With the development of molecular pathology, many types of epidermal growth factor receptor（EGFR） mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors（EGFR-TKIs） in non-small cell lung c...With the development of molecular pathology, many types of epidermal growth factor receptor（EGFR） mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors（EGFR-TKIs） in non-small cell lung cancer（NSCLC） patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations（co-occurrence of two or more different mutations）, has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate（DCR） was 93.7% with two patients（0.2%） achieving complete response（CR）, the median progression free survival（PFS） was 13.0 months（95% confidence interval [CI], 11.6–14.4 months）, and the median overall survival（OS） was 55.0 months（95% CI, 26.3–83.7 months）. Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858 R mutation（P〈0.001）. Patients with classic mutations（del-19 and/or L858 R mutations） demonstrated longer PFS（P〈0.001） and OS（P=0.017） than those with uncommon mutations（single rare and/or complex mutations）. Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS（hazard ratio [HR]=0.308, 95% CI, 0.191–0.494, P〈0.001） and OS（HR=0.221, 95% CI, 0.101–0.480, P〈0.001）. The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR-TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations（especially for the patients with single rare mutations） are needed to determine a better precision treatment.展开更多
BACKGROUND Gitelman syndrome(GS)is an unusual,autosomal recessive salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis,hypomagnesemia and hypocalciuria.It is caused by mutations in the solute carri...BACKGROUND Gitelman syndrome(GS)is an unusual,autosomal recessive salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis,hypomagnesemia and hypocalciuria.It is caused by mutations in the solute carrier family 12 member 3(SLC12A3)gene resulting in disordered function of the thiazidesensitive NaCl co-transporter.To date,many types of mutations in the SLC12A3 gene have been discovered that trigger different clinical manifestations.Therefore,gene sequencing should be considered before determining the course of treatment for GS patients.CASE SUMMARY A 55-year-old man was admitted to our department due to hand numbness and fatigue.Laboratory tests after admission showed hypokalemia,metabolic alkalosis and renal failure,all of which suggested a diagnosis of GS.Genome sequencing of DNA extracted from the patient’s peripheral blood showed a rare homozygous mutation in the SLC12A3 gene(NM_000339.2:chr16:56903671,Exon4,c.536T>A,p.Val179Asp).This study reports a rare homozygous mutation in SLC12A3 gene of a Chinese patient with GS.CONCLUSION Genetic studies may improve the diagnostic accuracy of Gitelman syndrome and improve genetic counseling for individuals and their families with these types of genetic disorders.展开更多
SMARCA4-deficient non small cell lung cancer (SMARCA4-dNSCLC) has recently garnered increasing attention due to its high malignancy and poor prognosis. The literature suggests that in non small cell lung cancer (NSCLC...SMARCA4-deficient non small cell lung cancer (SMARCA4-dNSCLC) has recently garnered increasing attention due to its high malignancy and poor prognosis. The literature suggests that in non small cell lung cancer (NSCLC), the loss of SMARCA4 frequently co-occurs with mutations in KRAS, KEAP1, and STK11 rather than in EGFR, ALK, and ROS1. Herein, we present the first documented case of SMARCA4-dNSCLC accompanied with rare mutations of EGFR exon 20 S768I and exon 18 G719X. The patient achieved partial response with afatinib for 17 months. Our case highlights the importance of EGFR mutations in the precision targeted treatment of SMARCA4-dNSCLC.展开更多
Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are ...Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are stand-ard care for the patients with these mutations.In this study,we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive patients in a cohort of treatment-naive Chinese LUAD patients and evaluated the sensitivity of rare compound mutations to different EGFR-TKIs in vitro.Material and methods Targeted sequencing covering the hotspot regions of eight LUAD driver genes was per-formed across 853 treatment-naive LUAD patients admitted in Henan Cancer Hospital(HNCH cohort).The mutational landscape of HNCH patients was compared with TCGA patients.Logistic regression analysis was used to determine the factors associated with presence of these mutations.Genetically modified LUAD PC9 cells were established to evaluate the sensitivity of selected EGFR rare compound mutations to different EGFR-TKIs.Results A total of 574 single nucleotide variants(SNVs),270 indels,88 amplifications,and 87 rearrangements were identified in this study,with EGFR and KRAS being the most frequently mutated genes.Females,mostly life-long non-smokers,had significantly higher EGFR mutation rates than males.Males,primarily smokers,more frequently had KRAS mutations.HNCH patients in general had a higher mutation count than TCGA patients(1.09 vs 0.93 mutations per patient(m/p)),in consistent with its higher proportion of patients with advanced disease.Rare EGFR compound mutations identified in this study,including Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873,conferred genetically modified PC9 cells more sensitive to second-generation EGFR-TKI afatinib in-vivo.Conclusion This NGS-based 8-gene test efficiently identified over 70%of Chinese treatment-naive LUAD patients who are targetable for TKIs.Patients with rare EGFR compound mutations might consider second-generation EGFR-TKIs for treatment.展开更多
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 fact...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.展开更多
With the rapid development of lung cancer molecular detection and precisiontherapy, targeted therapy has covered the entire process of diagnosis andtreatment of nonsmall cell lung cancer patients. Overall mortality fr...With the rapid development of lung cancer molecular detection and precisiontherapy, targeted therapy has covered the entire process of diagnosis andtreatment of nonsmall cell lung cancer patients. Overall mortality from lungcancer has decreased significantly over the past 20 years, especially since theintroduction of targeted drugs in 2013. In 2022, targeted therapy for lungcancer has developed rapidly. The optimization of treatment modes and theexploration of new target drugs such as antibody‐drug conjugates will broadenthe selection range of nonsmall cell lung cancer patients with positive drivergenes. This article reviews the latest advances in targeted therapy for drivergene‐positive lung cancer in 2022.展开更多
Next-generation sequencing(NGS),represented by Illumina platforms,has been an essential cornerstone of basic and applied research.However,the sequencing error rate of 1 per 1000 bp(10^(−3))represents a serious hurdle ...Next-generation sequencing(NGS),represented by Illumina platforms,has been an essential cornerstone of basic and applied research.However,the sequencing error rate of 1 per 1000 bp(10^(−3))represents a serious hurdle for research areas focusing on rare mutations,such as somatic mosaicism or microbe heterogeneity.By examining the high-fidelity sequencing methods developed in the past decade,we summarized three major factors underlying errors and the corresponding 12 strategies mitigating these errors.We then proposed a novel framework to classify 11 preexisting representative methods according to the corresponding combinatory strategies and identified three trends that emerged during methodological developments.We further extended this analysis to eight long-read sequencing methods,emphasizing error reduction strategies.Finally,we suggest two promising future directions that could achieve comparable or even higher accuracy with lower costs in both NGS and long-read sequencing.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81372407)Health and Family Planning Scientific Research Project of Hubei Province(No.WJ2017Q007)
文摘With the development of molecular pathology, many types of epidermal growth factor receptor（EGFR） mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors（EGFR-TKIs） in non-small cell lung cancer（NSCLC） patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations（co-occurrence of two or more different mutations）, has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate（DCR） was 93.7% with two patients（0.2%） achieving complete response（CR）, the median progression free survival（PFS） was 13.0 months（95% confidence interval [CI], 11.6–14.4 months）, and the median overall survival（OS） was 55.0 months（95% CI, 26.3–83.7 months）. Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858 R mutation（P〈0.001）. Patients with classic mutations（del-19 and/or L858 R mutations） demonstrated longer PFS（P〈0.001） and OS（P=0.017） than those with uncommon mutations（single rare and/or complex mutations）. Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS（hazard ratio [HR]=0.308, 95% CI, 0.191–0.494, P〈0.001） and OS（HR=0.221, 95% CI, 0.101–0.480, P〈0.001）. The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR-TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations（especially for the patients with single rare mutations） are needed to determine a better precision treatment.
基金Supported by the National Natural Science Foundation of China,No.81700649.
文摘BACKGROUND Gitelman syndrome(GS)is an unusual,autosomal recessive salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis,hypomagnesemia and hypocalciuria.It is caused by mutations in the solute carrier family 12 member 3(SLC12A3)gene resulting in disordered function of the thiazidesensitive NaCl co-transporter.To date,many types of mutations in the SLC12A3 gene have been discovered that trigger different clinical manifestations.Therefore,gene sequencing should be considered before determining the course of treatment for GS patients.CASE SUMMARY A 55-year-old man was admitted to our department due to hand numbness and fatigue.Laboratory tests after admission showed hypokalemia,metabolic alkalosis and renal failure,all of which suggested a diagnosis of GS.Genome sequencing of DNA extracted from the patient’s peripheral blood showed a rare homozygous mutation in the SLC12A3 gene(NM_000339.2:chr16:56903671,Exon4,c.536T>A,p.Val179Asp).This study reports a rare homozygous mutation in SLC12A3 gene of a Chinese patient with GS.CONCLUSION Genetic studies may improve the diagnostic accuracy of Gitelman syndrome and improve genetic counseling for individuals and their families with these types of genetic disorders.
文摘SMARCA4-deficient non small cell lung cancer (SMARCA4-dNSCLC) has recently garnered increasing attention due to its high malignancy and poor prognosis. The literature suggests that in non small cell lung cancer (NSCLC), the loss of SMARCA4 frequently co-occurs with mutations in KRAS, KEAP1, and STK11 rather than in EGFR, ALK, and ROS1. Herein, we present the first documented case of SMARCA4-dNSCLC accompanied with rare mutations of EGFR exon 20 S768I and exon 18 G719X. The patient achieved partial response with afatinib for 17 months. Our case highlights the importance of EGFR mutations in the precision targeted treatment of SMARCA4-dNSCLC.
基金J.Li was supported by Henan Young Researcher training program(HNSWJW-2020007)supported by the Department of Science and Technology of Henan Province(212102310675,201300310400).
文摘Background Lung adenocarcinoma(LUAD)is the most predominant histological subtype of lung cancer character-ized by driver mutations detected in a substantial proportion of the cases.Tyrosine kinase inhibitors(TKIs)are stand-ard care for the patients with these mutations.In this study,we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive patients in a cohort of treatment-naive Chinese LUAD patients and evaluated the sensitivity of rare compound mutations to different EGFR-TKIs in vitro.Material and methods Targeted sequencing covering the hotspot regions of eight LUAD driver genes was per-formed across 853 treatment-naive LUAD patients admitted in Henan Cancer Hospital(HNCH cohort).The mutational landscape of HNCH patients was compared with TCGA patients.Logistic regression analysis was used to determine the factors associated with presence of these mutations.Genetically modified LUAD PC9 cells were established to evaluate the sensitivity of selected EGFR rare compound mutations to different EGFR-TKIs.Results A total of 574 single nucleotide variants(SNVs),270 indels,88 amplifications,and 87 rearrangements were identified in this study,with EGFR and KRAS being the most frequently mutated genes.Females,mostly life-long non-smokers,had significantly higher EGFR mutation rates than males.Males,primarily smokers,more frequently had KRAS mutations.HNCH patients in general had a higher mutation count than TCGA patients(1.09 vs 0.93 mutations per patient(m/p)),in consistent with its higher proportion of patients with advanced disease.Rare EGFR compound mutations identified in this study,including Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873,conferred genetically modified PC9 cells more sensitive to second-generation EGFR-TKI afatinib in-vivo.Conclusion This NGS-based 8-gene test efficiently identified over 70%of Chinese treatment-naive LUAD patients who are targetable for TKIs.Patients with rare EGFR compound mutations might consider second-generation EGFR-TKIs for treatment.
文摘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.
文摘With the rapid development of lung cancer molecular detection and precisiontherapy, targeted therapy has covered the entire process of diagnosis andtreatment of nonsmall cell lung cancer patients. Overall mortality from lungcancer has decreased significantly over the past 20 years, especially since theintroduction of targeted drugs in 2013. In 2022, targeted therapy for lungcancer has developed rapidly. The optimization of treatment modes and theexploration of new target drugs such as antibody‐drug conjugates will broadenthe selection range of nonsmall cell lung cancer patients with positive drivergenes. This article reviews the latest advances in targeted therapy for drivergene‐positive lung cancer in 2022.
基金supported by the Ministry of Agriculture and Rural Affairs of China,the National Key R&D Program of China(Grant No.2019YFA0802600)the Chinese Academy of Sciences(Grant Nos.ZDBS-LY-SM005 and XDPB17)the National Natural Science Foundation of China(Grant No.31970565).
文摘Next-generation sequencing(NGS),represented by Illumina platforms,has been an essential cornerstone of basic and applied research.However,the sequencing error rate of 1 per 1000 bp(10^(−3))represents a serious hurdle for research areas focusing on rare mutations,such as somatic mosaicism or microbe heterogeneity.By examining the high-fidelity sequencing methods developed in the past decade,we summarized three major factors underlying errors and the corresponding 12 strategies mitigating these errors.We then proposed a novel framework to classify 11 preexisting representative methods according to the corresponding combinatory strategies and identified three trends that emerged during methodological developments.We further extended this analysis to eight long-read sequencing methods,emphasizing error reduction strategies.Finally,we suggest two promising future directions that could achieve comparable or even higher accuracy with lower costs in both NGS and long-read sequencing.
