML, the long term survival of patients with the disease remains poor. Understanding the pathogenesis of AML better is crucial for finding new treatment approaches. During AML development hematopoietic precursor cells undergo clonal transformation in a multistep process through acquisition of chromosomal rearrangements and/or different gene mutations. Over recent years, novel gene mutations have been found in patients with AML. These mutations can be divided into two important categories, class I mutations that confer a proliferation advantage and class II mutations that inhibit myeloid differentiation. Screening for some of these mutations is now part of the initial diagnostic work-up in newly diagnosed AML patients. Information about the mutation status of specific genes is useful for risk-stratification, minimal residual disease (MRD) monitoring and increasingly also for targeted therapy, especially for patients with cytogenetically normal AML (CN-AML). Besides chromosomal rearrangements and gene mutations, epigenetic regulation of genes – meaning changes in gene expression by mechanisms other than changes in the underlying DNA sequence – also represents an important mechanism of leukemogenesis. This article reviews some of the most common mutations in CN-AML and gives a perspective of the translation of these discoveries from bench to bedside.

关键词： acute myeloid leukemia     mutations     risk stratification    

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Genetic evidence in planar cell polarity signaling pathway in human neural tube defects

null

《医学前沿（英文）》 2014年 第8卷 第1期   页码 68-78 doi: 10.1007/s11684-014-0308-4

摘要：

Neural tube defects (NTDs) are a group of birth anomalies having a profound physical, emotional, and financial effects on families and communities. Their etiology is complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure and has been implicated in the pathogenesis of NTDs in animal models and human cohorts. This review summarizes the cumulative results of recent studies on PCP signaling pathway and human NTDs. These results demonstrate that PCP gene alterations contribute to the etiology of human NTDs.

关键词： planar cell polarity     neural tube defects     rare mutations    

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Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Jianfeng Li, Yuting Dai, Liang Wu, Ming Zhang, Wen Ouyang, Jinyan Huang, Saijuan Chen

《医学前沿（英文）》 2021年 第15卷 第3期   页码 347-371 doi: 10.1007/s11684-020-0821-6

摘要： B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as rearrangements, rearrangements, rearrangements, rearrangements, / and/or rearrangements, like gene expression, PAX5alt (diverse alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

关键词： BCP-ALL     subtypes     translocation     aneuploidy     sequence mutations    

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Research progress on human infection with avian influenza H7N9

Xiaoxin Wu, Lanlan Xiao, Lanjuan Li

《医学前沿（英文）》 2020年 第14卷 第1期   页码 8-20 doi: 10.1007/s11684-020-0739-z

摘要： Since the first case of novel H7N9 infection was reported, China has experienced five epidemics of H7N9. During the fifth wave, a highly pathogenic H7N9 strain emerged. Meanwhile, the H7N9 virus continues to accumulate mutations, and its affinity for the human respiratory epithelial sialic acid 2-6 receptor has increased. Therefore, a pandemic is still possible. In the past 6 years, we have accumulated rich experience in dealing with H7N9, especially in terms of virus tracing, epidemiological research, key site mutation monitoring, critical disease mechanisms, clinical treatment, and vaccine development. In the research fields above, significant progress has been made to effectively control the spread of the epidemic and reduce the fatality rate. To fully document the research progress concerning H7N9, we reviewed the clinical and epidemiological characteristics of H7N9, the key gene mutations of the virus, and H7N9 vaccine, thus providing a scientific basis for further monitoring and prevention of H7N9 influenza epidemics.

关键词： H7N9     pandemic     epidemiology     mutations     vaccine     influenza    

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Clinical characterization and diagnosis of cystic fibrosis through exome sequencing in Chinese infants with Bartter-syndrome-like hypokalemia alkalosis

Liru Qiu, Fengjie Yang, Yonghua He, Huiqing Yuan, Jianhua Zhou

《医学前沿（英文）》 2018年 第12卷 第5期   页码 550-558 doi: 10.1007/s11684-017-0567-y

摘要：

Cystic fibrosis (CF) is a fatal autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by recurrent pulmonary infection with obstructive pulmonary disease. CF is common in the Caucasian population but is rare in the Chinese population. The symptoms of early-stage CF are often untypical and may sometimes manifest as Bartter syndrome (BS)-like hypokalemic alkalosis. Therefore, the ability of doctors to differentiate CF from BS-like hypokalemic alkalosis in Chinese infants is a great challenge in the timely and accurate diagnosis of CF. In China, sporadic CF has not been diagnosed in children younger than three years of age to date. Three infants, who were initially admitted to our hospital over the period of June 2013 to September 2014 with BS-like hypokalemic alkalosis, were diagnosed with CF through exome sequencing and sweat chloride measurement. The compound heterozygous mutations of the CFTR gene were detected in two infants, and a homozygous missense mutation was found in one infant. Among the six identified mutations, two are novel point mutations (c.1526G>C and c.3062C>T) that are possibly pathogenic. The three infants are the youngest Chinese patients to have been diagnosed with sporadic CF at a very early stage. Follow-up examination showed that all of the cases remained symptom-free after early intervention, indicating the potential benefit of very early diagnosis and timely intervention in children with CF. Our results demonstrate the necessity of distinguishing CF from BS in Chinese infants with hypokalemic alkalosis and the significant diagnostic value of powerful exome sequencing for rare genetic diseases. Furthermore, our findings expand the CFTR mutation spectrum associated with CF.

关键词： cystic fibrosis     pseudo-Bartter syndrome     hypokalemic alkalosis     CFTR gene     mutations     infants     diagnosis    

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标题 作者 时间 类型 操作

Identification of novel mutations in and in a family with craniofacial microsomia: evidence of digenic

期刊论文

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future

期刊论文

Characteristics of compensatory mutations in the

Shengfen Wang, Yang Zhou, Bing Zhao, Xichao Ou, Hui Xia, Yang Zheng, Yuanyuan Song, Qian Cheng, Xinyang Wang, Yanlin Zhao

期刊论文

122-binding site polymorphism at the interleukin-1 α gene and its interaction with hepatitis B virus mutations

null

期刊论文

Distinct gene expression pattern of mutations coordinated by target repression and promoter hypermethylation

期刊论文

宿主微生物组内的基因组突变——适应性进化或净化选择

张家超, Rob Knight

期刊论文

Association of novel mutations and heplotypes in the preS region of hepatitis B virus with hepatocellular

Jia-Xin XIE, Jian-Hua YIN, Qi ZHANG, Rui PU, Wen-Ying LU, Hong-Wei ZHANG, Guang-Wen CAO, Jun ZHAO, Hong-Yang WANG,

期刊论文

Molecular pathogenesis of acute myeloid leukemia: A diverse disease with new perspectives

Felicitas THOL, Arnold GANSER

期刊论文

Genetic evidence in planar cell polarity signaling pathway in human neural tube defects

null

期刊论文

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Jianfeng Li, Yuting Dai, Liang Wu, Ming Zhang, Wen Ouyang, Jinyan Huang, Saijuan Chen

期刊论文

Research progress on human infection with avian influenza H7N9

Xiaoxin Wu, Lanlan Xiao, Lanjuan Li

期刊论文

Clinical characterization and diagnosis of cystic fibrosis through exome sequencing in Chinese infants with Bartter-syndrome-like hypokalemia alkalosis

Liru Qiu, Fengjie Yang, Yonghua He, Huiqing Yuan, Jianhua Zhou

期刊论文