As the world is closely watching the current 2009 H1N1 pandemic unfold, there is a great interest and need in understanding its origin, genetic structures, virulence, and pathogenicity. The two surface proteins, hemag...As the world is closely watching the current 2009 H1N1 pandemic unfold, there is a great interest and need in understanding its origin, genetic structures, virulence, and pathogenicity. The two surface proteins, hemagglutinin (HA) and neuraminidase (NA), of the influenza virus have been the focus of most flu research due to their crucial biological functions. In our previous study on 2009 H1N1, three aspects of NA were investigated: the mutations and co-mutations, the stalk motifs, and the phylogenetic analysis. In this study, we turned our attention to HA and the interaction between HA and NA. The 118 mutations of 2009 H1N1 HA were found and mapped to the 3D homology model of H1, and the mutations on the five epitope regions on H1 were identified. This information is essential for developing new drugs and vaccine. The distinct response patterns of HA to the changes of NA stalk motifs were discovered, illustrating the functional dependence between HA and NA. With help from our previous results, two co-mutation networks were uncovered, one in HA and one in NA, where each mutation in one network co-mutates with the mutations in the other network across the two proteins HA and NA. These two networks residing in HA and NA separately may provide a functional linkage between the mutations that can impact the drug binding sites in NA and those that can affect the host immune response or vaccine efficacy in HA. Our findings demonstrated the value of conducting timely analysis on the 2009 H1N1 virus and of the integrated approach to studying both surface proteins HA and NA together to reveal their interdependence, which could not be accomplished by studying them individually.展开更多
Acute myeloid leukemia(AML)is characterized by the accumulation of cytogenetic and molecular abnormalities.Isocitrate dehydrogenase 1 and 2(IDH1/2)mutations occur in 11%to 20%of adults with AML.The outcome of IDH1/2-m...Acute myeloid leukemia(AML)is characterized by the accumulation of cytogenetic and molecular abnormalities.Isocitrate dehydrogenase 1 and 2(IDH1/2)mutations occur in 11%to 20%of adults with AML.The outcome of IDH1/2-mutated AML is heterogeneous and affected by co-mutational patterns.We retrospectively analyzed 118 patients with IDH1/2-mutated AML who were retrieved from 1597 patients newly diagnosed with AML and treated with intensive chemotherapy.Univariate analysis revealed the NPM1 mutation was a favorable factor(p=0.019)for overall survival(OS),whereas the DNMT3A mutation was consistently associated with a poor outcome(3-year OS,52.0%;3-year relapse-free survival[RFS],44.8%;and 3-year cumulative incidence of relapse[CIR],42.6%).Interestingly,the DNMT3A mutation still identified patients with a poorer prognosis,even when measurable residual disease(MRD)was negative after 2 courses of chemotherapy.In a multivariate regression model,age,DNMT3A mutation and MRD positivity were retained as independent adverse markers for OS,RFS,and CIR.In the absence of the DNMT3A or FLT3-ITD mutations,the NPM1 mutation identified patients with a very favorable OS(3-year OS,96.3%and 86.3%,respectively).Finally,hematopoietic stem cell transplantation in first complete remission significantly improved RFS(p=0.015)and there was a trend toward improvement in OS(p=0.282)for patients with the DNMT3A mutation but it did not benefit 2 subgroups with the IDH1/2+/NPM1+/DNMT3A−and IDH1/2+/NPM1+/FLT3-ITD−genotypes.In summary,this study provides a reference for risk stratification and treatment implications for patients with IDH1/2-mutated AML as well as for comparison with results of IDH inhibitor-or venetoclax-based combination therapy.展开更多
BACKGROUND Although the relationship between somatic DNA polymerase epsilon(POLE)exonuclease domain mutations(EDMs)and colorectal cancer(CRC)is well established,the role of POLE non-EDMs in CRC remains unclear.AIM To ...BACKGROUND Although the relationship between somatic DNA polymerase epsilon(POLE)exonuclease domain mutations(EDMs)and colorectal cancer(CRC)is well established,the role of POLE non-EDMs in CRC remains unclear.AIM To identify POLE non-EDMs and EDMs in CRC,and to determine their associations with accompanying mutations and microsatellite instability(MSI).METHODS In this retrospective study,next-generation sequencing was performed using a targeted colon cancer panel(Qiagen,DHS-003Z)on 356 CRC patients.Of these,191 patients were found to carry POLE mutations.For these patients,MSI status was assessed using both real-time PCR(EasyPGX^(■)Ready MSI kit)and immunohistochemistry,and accompanying somatic mutations were investigated.RESULTS POLE mutations were identified in 53.65%of the CRC patients.Among the POLE-mutant patients,87.96%were classified as pMMR(MSI-L),and 12.04%as dMMR(MSI-H).The most frequently observed POLE non-EDM variant was exon 34 c.4337_4338delTG p.V1446fs*3.The POLE EDMs were present in exon 14,with two specific variants p.Y458F(0.52%)and p.Y468N(0.52%).The most common pathogenic variants accompanying the POLE mutations were in MLH3,MSH3,KRAS,PIK3CA,and BRAF genes.POLE mutations were associated with a high mutational burden and MSI in CRC,particularly in the dMMR phenotype.This association suggests that POLE mutations may serve as important biomarkers for understanding the genetic profile of the disease and may be used in the clinical management of CRC.CONCLUSION POLE mutations,especially non-EDMs,are frequent in MSI-L CRC and often co-occur with MLH3,MSH3,KRAS,PIK3CA,and BRAF,highlighting their potential role in tumor biology and as biomarkers for personalized treatment.Functional validation and multicenter studies are needed.展开更多
BACKGROUND Primary myelofibrosis(PMF)is a myeloproliferative neoplasm(MPN)characterized by recurrent mutations in the JAK2,CALR,and MPL genes.The CALR and MPL co-mutation is very rare.To our knowledge,no more than fiv...BACKGROUND Primary myelofibrosis(PMF)is a myeloproliferative neoplasm(MPN)characterized by recurrent mutations in the JAK2,CALR,and MPL genes.The CALR and MPL co-mutation is very rare.To our knowledge,no more than five cases have been reported.Here,we report a case of PMF in which a CALR and MPL co-mutation was detected by next-generation sequencing(NGS)technology,and a literature review was performed.CASE SUMMARY A 73-year-old woman was admitted to our hospital in 2018 due to abdominal distension.The patient had splenomegaly,lymphadenopathy,leukopenia,anemia,and immature granulocytes in peripheral blood.There were dacrocytes and atypical megakaryocytes in bone marrow,and megakaryocytic proliferation was very active,accompanied by reticulin fibrosis grade 2.By NGS analysis of the bone marrow sample,we detected mutations in CALR,MPL,and PIK3RI,while JAK2 V617F and BCR-ABL were negative.Therefore,the patient was diagnosed with PMF and received oral ruxolitinib.However,the spleen and hematologic responses were poor.We review the literature,analyze previous reports of the mutation sites in our patient and differences between our patient and other reported cases of co-mutated CALR and MPL genes,and discuss the reason why the CALR and MPL co-mutations are rare and possible mechanisms and their impact on the prognosis of patients.CONCLUSION CALR and MPL mutations can be concurrent in MPN,but they are rare.The use of NGS may help to identify more patients with co-mutated CALR and MPL genes.This will help to further explore the mechanism and its impact on these patients to develop appropriate treatment strategies.展开更多
The NP, PA, PB1, and PB2 proteins of influenza viruses together are responsible for the transcription and replication of viral RNA, and the latter three proteins comprise the viral polymerase. Two recent reports indic...The NP, PA, PB1, and PB2 proteins of influenza viruses together are responsible for the transcription and replication of viral RNA, and the latter three proteins comprise the viral polymerase. Two recent reports indicated that the mutation at site 627 of PB2 plays a key role in host range and increased virulence of influenza viruses, and could be compensated by multiple mutations at other sites of PB2, suggesting the association of this mutation with those at other sites. The objective of this study was to analyze the co-mutated sites within and between these important proteins of influenza. With mutual information, a set of statistically significant co- mutated position pairs (P value = 0) in NP, PA, PB1, and PB2 of avian, human, pandemic 2009 H1N1, and swine influenza were identified, based on which several highly connected networks of correlated sites in NP, PA, PB1, and PB2 were discovered. These correlation networks further illustrated the inner functional dependence of the four proteins that are critical for host adaptation and pathogenicity. Mutual information was also applied to quantify the correlation of sites within each individual protein and between proteins. In general, the inter protein correlation of the four proteins was stronger than the intra protein correlation. Finally, the correlation patterns of the four proteins of pandemic 2009 H1N1 were found to be closer to those of avian and human than to swine influenza, thus rendering a novel insight into the interaction of the four proteins of the pandemic 2009 H1N1 virus when compared to avian, human, and swine influenza and how the origin of these four proteins might affect the correlation patterns uncovered in this analysis.展开更多
The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evoluti...The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evolutionary constraints, host distinction, and co-mutations of influenza. Most previous studies of overlapping genes focused on their unique evolutionary constraints, and very little was achieved to assess the potential impact of the overlap on other biological aspects of influenza. In this study, our aim was to explore the mutual dependence in host differentiation and co-mutations in M, NS, and PB1 of avian, human, 2009 H1N1, and swine viruses, with Random Forests, information entropy, and mutual information. The host markers and highly co-mutated individual sites and site pairs (P values < 0.035) in the three gene segments were identified with their relative significance between the overlapping genes calculated. Further, Random Forests predicted that among the three stop codons in the current PB1-F2 gene of 2009 H1N1, the significance of a mutation at these sites for host differentiation was, in order from most to least, that at 12, 58, and 88, i.e., the closer to the start of the gene the more important the mutation was. Finally, our sequence analysis surprisingly revealed that the full-length PB1-F2, if the three stop codons were all mutated, would function more as a swine protein than a human protein, although the PB1 of 2009 H1N1 was derived from human H3N2.展开更多
The 2009 H1N1 influenza pandemic has attracted worldwide attention. The new virus first emerged in Mexico in April, 2009 was identified as a unique combination of a triple- reassortant swine influenza A virus, compose...The 2009 H1N1 influenza pandemic has attracted worldwide attention. The new virus first emerged in Mexico in April, 2009 was identified as a unique combination of a triple- reassortant swine influenza A virus, composed of genetic information from pigs, hu- mans, birds, and a Eurasian swine influenza virus. Several recent studies on the 2009 H1N1 virus util-ized small datasets to conduct analysis. With new sequences available up to date, we were able to extend the previous research in three areas. The first was finding two networks of co-mutations that may po-tentially affect the current flu-drug binding sites on neuraminidase (NA), one of the two surface proteins of flu virus. The second was discovering a special stalk motif, which was dominant in the H5N1 strains in the past, in the 2009 H1N1 strains for the first time. Due to the high virulence of this motif, the second finding is significant in our current research on 2009 H1N1. The third was updating the phylogenetic an- alysis of current NA sequences of 2009 H1N1 and H5N1, which demonstrated that, in clear contrast to previous findings, the N1 sequences in 2009 are di-verse enough to cover different major branches of the phylogenetic tree of those in previous years. As the novel influenza A H1N1 virus continues to spread globally, our results highlighted the importance of performing timely analysis on the 2009 H1N1 virus.展开更多
BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechani...BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechanism,clinicopathological features,and optimization of targeted drugs have not yet been completely elucidated.AIM To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes,with hopes of scientifically guiding similar patients towards selected,targeted drugs.METHODS Two hundred and thirty-seven LUAD patients were enrolled.EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique,while the expression of ALK rearrangement was screened by the 5′/3′imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis.The clinicopathological features of these patients were analysed retrospectively,and the follow-up data were collected.RESULTS There were six cases with co-mutations of EGFR and ALK genes,which were more common in women,non-smoking and stage IV LUAD patients with bone metastasis,hence a positive rate of 2.53%(6/237).EGFR-tyrosine kinase inhibitors(EGFR-TKIs)were their preferred drugs for targeted therapy in these patients,with progression-free survival ranging from two months to six months.CONCLUSION In Gannan region,the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high,and the co-mutations are more common in women,non-smoking and stage IV patients with bone metastasis.These patients prefer EGFR-TKIs as their preferred targeted drugs,but the therapeutic effect is not good.EGFR/ALK dual-TKIs may be more effective targeted drugs,which needs further study.展开更多
BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically conside...BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically considered to be mutually exc-lusive.EGFR/ROS1 co-mutation is a rare event,and the standard treatment appr-oach for such cases is still equivocal.CASE SUMMARY Herein,we report the case of a 64-year-old woman diagnosed with lung adenocar-cinoma,with concomitant EGFR L858R mutation and ROS1 rearrangement.The patient received two cycles of chemotherapy after surgery,but the disease prog-ressed.Following 1-month treatment with gefitinib,the disease progressed again.However,after switching to crizotinib,the lesion became stable.Currently,crizotinib has been administered for over 53 months with a remarkable treatment effect.CONCLUSION The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation.This report will aid future treatment of such patients.展开更多
TP53 mutations was reported to be correlated to the efficacy of program death-1(PD-1)and program death ligand-1(PD-L1).The role of co-mutations of TP53 with other recurrently mutated genes in outcome of anti-PD-(L)1 t...TP53 mutations was reported to be correlated to the efficacy of program death-1(PD-1)and program death ligand-1(PD-L1).The role of co-mutations of TP53 with other recurrently mutated genes in outcome of anti-PD-(L)1 treatment for non-small cell lung cancer(NSCLC)is unknown.Here we mined a previously generated dataset to address the effect of co-mutations on the progression free survival(PFS)of NSCLC patients.Non-synonymous mutations and clinical data of 240 NSCLC patients with anti-PD-(L)1 based therapy was downloaded from cBioPortal.Totally 206 patients received monotherapy and 34 patients received combination therapy.In 240 NSCLC patients,TP53 mutation rate was 59.2%.For the monotherapy cohort,TP53 mutated NSCLC patients have a significantly longer PFS(4.3 vs.2.5 months,P=0.0019)compared with TP53 wild type NSCLC patients.The same tendency was also observed in the combination therapy cohort,but the difference in PFS(6.3 vs.5.4 months,P=0.12)was not significant.Ever-smoker had a longer PFS compared to never-smokers(4.0 vs.2.7 months).For further co-mutation analysis with TP53 including KEAP1 mutation(53/240,22.1%),KMT3C mutation(26/240,10.8%),STK11 mutation(56/240,23.3%),EGFR mutation(28/240,11.7%)and KRAS mutation(86/240,35.8%).Patients with both TP53 plus KEAP1 mutations in all 240 patients had a longer PFS compared with co-wild population(PFS 9.2 vs.4.2 months,P=0.012)when treated with PD-1/PD-L1 inhibitors.TP53 might be the dominating mutation correlating with longer PFS in PD-1/PD-L1 monotherapy.Different genes displayed distinct effect when co-mutated with TP53 in NSCLC patients.展开更多
KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.He...KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.Herein,we present a novel self-assembled nanoparticle(HA-TPP/A)that are functionalized nano-carrier hyaluronic acid(HA)-TPP conjugate(HA-TPP)to degrade mutant p53 proteins(mutp53)and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways.The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria.Furthermore,these nanoparticles abrogated the gain-of-function(GOF)phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing,thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation.The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model,particularly in KRAS-TP53 double mutant expressing cancer cells,compared with single drug and combined free drug groups.Notably,HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53,providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.展开更多
Over the past two decades,high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies.CDK4/6 inhibitors have long been identified as a potential treatment option for advanc...Over the past two decades,high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies.CDK4/6 inhibitors have long been identified as a potential treatment option for advanced breast cancer patients.However,acquired HER2 heterogeneity leading to resistance during the treatment has been identified as a bottleneck.This review focuses on the recent resistance mechanisms identified and potential therapeutic targets for conventional and combination endocrine therapies with CDK4/6 inhibitors by various breast cancer clinical trials and research groups in HER amplified and/or mutated breast cancer tumour.Activating HER2 alterations,JNK pathway,hyperactivated TORC1,co-mutations in HER2 and HER3,phenotypic changes of HER2,and few other advanced findings are identified as potential therapeutic targets in treating current HER2 endocrine therapy-resistant tumour.Along with the HER2-focused resistance mechanisms,we also describe how the microbiome may play a role in breast cancer therapy and its potential for new therapeutic strategies to overcome drug resistance in breast cancers.展开更多
文摘As the world is closely watching the current 2009 H1N1 pandemic unfold, there is a great interest and need in understanding its origin, genetic structures, virulence, and pathogenicity. The two surface proteins, hemagglutinin (HA) and neuraminidase (NA), of the influenza virus have been the focus of most flu research due to their crucial biological functions. In our previous study on 2009 H1N1, three aspects of NA were investigated: the mutations and co-mutations, the stalk motifs, and the phylogenetic analysis. In this study, we turned our attention to HA and the interaction between HA and NA. The 118 mutations of 2009 H1N1 HA were found and mapped to the 3D homology model of H1, and the mutations on the five epitope regions on H1 were identified. This information is essential for developing new drugs and vaccine. The distinct response patterns of HA to the changes of NA stalk motifs were discovered, illustrating the functional dependence between HA and NA. With help from our previous results, two co-mutation networks were uncovered, one in HA and one in NA, where each mutation in one network co-mutates with the mutations in the other network across the two proteins HA and NA. These two networks residing in HA and NA separately may provide a functional linkage between the mutations that can impact the drug binding sites in NA and those that can affect the host immune response or vaccine efficacy in HA. Our findings demonstrated the value of conducting timely analysis on the 2009 H1N1 virus and of the integrated approach to studying both surface proteins HA and NA together to reveal their interdependence, which could not be accomplished by studying them individually.
基金supported by the National Key Research and Development Program of China(2021YFC2500300)the National Natural Science Foundation of China(82341213,82000131)CAMS Innovation Fund for Medical Sciences(2021-I2M-1-041).
文摘Acute myeloid leukemia(AML)is characterized by the accumulation of cytogenetic and molecular abnormalities.Isocitrate dehydrogenase 1 and 2(IDH1/2)mutations occur in 11%to 20%of adults with AML.The outcome of IDH1/2-mutated AML is heterogeneous and affected by co-mutational patterns.We retrospectively analyzed 118 patients with IDH1/2-mutated AML who were retrieved from 1597 patients newly diagnosed with AML and treated with intensive chemotherapy.Univariate analysis revealed the NPM1 mutation was a favorable factor(p=0.019)for overall survival(OS),whereas the DNMT3A mutation was consistently associated with a poor outcome(3-year OS,52.0%;3-year relapse-free survival[RFS],44.8%;and 3-year cumulative incidence of relapse[CIR],42.6%).Interestingly,the DNMT3A mutation still identified patients with a poorer prognosis,even when measurable residual disease(MRD)was negative after 2 courses of chemotherapy.In a multivariate regression model,age,DNMT3A mutation and MRD positivity were retained as independent adverse markers for OS,RFS,and CIR.In the absence of the DNMT3A or FLT3-ITD mutations,the NPM1 mutation identified patients with a very favorable OS(3-year OS,96.3%and 86.3%,respectively).Finally,hematopoietic stem cell transplantation in first complete remission significantly improved RFS(p=0.015)and there was a trend toward improvement in OS(p=0.282)for patients with the DNMT3A mutation but it did not benefit 2 subgroups with the IDH1/2+/NPM1+/DNMT3A−and IDH1/2+/NPM1+/FLT3-ITD−genotypes.In summary,this study provides a reference for risk stratification and treatment implications for patients with IDH1/2-mutated AML as well as for comparison with results of IDH inhibitor-or venetoclax-based combination therapy.
文摘BACKGROUND Although the relationship between somatic DNA polymerase epsilon(POLE)exonuclease domain mutations(EDMs)and colorectal cancer(CRC)is well established,the role of POLE non-EDMs in CRC remains unclear.AIM To identify POLE non-EDMs and EDMs in CRC,and to determine their associations with accompanying mutations and microsatellite instability(MSI).METHODS In this retrospective study,next-generation sequencing was performed using a targeted colon cancer panel(Qiagen,DHS-003Z)on 356 CRC patients.Of these,191 patients were found to carry POLE mutations.For these patients,MSI status was assessed using both real-time PCR(EasyPGX^(■)Ready MSI kit)and immunohistochemistry,and accompanying somatic mutations were investigated.RESULTS POLE mutations were identified in 53.65%of the CRC patients.Among the POLE-mutant patients,87.96%were classified as pMMR(MSI-L),and 12.04%as dMMR(MSI-H).The most frequently observed POLE non-EDM variant was exon 34 c.4337_4338delTG p.V1446fs*3.The POLE EDMs were present in exon 14,with two specific variants p.Y458F(0.52%)and p.Y468N(0.52%).The most common pathogenic variants accompanying the POLE mutations were in MLH3,MSH3,KRAS,PIK3CA,and BRAF genes.POLE mutations were associated with a high mutational burden and MSI in CRC,particularly in the dMMR phenotype.This association suggests that POLE mutations may serve as important biomarkers for understanding the genetic profile of the disease and may be used in the clinical management of CRC.CONCLUSION POLE mutations,especially non-EDMs,are frequent in MSI-L CRC and often co-occur with MLH3,MSH3,KRAS,PIK3CA,and BRAF,highlighting their potential role in tumor biology and as biomarkers for personalized treatment.Functional validation and multicenter studies are needed.
文摘BACKGROUND Primary myelofibrosis(PMF)is a myeloproliferative neoplasm(MPN)characterized by recurrent mutations in the JAK2,CALR,and MPL genes.The CALR and MPL co-mutation is very rare.To our knowledge,no more than five cases have been reported.Here,we report a case of PMF in which a CALR and MPL co-mutation was detected by next-generation sequencing(NGS)technology,and a literature review was performed.CASE SUMMARY A 73-year-old woman was admitted to our hospital in 2018 due to abdominal distension.The patient had splenomegaly,lymphadenopathy,leukopenia,anemia,and immature granulocytes in peripheral blood.There were dacrocytes and atypical megakaryocytes in bone marrow,and megakaryocytic proliferation was very active,accompanied by reticulin fibrosis grade 2.By NGS analysis of the bone marrow sample,we detected mutations in CALR,MPL,and PIK3RI,while JAK2 V617F and BCR-ABL were negative.Therefore,the patient was diagnosed with PMF and received oral ruxolitinib.However,the spleen and hematologic responses were poor.We review the literature,analyze previous reports of the mutation sites in our patient and differences between our patient and other reported cases of co-mutated CALR and MPL genes,and discuss the reason why the CALR and MPL co-mutations are rare and possible mechanisms and their impact on the prognosis of patients.CONCLUSION CALR and MPL mutations can be concurrent in MPN,but they are rare.The use of NGS may help to identify more patients with co-mutated CALR and MPL genes.This will help to further explore the mechanism and its impact on these patients to develop appropriate treatment strategies.
文摘The NP, PA, PB1, and PB2 proteins of influenza viruses together are responsible for the transcription and replication of viral RNA, and the latter three proteins comprise the viral polymerase. Two recent reports indicated that the mutation at site 627 of PB2 plays a key role in host range and increased virulence of influenza viruses, and could be compensated by multiple mutations at other sites of PB2, suggesting the association of this mutation with those at other sites. The objective of this study was to analyze the co-mutated sites within and between these important proteins of influenza. With mutual information, a set of statistically significant co- mutated position pairs (P value = 0) in NP, PA, PB1, and PB2 of avian, human, pandemic 2009 H1N1, and swine influenza were identified, based on which several highly connected networks of correlated sites in NP, PA, PB1, and PB2 were discovered. These correlation networks further illustrated the inner functional dependence of the four proteins that are critical for host adaptation and pathogenicity. Mutual information was also applied to quantify the correlation of sites within each individual protein and between proteins. In general, the inter protein correlation of the four proteins was stronger than the intra protein correlation. Finally, the correlation patterns of the four proteins of pandemic 2009 H1N1 were found to be closer to those of avian and human than to swine influenza, thus rendering a novel insight into the interaction of the four proteins of the pandemic 2009 H1N1 virus when compared to avian, human, and swine influenza and how the origin of these four proteins might affect the correlation patterns uncovered in this analysis.
文摘The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evolutionary constraints, host distinction, and co-mutations of influenza. Most previous studies of overlapping genes focused on their unique evolutionary constraints, and very little was achieved to assess the potential impact of the overlap on other biological aspects of influenza. In this study, our aim was to explore the mutual dependence in host differentiation and co-mutations in M, NS, and PB1 of avian, human, 2009 H1N1, and swine viruses, with Random Forests, information entropy, and mutual information. The host markers and highly co-mutated individual sites and site pairs (P values < 0.035) in the three gene segments were identified with their relative significance between the overlapping genes calculated. Further, Random Forests predicted that among the three stop codons in the current PB1-F2 gene of 2009 H1N1, the significance of a mutation at these sites for host differentiation was, in order from most to least, that at 12, 58, and 88, i.e., the closer to the start of the gene the more important the mutation was. Finally, our sequence analysis surprisingly revealed that the full-length PB1-F2, if the three stop codons were all mutated, would function more as a swine protein than a human protein, although the PB1 of 2009 H1N1 was derived from human H3N2.
文摘The 2009 H1N1 influenza pandemic has attracted worldwide attention. The new virus first emerged in Mexico in April, 2009 was identified as a unique combination of a triple- reassortant swine influenza A virus, composed of genetic information from pigs, hu- mans, birds, and a Eurasian swine influenza virus. Several recent studies on the 2009 H1N1 virus util-ized small datasets to conduct analysis. With new sequences available up to date, we were able to extend the previous research in three areas. The first was finding two networks of co-mutations that may po-tentially affect the current flu-drug binding sites on neuraminidase (NA), one of the two surface proteins of flu virus. The second was discovering a special stalk motif, which was dominant in the H5N1 strains in the past, in the 2009 H1N1 strains for the first time. Due to the high virulence of this motif, the second finding is significant in our current research on 2009 H1N1. The third was updating the phylogenetic an- alysis of current NA sequences of 2009 H1N1 and H5N1, which demonstrated that, in clear contrast to previous findings, the N1 sequences in 2009 are di-verse enough to cover different major branches of the phylogenetic tree of those in previous years. As the novel influenza A H1N1 virus continues to spread globally, our results highlighted the importance of performing timely analysis on the 2009 H1N1 virus.
文摘BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechanism,clinicopathological features,and optimization of targeted drugs have not yet been completely elucidated.AIM To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes,with hopes of scientifically guiding similar patients towards selected,targeted drugs.METHODS Two hundred and thirty-seven LUAD patients were enrolled.EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique,while the expression of ALK rearrangement was screened by the 5′/3′imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis.The clinicopathological features of these patients were analysed retrospectively,and the follow-up data were collected.RESULTS There were six cases with co-mutations of EGFR and ALK genes,which were more common in women,non-smoking and stage IV LUAD patients with bone metastasis,hence a positive rate of 2.53%(6/237).EGFR-tyrosine kinase inhibitors(EGFR-TKIs)were their preferred drugs for targeted therapy in these patients,with progression-free survival ranging from two months to six months.CONCLUSION In Gannan region,the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high,and the co-mutations are more common in women,non-smoking and stage IV patients with bone metastasis.These patients prefer EGFR-TKIs as their preferred targeted drugs,but the therapeutic effect is not good.EGFR/ALK dual-TKIs may be more effective targeted drugs,which needs further study.
基金Supported by Wu Jieping Medical Foundation,No.320.6750.2022-20-25and Chongqing Health Commission,No.[2020]68.
文摘BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically considered to be mutually exc-lusive.EGFR/ROS1 co-mutation is a rare event,and the standard treatment appr-oach for such cases is still equivocal.CASE SUMMARY Herein,we report the case of a 64-year-old woman diagnosed with lung adenocar-cinoma,with concomitant EGFR L858R mutation and ROS1 rearrangement.The patient received two cycles of chemotherapy after surgery,but the disease prog-ressed.Following 1-month treatment with gefitinib,the disease progressed again.However,after switching to crizotinib,the lesion became stable.Currently,crizotinib has been administered for over 53 months with a remarkable treatment effect.CONCLUSION The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation.This report will aid future treatment of such patients.
基金This work was supported by Chinese Academy of Medical Sciences(No.2019XK320068).
文摘TP53 mutations was reported to be correlated to the efficacy of program death-1(PD-1)and program death ligand-1(PD-L1).The role of co-mutations of TP53 with other recurrently mutated genes in outcome of anti-PD-(L)1 treatment for non-small cell lung cancer(NSCLC)is unknown.Here we mined a previously generated dataset to address the effect of co-mutations on the progression free survival(PFS)of NSCLC patients.Non-synonymous mutations and clinical data of 240 NSCLC patients with anti-PD-(L)1 based therapy was downloaded from cBioPortal.Totally 206 patients received monotherapy and 34 patients received combination therapy.In 240 NSCLC patients,TP53 mutation rate was 59.2%.For the monotherapy cohort,TP53 mutated NSCLC patients have a significantly longer PFS(4.3 vs.2.5 months,P=0.0019)compared with TP53 wild type NSCLC patients.The same tendency was also observed in the combination therapy cohort,but the difference in PFS(6.3 vs.5.4 months,P=0.12)was not significant.Ever-smoker had a longer PFS compared to never-smokers(4.0 vs.2.7 months).For further co-mutation analysis with TP53 including KEAP1 mutation(53/240,22.1%),KMT3C mutation(26/240,10.8%),STK11 mutation(56/240,23.3%),EGFR mutation(28/240,11.7%)and KRAS mutation(86/240,35.8%).Patients with both TP53 plus KEAP1 mutations in all 240 patients had a longer PFS compared with co-wild population(PFS 9.2 vs.4.2 months,P=0.012)when treated with PD-1/PD-L1 inhibitors.TP53 might be the dominating mutation correlating with longer PFS in PD-1/PD-L1 monotherapy.Different genes displayed distinct effect when co-mutated with TP53 in NSCLC patients.
基金supported by the National Key Research and Development Plan(2022YFC3401000)National Natural Science Foundation of China(81871994,82022037,T2222014 and 32071398)+2 种基金Guangdong Provincial Natural Science Foundation(2019B151502063)Guangdong Basic and Applied Basic Research Foundation(2021B1515230009)Key Research and Development Plan of Guangdong Province(2020B0101030006,2020B1515120096 and 2022B0202010002).
文摘KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.Herein,we present a novel self-assembled nanoparticle(HA-TPP/A)that are functionalized nano-carrier hyaluronic acid(HA)-TPP conjugate(HA-TPP)to degrade mutant p53 proteins(mutp53)and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways.The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria.Furthermore,these nanoparticles abrogated the gain-of-function(GOF)phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing,thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation.The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model,particularly in KRAS-TP53 double mutant expressing cancer cells,compared with single drug and combined free drug groups.Notably,HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53,providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.
文摘Over the past two decades,high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies.CDK4/6 inhibitors have long been identified as a potential treatment option for advanced breast cancer patients.However,acquired HER2 heterogeneity leading to resistance during the treatment has been identified as a bottleneck.This review focuses on the recent resistance mechanisms identified and potential therapeutic targets for conventional and combination endocrine therapies with CDK4/6 inhibitors by various breast cancer clinical trials and research groups in HER amplified and/or mutated breast cancer tumour.Activating HER2 alterations,JNK pathway,hyperactivated TORC1,co-mutations in HER2 and HER3,phenotypic changes of HER2,and few other advanced findings are identified as potential therapeutic targets in treating current HER2 endocrine therapy-resistant tumour.Along with the HER2-focused resistance mechanisms,we also describe how the microbiome may play a role in breast cancer therapy and its potential for new therapeutic strategies to overcome drug resistance in breast cancers.
