The period-3 behaviors of 105 exons from 20 genes in human were studied by Fourier power spectrum. The results indicated that not all exons show the period-3 behavior. The exons were adjusted in order to make them acc...The period-3 behaviors of 105 exons from 20 genes in human were studied by Fourier power spectrum. The results indicated that not all exons show the period-3 behavior. The exons were adjusted in order to make them accord with the order of the protein translated, and we found that the period-3 character is relation to the length of exons and the bases distribution in the three codon position. Furthermore, as long as the exons with period-3 behavior accord with the order of protein translated, they would exhibit the synonymous codons usage preference, and the codons with g/c at the third position are used in higher frequency. The results are significant to the gene prediction and the research on the introns.展开更多
In this study,three weight vectors L1,L2 and L3 were set.After calculating the probability of three bases in the exons or introns in the genomic DNA of Arabidopsis thaliana,64-dimensional vector P was obtained.Dot pro...In this study,three weight vectors L1,L2 and L3 were set.After calculating the probability of three bases in the exons or introns in the genomic DNA of Arabidopsis thaliana,64-dimensional vector P was obtained.Dot products of P vector and three weight vectors were the feature coordinates for the exons and introns in 3-dimensional phase space.The expression for the interface between the exons and the introns in the genomic DNA of Arabidopsis thaliana in 3-dimensional phase space was established,which could be used to distinguish the exons and the introns in the genomic DNA of Arabidopsis thaliana with an accuracy higher than85%in 3-dimensional phase space.展开更多
Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase in...Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patients with EGFR 19 del and 19 with L858 R mutations were analyzed by NGS,and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.Conclusions:Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858 R mutations.Whether the heterogeneity of tumors with EGFR 19 del and L858 R mutations contribute to a therapeutic response difference needs further investigation.展开更多
Summary: To examine the deletion and point mutation of WWOX (WW domain containing oxidoreductase) exons 6-8 in human non-small cell lung cancer and their possible relationship with pathological stages, tumor tissues ...Summary: To examine the deletion and point mutation of WWOX (WW domain containing oxidoreductase) exons 6-8 in human non-small cell lung cancer and their possible relationship with pathological stages, tumor tissues and the corresponding normal tissues were obtained from 44 Chinese patients who had undergone surgery for non-small cell lung cancer. RNA was extracted from each sample and deletion and mutation of WWOX exons 6-8 were analyzed by RT-PCR and DNA sequencing. Our results showed that 28 of 44 (63.6 %) lung cancer samples showed loss of WWOX exons 6-8 transcript and the deletion was detected in only 3 of 44 (6.8 %) corresponding adjacent normal tissues (P<0.05). The transcript sequencing analyses of the 16 lung cancer samples without transcript loss of WWOX exons 6-8 revealed no difference from the sequence of GenBank. Moreover, the deletion of WWOX exons 6-8 was significantly higher in the smokers when compared with the non-smokers. It is also higher in the men and squamous carcinomas than in women and adenocarcinomas (P<0.05). The deletion, however, was not found to be associated with pathological stages of the tumors. Our study documented a high incidence of deletion of WWOX exons 6-8 in non-small cell lung cancer in Chinese patients and suggested that the frequent loss of WWOX exons 6-8 might play an important role in the tumorigenesis of non-small cell lung cancer in Chinese. WWOX exons 6-8 may serves as a candidate molecular target of smoking carcinogenesis, and point mutation is not a predominant way of alteration of WWOX exons 6-8.展开更多
BACKGROUND For patients with advanced gastrointestinal stromal tumors(GISTs)carrying the ckit exon 11 mutation,imatinib(IM)at a standard dosage of 400 mg per day is the preferred first-line treatment.In cases where tr...BACKGROUND For patients with advanced gastrointestinal stromal tumors(GISTs)carrying the ckit exon 11 mutation,imatinib(IM)at a standard dosage of 400 mg per day is the preferred first-line treatment.In cases where treatment with IM fails,there is an urgent need for a more precise assessment method to determine whether to switch therapies or escalate the IM dosage.This approach will enhance clinical decision-making and optimize patient outcomes.AIM To investigate IM plasma concentration’s role in second-line treatment decisions for c-kit 11-mutated advanced GISTs post-IM failure.METHODS Patients with advanced GIST harboring c-kit 11 mutation who experienced failure with IM 400 mg per day as first-line treatment at our hospital were retrospectively analyzed.Patients were categorized into a low plasma(LP)concentration group(LP group,<1100 ng/mL)and high plasma(HP)concentration group(HP group,≥1100 ng/mL).Each group was further subdivided into Group A(dose-escalation group)and Group B(drug-switch group).Baseline characteristics were compared and Kaplan-Meier curves were used to analyze the survival of patients.RESULTS Seventy-five patients were included in the analysis.For the LP group(n=28),Group A(n=14)had longer overall survival(OS)than Group B(n=14)(P=0.02).No differences were observed between the two subgroups in disease control rate(DCR),objective response rate,and progression-free survival(PFS)(P>0.05).For the HP group(n=47),Group B(n=18)had a higher DCR and longer PFS than Group A(n=29)(P=0.008 and P=0.03,respectively).No difference in OS was observed between the two subgroups(P>0.05).CONCLUSION Increasing IM dosage for c-kit 11-mutated advanced GISTs post-IM failure may prolong OS if plasma concentration is<1100 ng/mL.Switching tyrosine kinase inhibitors may improve DCR and PFS if≥1100 ng/mL.展开更多
Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significant...Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.展开更多
The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)pre-mRNAs.We recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after...The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)pre-mRNAs.We recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after nonsense-associated altered splicing(NAS)events.Remarkably,the expression of these truncated Ig polypeptides heightens endoplasmic reticulum stress and shortens plasma cell(PC)lifespan.Many questions remain regarding the molecular mechanisms underlying this new truncated Ig exclusion(TIE-)checkpoint and its restriction to the ultimate stage of B-cell differentiation.To address these issues,we evaluated the extent of NAS of Ig pre-mRNAs using an Ig heavy chain(IgH)knock-in model that allows for uncoupling of V exon skipping from TIE-induced apoptosis.We found high levels of V exon skipping in PCs compared with B cells,and this skipping was correlated with a biallelic boost in IgH transcription during PC differentiation.Chromatin analysis further revealed that the skipped V exon turned into a pseudo-intron.Finally,we showed that hypertranscription of Ig genes facilitated V exon skipping upon passive administration of splice-switching antisense oligonucleotides(ASOs).Thus,V exon skipping is coupled to transcription and increases as PC differentiation proceeds,likely explaining the late occurrence of the TIE-checkpoint and opening new avenues for ASO-mediated strategies in PC disorders.展开更多
To isolate the novel genes related to human hepatocellular carcinoma (HCC), we sequenced P1-derived artificial chromosome PAC579 (D17S926 locus) mapped in the minimum LOH (loss of heterozygosity) deletion region of ch...To isolate the novel genes related to human hepatocellular carcinoma (HCC), we sequenced P1-derived artificial chromosome PAC579 (D17S926 locus) mapped in the minimum LOH (loss of heterozygosity) deletion region of chromosome 17p13.3 in HCC, Four novel genes mapped in this genomic sequence area were isolated and cloned by wet-lab experiments, and the exons of these genes were located. 0-60 kb of this genomic sequence including the genes of interest was scanned with five different computational exon prediction programs as well as four splice site recognition programs. After analyzing and comparing the computationally predicted results with the wet-lab experiment results, some potential exons were predicted in the genomic sequence by using these programs.展开更多
CRISPR/Cas9 technology is a powerful genome manipulation tool in insects.However,little is known about whether mRNA and protein of a target gene are completely cleared in homozygous mutants.This study generated homozy...CRISPR/Cas9 technology is a powerful genome manipulation tool in insects.However,little is known about whether mRNA and protein of a target gene are completely cleared in homozygous mutants.This study generated homozygous mutants of the insulin receptor gene 2(NlInR2)in the brown planthopper(Nilaparvata lugens)using CRISPR/Cas9 genome editing.Both frameshift mutants,E5_D17 and E6_I7,differentiated towards long wings,but there were differences in wing morphology,with E5_D17 showing wing deformities.Subsequent investigations revealed the presence of residual expression of NlInR2 mRNA in both mutants,as well as the occurrence of spliceosomes featuring exon skipping splicing in E5_D17.Additionally,the E5_D17 exhibited the detection of N-terminally truncated NlInR2 protein.RNA interference experiments indicated that the knockdown of NlInR2 expression in the E5_D17 mutant line increased the proportion of wing deformities from 11.1 to 65.6%,suggesting that the residual NlInR2 mRNA of the E5_D17 mutant might have retained some genetic functions.Our results imply that systematic characterization of residual protein expression or function in CRISPR/Cas9-generated mutant lines is necessary for phenotypic interpretation.展开更多
基金This work was supported by the National Natural Science Foundation of China(Grants 20475068)the Natural Science Foundation of Guangdong Province(Contact No.031577)the Opening Foundation of State Key Laboratory of Chem/Biosensing and Chemometrics of Hunan University(2003).
文摘The period-3 behaviors of 105 exons from 20 genes in human were studied by Fourier power spectrum. The results indicated that not all exons show the period-3 behavior. The exons were adjusted in order to make them accord with the order of the protein translated, and we found that the period-3 character is relation to the length of exons and the bases distribution in the three codon position. Furthermore, as long as the exons with period-3 behavior accord with the order of protein translated, they would exhibit the synonymous codons usage preference, and the codons with g/c at the third position are used in higher frequency. The results are significant to the gene prediction and the research on the introns.
基金Supported by Eleventh Five-Year Development Planning For Instructional Science in Hubei Province(2006B131)
文摘In this study,three weight vectors L1,L2 and L3 were set.After calculating the probability of three bases in the exons or introns in the genomic DNA of Arabidopsis thaliana,64-dimensional vector P was obtained.Dot products of P vector and three weight vectors were the feature coordinates for the exons and introns in 3-dimensional phase space.The expression for the interface between the exons and the introns in the genomic DNA of Arabidopsis thaliana in 3-dimensional phase space was established,which could be used to distinguish the exons and the introns in the genomic DNA of Arabidopsis thaliana with an accuracy higher than85%in 3-dimensional phase space.
基金supported by grants from the National Natural Sciences Foundation Key Program(No.81330062)Education Ministry Innovative Research Team Program(No.IRT13003)+1 种基金Peking University-Tsinghua University Joint Center for Life Sciences Clinical Investigator,National High Technology Research and Development Program 863(No.SS2015AA020403)Beijing Technology Project(No.Z141100000214013)
文摘Background:Epidermal growth factor receptor(EGFR) mutations,including a known exon 19 deletion(19 del) and exon 21 L858 R point mutation(L858R mutation),are strong predictors of the response to EGFR tyrosine kinase inhibitor(EGFR-TKI) treatment in lung adenocarcinoma.However,whether patients carrying EGFR 19 del and L858 R mutations exhibit different responsiveness to EGFR-TKls and what are the potential mechanism for this difference remain controversial.This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858 R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.Methods:Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858 R mutations,532 received EGFR-TKI treatment and were included in this study.EGFR 19 del and L858 R mutations were detected by using denaturing high-performance liquid chromatography(DHPLC).T790 M mutation,which is a common resistant mutation on exon 20 of EGFR,was detected by amplification refractory mutation system(ARMS).Next-generation sequencing(NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858 R mutations.Results:Of the 532 patients,319(60.0%) had EGFR 19 del,and 213(40.0%) had L858 R mutations.The patients with EGFR 19 del presented a significantly higher overall response rate(ORR) for EGFR-TKI treatment(55.2%vs.43.7%,P = 0.017) and had a longer progression-free survival(PFS) after first-line EGFR-TKI treatment(14.4 vs.11.4 months,P = 0.034) compared with those with L858 R mutations.However,no statistically significant difference in overall survival(OS) was observed between the two groups of patients.T790 M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment,and there was no significant difference in the co-existence of T790 M mutation with EGFR 19 del and L858 R mutations before EGFR-TKI treatment(5.6%vs.8.8%,P = 0.554)or after treatment(24.4%vs.35.4%,P = 0.176).In addition,24 patients with EGFR 19 del and 19 with L858 R mutations were analyzed by NGS,and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.Conclusions:Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858 R mutations.Whether the heterogeneity of tumors with EGFR 19 del and L858 R mutations contribute to a therapeutic response difference needs further investigation.
文摘Summary: To examine the deletion and point mutation of WWOX (WW domain containing oxidoreductase) exons 6-8 in human non-small cell lung cancer and their possible relationship with pathological stages, tumor tissues and the corresponding normal tissues were obtained from 44 Chinese patients who had undergone surgery for non-small cell lung cancer. RNA was extracted from each sample and deletion and mutation of WWOX exons 6-8 were analyzed by RT-PCR and DNA sequencing. Our results showed that 28 of 44 (63.6 %) lung cancer samples showed loss of WWOX exons 6-8 transcript and the deletion was detected in only 3 of 44 (6.8 %) corresponding adjacent normal tissues (P<0.05). The transcript sequencing analyses of the 16 lung cancer samples without transcript loss of WWOX exons 6-8 revealed no difference from the sequence of GenBank. Moreover, the deletion of WWOX exons 6-8 was significantly higher in the smokers when compared with the non-smokers. It is also higher in the men and squamous carcinomas than in women and adenocarcinomas (P<0.05). The deletion, however, was not found to be associated with pathological stages of the tumors. Our study documented a high incidence of deletion of WWOX exons 6-8 in non-small cell lung cancer in Chinese patients and suggested that the frequent loss of WWOX exons 6-8 might play an important role in the tumorigenesis of non-small cell lung cancer in Chinese. WWOX exons 6-8 may serves as a candidate molecular target of smoking carcinogenesis, and point mutation is not a predominant way of alteration of WWOX exons 6-8.
文摘BACKGROUND For patients with advanced gastrointestinal stromal tumors(GISTs)carrying the ckit exon 11 mutation,imatinib(IM)at a standard dosage of 400 mg per day is the preferred first-line treatment.In cases where treatment with IM fails,there is an urgent need for a more precise assessment method to determine whether to switch therapies or escalate the IM dosage.This approach will enhance clinical decision-making and optimize patient outcomes.AIM To investigate IM plasma concentration’s role in second-line treatment decisions for c-kit 11-mutated advanced GISTs post-IM failure.METHODS Patients with advanced GIST harboring c-kit 11 mutation who experienced failure with IM 400 mg per day as first-line treatment at our hospital were retrospectively analyzed.Patients were categorized into a low plasma(LP)concentration group(LP group,<1100 ng/mL)and high plasma(HP)concentration group(HP group,≥1100 ng/mL).Each group was further subdivided into Group A(dose-escalation group)and Group B(drug-switch group).Baseline characteristics were compared and Kaplan-Meier curves were used to analyze the survival of patients.RESULTS Seventy-five patients were included in the analysis.For the LP group(n=28),Group A(n=14)had longer overall survival(OS)than Group B(n=14)(P=0.02).No differences were observed between the two subgroups in disease control rate(DCR),objective response rate,and progression-free survival(PFS)(P>0.05).For the HP group(n=47),Group B(n=18)had a higher DCR and longer PFS than Group A(n=29)(P=0.008 and P=0.03,respectively).No difference in OS was observed between the two subgroups(P>0.05).CONCLUSION Increasing IM dosage for c-kit 11-mutated advanced GISTs post-IM failure may prolong OS if plasma concentration is<1100 ng/mL.Switching tyrosine kinase inhibitors may improve DCR and PFS if≥1100 ng/mL.
文摘Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.
基金supported by grants from Fondation ARC(PJA 20161204724/PGA120150202338)INCa(PLBIO15-256)+3 种基金ANR(2017-CE15-0024-01)Ligue Contre le Cancer(comites Correze,Haute-Vienne)Fondation Française pour la Recherche contre le Myelome et les Gammapathies monoclonales(FFRMG)Comited’Organisation de la Recherche sur le Cancer du Limousin(CORC).
文摘The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)pre-mRNAs.We recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after nonsense-associated altered splicing(NAS)events.Remarkably,the expression of these truncated Ig polypeptides heightens endoplasmic reticulum stress and shortens plasma cell(PC)lifespan.Many questions remain regarding the molecular mechanisms underlying this new truncated Ig exclusion(TIE-)checkpoint and its restriction to the ultimate stage of B-cell differentiation.To address these issues,we evaluated the extent of NAS of Ig pre-mRNAs using an Ig heavy chain(IgH)knock-in model that allows for uncoupling of V exon skipping from TIE-induced apoptosis.We found high levels of V exon skipping in PCs compared with B cells,and this skipping was correlated with a biallelic boost in IgH transcription during PC differentiation.Chromatin analysis further revealed that the skipped V exon turned into a pseudo-intron.Finally,we showed that hypertranscription of Ig genes facilitated V exon skipping upon passive administration of splice-switching antisense oligonucleotides(ASOs).Thus,V exon skipping is coupled to transcription and increases as PC differentiation proceeds,likely explaining the late occurrence of the TIE-checkpoint and opening new avenues for ASO-mediated strategies in PC disorders.
基金The authors would like to thank Shanghai Genecore Company for finishing all the sequencing work.Thanks are due to Dr. Sun Fenyong, Dr. Ren Gongyi and Dr. Han Liwei for their excellent experimental work. Thanks also go to Prof. Gu Xiaocheng, Luo Jingchu
文摘To isolate the novel genes related to human hepatocellular carcinoma (HCC), we sequenced P1-derived artificial chromosome PAC579 (D17S926 locus) mapped in the minimum LOH (loss of heterozygosity) deletion region of chromosome 17p13.3 in HCC, Four novel genes mapped in this genomic sequence area were isolated and cloned by wet-lab experiments, and the exons of these genes were located. 0-60 kb of this genomic sequence including the genes of interest was scanned with five different computational exon prediction programs as well as four splice site recognition programs. After analyzing and comparing the computationally predicted results with the wet-lab experiment results, some potential exons were predicted in the genomic sequence by using these programs.
基金the National Natural Science Foundation of China(31730073).
文摘CRISPR/Cas9 technology is a powerful genome manipulation tool in insects.However,little is known about whether mRNA and protein of a target gene are completely cleared in homozygous mutants.This study generated homozygous mutants of the insulin receptor gene 2(NlInR2)in the brown planthopper(Nilaparvata lugens)using CRISPR/Cas9 genome editing.Both frameshift mutants,E5_D17 and E6_I7,differentiated towards long wings,but there were differences in wing morphology,with E5_D17 showing wing deformities.Subsequent investigations revealed the presence of residual expression of NlInR2 mRNA in both mutants,as well as the occurrence of spliceosomes featuring exon skipping splicing in E5_D17.Additionally,the E5_D17 exhibited the detection of N-terminally truncated NlInR2 protein.RNA interference experiments indicated that the knockdown of NlInR2 expression in the E5_D17 mutant line increased the proportion of wing deformities from 11.1 to 65.6%,suggesting that the residual NlInR2 mRNA of the E5_D17 mutant might have retained some genetic functions.Our results imply that systematic characterization of residual protein expression or function in CRISPR/Cas9-generated mutant lines is necessary for phenotypic interpretation.
