Objectives:The tumorigenic progression of Lung adenocarcinoma(LUAD),the predominant NSCLC subtype,is predominantly driven by co-occurring mutations in KRAS proto-oncogene(KRAS)/Tumor protein p53(TP53).However,their im...Objectives:The tumorigenic progression of Lung adenocarcinoma(LUAD),the predominant NSCLC subtype,is predominantly driven by co-occurring mutations in KRAS proto-oncogene(KRAS)/Tumor protein p53(TP53).However,their impact on tumor microenvironment(TME)heterogeneity,particularly neutrophil dynamics,remains poorly understood.This present study aims to elucidate how KRAS/TP53 mutations reprogram the TME and develop a neutrophil-centric prognostic signature for LUAD.Methods:Leveraging single-cell RNA sequencing data and transcriptome data,neutrophil subpopulations were identified using Seurat and CellChat R packages,with trajectory analysis via Monocle2 R package.High-dimensional weighted gene co-expression network analysis(hdWGCNA),univariate Cox regression,and least absolute shrinkage and selection operator(LASSO)regression analyses were employed to generate a prognostic signature.Functional validation included Ras homolog family member V(RHOV)knockdown in A549/H1299 cells using siRNA,were assessed by cell counting kit 8(CCK8)assay,wound healing assay,and transwell assay.Results:KRAS/TP53-mutated LUAD exhibited increased neutrophil infiltration,particularly IS MUT subtypes with enhanced OSM/CALCR/IL-1 signaling.A five-gene prognostic signature(MS4A1,ANLN,FAM83A,RHOV,KRT6A)stratified patients into high-and low-risk groups with divergent overall survival in the TCGA-LUAD cohort(p<0.0001).AUCs achieved 0.73,0.70,and 0.66 at 1-,3-,and 5-year,respectively.External validation in immunotherapy cohorts(IMvigor210,GSE78220)confirmed the fine predictive capability of the prognostic signature in predicting treatment response.An integrated prognostic nomogram combining clinicopathological features and risk score further improved its clinical utility.Pseudotime analysis found that RHOV was essential for the growth of lung epithelial cells.RHOV knockdown significantly reduced the proliferation,migration,and invasion capabilities of A549/H1299 cells in vitro.Conclusion:KRAS/TP53 mutations may drive neutrophil heterogeneity in the TME of LUAD,addressing prognostic and therapeutic value.The five-gene signature and RHOV targeting offer translational relevance for risk stratification and therapy.These findings bridge genomic alterations with TME remodeling,advancing precision oncology in LUAD.展开更多
Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an i...Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.展开更多
As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer of...As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.展开更多
Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for th...Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2(HER2)-targeted therapy in breast cancer remains controversial.In the present study,we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA(ctDNA)from breast cancer patients in China.Methods:We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients withmetastatic breast cancer.TP53 mutations were detected by target region capture-based next-generation sequencing.The relationship between TP53 mutation status and disease-free survival(DFS)was analyzed in 444 patientswithmetastatic breast cancer.Moreover,the relationship between TP53 mutation status and progression-free survival(PFS)was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy.Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups,and the log-rank test was used to compare the curves.A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95%confidence intervals(CIs)associated with the DFS and PFS.Results:Among the 804 investigated patients,431(53.6%)patients harbored TP53 mutations.TP53 mutations were differentially distributed among different molecular subtypes of breast cancer(P<0.05).Patients with TP53 mutations had a shorter DFS than those with wild-type TP53(hazard ratio=1.32,95%CI=1.09-1.61,P=0.005).TP53 mutations in exons 5-8 were associated with worse outcome(hazard ratio=1.50,95%CI=1.11-2.03,P=0.009).However,TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received firstline trastuzumab-based therapy(P=0.966).Interestingly,in the taxane combination group,patients with TP53 mutations exhibited longer PFS than those without TP53 mutations(hazard ratio=0.08,95%CI=0.02-0.30,P<0.001).However,in the nontaxane combination group,patients with TP53 mutations displayed shorter PFS than those with wild-type TP53(hazard ratio=4.84,95%CI=1.60-14.66,P=0.005).Conclusions:TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.展开更多
BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers lit...BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers little benefit to individuals.AIM To investigate the clinical outcomes of TP53 and CDH1 mutations in GC.METHODS In this study,202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected.A total of 490 genes were identified using target capture.Through t-test and Wilcoxon rank-sum test,somatic mutations,microsatellite instability,and clinical statistics,including overall survival,were detected,compared,and calculated.RESULTS The mutation rates of 32 genes,including TP53,SPEN,FAT1,and CDH1 exceeded 10%.TP53 mutations had a slightly lower overall occurrence rate(33%).The TP53 mutation rate was significantly higher in advanced stages(stage Ⅲ/Ⅳ)than that in early stages(stage Ⅰ/Ⅱ)(P<0.05).In contrast,CDH1 mutations were significantly associated with diffuse GC.TP53 is related to poor prognosis of advanced-stage tumors;nevertheless,CDH1 corresponds to a diffuse type of cancer.TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms.CONCLUSION Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.展开更多
BACKGROUND The diagnosis and etiology of multiple primary malignant neoplasms(MPMNs)are difficult to establish.Here,we report a case of heterochronic triple primary malignancies with gastric cancer,nasopharyngeal squa...BACKGROUND The diagnosis and etiology of multiple primary malignant neoplasms(MPMNs)are difficult to establish.Here,we report a case of heterochronic triple primary malignancies with gastric cancer,nasopharyngeal squamous cell cancer,and then rectal cancer.CASE SUMMARY The patient was first diagnosed with gastric cancer at the age of 33 in 2014 and underwent distal gastrectomy and gastrojejunostomy and six cycles of adjuvant chemotherapy.Three years later,he was diagnosed with nasopharyngeal cancer and treated with radical chemoradiotherapy in 2017.Recently,a mass in the middle of the rectum was resected and reported as ulcerative,moderately to poorly differentiated adenocarcinoma.Research on the etiology of MPMNs showed that Epstein-Barr virus(EBV)infection may be the cause of gastric cancer and nasopharyngeal squamous cell cancer since these two primary lesions were positive for transcripts of EBV-encoded ribonucleic acid using an in situ hybridization EBV-encoded ribonucleic acid probe in formalin-fixed,paraffinembedded tissue.The cause of rectal cancer may be due to a somatic mutation of tumor protein 53 gene in exon 8(c.844C>T,p.Arg282Trp)through highthroughput sequencing for the rectal cancer.Appropriate standard therapy for each primary cancer was administered,and the patient has no evidence of cancer disease to date.CONCLUSION To our knowledge,this is the first report on heterochronic triple primary malignancies whose cause may be associated with EBV infection and tumor protein 53 genetic mutations.The etiological research may not only elucidate the cause of MPMN but also has implications in clinical management.展开更多
This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors(ICIs)by conducting systematic literature search in electronic databases up to May 31,2021.The main...This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors(ICIs)by conducting systematic literature search in electronic databases up to May 31,2021.The main outcomes including overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and durable clinical benefit(DCB)were correlated with tumor genomic features.A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies.The Kirsten rat sarcoma viral oncogene homolog G12C(KRAS^(G12C))mutation combined with tumor protein P53(TP53)mutation revealed the promising efficacy of ICI therapy in these patients.Furthermore,patients with epidermal growth factor receptor(EGFR)classical activating mutations(including EGFRL858Rand EGFRΔ19)exhibited worse outcomes to ICIs in OS(adjusted hazard ratio(HR),1.40;95%confidence interval(CI),1.01-1.95;P=0.0411)and PFS(adjusted HR,1.98;95%CI,1.49-2.63;P<0.0001),while classical activating mutations with EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min OS(adjusted HR,0.96;95%CI,0.48-1.94;P=0.9157)or PFS(adjusted HR,0.72;95%CI,0.39-1.35;P=0.3050).Of note,for patients harboring the Usher syndrome type-2A(USH2A)missense mutation,correspondingly better outcomes were observed in OS(adjusted HR,0.52;95%CI,0.32-0.82;P=0.0077),PFS(adjusted HR,0.51;95%CI,0.38-0.69;P<0.0001),DCB(adjusted odds ratio(OR),4.74;95%CI,2.75-8.17;P<0.0001),and ORR(adjusted OR,3.45;95%CI,1.88-6.33;P<0.0001).Our findings indicated that,USH2A missense mutations and the KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed the opposite role in the ICI therapy among lung cancer patients.Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.展开更多
BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and...BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and HGBL-not otherwise specific(HGBL-NOS),which are morphologically characteristic of HGBL but lack MYC,BCL-2,or BCL-6 rearrangements.HGBL is partially transformed by follicular lymphoma and other indolent lymphoma,with few cases of marginal zone lymphoma(MZL)transformation.HGBL often has a poor prognosis and intensive therapy is currently mainly advocated,but there is no good treatment for these patients who cannot tolerate chemotherapy.CASE SUMMARY We reported a case of MZL transformed into HGBL-NOS with TP53 mutation and terminal deoxynucleotidyl transferase expression.Gene analysis revealed the gene expression profile was identical in the pre-and post-transformed tissues,suggesting that the two diseases are homologous,not secondary tumors.The chemotherapy was ineffective and the side effect was severe,so we tried combination therapy including venetoclax and obinutuzumab.The patient tolerated treatment well,and reached partial response.The patient had recurrence of hepatocellular carcinoma and died of multifunctional organ failure.He survived for 12 months after diagnosis.CONCLUSION Venetoclax combined with obinutuzumab might improve the survival in some HGBL patients,who are unsuitable for chemotherapy.展开更多
Approximately 60%of colorectal cancer(CRC)patients exhibit TP53 mutations,which are strongly associated with tumor progression,chemotherapy resistance,and an unfavorable prognosis.However,targeting p53 has historicall...Approximately 60%of colorectal cancer(CRC)patients exhibit TP53 mutations,which are strongly associated with tumor progression,chemotherapy resistance,and an unfavorable prognosis.However,targeting p53 has historically been challenging,and currently,there are no approved p53-based therapeutics for clinical use worldwide.In this study,we discovered that ubiquitin carboxyl terminal hydrolase L3(UCHL3)plays a crucial role in high-level glycolysis,enhanced stem-like properties,and 5-fluorouracil(5-FU)chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilizeα-enolase(ENO1)protein.Notably,we identified a newly Food and Drug Administration(FDA)-approved drug,pacritinib,that potently suppresses UCHL3 expression by blocking the janus kinase 2(JAK2)–signal transducer and activator of transcription 3(STAT3)pathway in TP53-mutant CRC.Furthermore,Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC.Our findings suggest that targeting the JAK2–STAT3–UCHL3–ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC.Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.展开更多
TO THE EDITORAlthough the incidence of gastric cancer has declined somewhat in recent years, it remains one of the most common cancers worldwide[1], and is the most common cancer in East Asian countries such as Korea ...TO THE EDITORAlthough the incidence of gastric cancer has declined somewhat in recent years, it remains one of the most common cancers worldwide[1], and is the most common cancer in East Asian countries such as Korea and Japan[2].In terms of the genetics of gastric cancer, mutations in CDH1 (E-cadberin) have been associated with hereditary diffuse gastric cancer (HDGC). The first germline mutation in CDH1 was reported in a large Maori HDGC family[1],with subsequent corroborations in Western and Asian HDGC families[3-5], CDH1 mutations are believed to be associated with up to 50% of HDGC families[5], but have not been linked with sporadic or intestinal types of gastric cancer[5].展开更多
Background:To assess whether changes in TP53 mutations and copy number alterations(CNA)in plasma circulating tumor DNA(ctDNA)can predict treatment response and prognosis in platinum-resistant recurrent ovarian cancer(...Background:To assess whether changes in TP53 mutations and copy number alterations(CNA)in plasma circulating tumor DNA(ctDNA)can predict treatment response and prognosis in platinum-resistant recurrent ovarian cancer(PROC)patients.Methods:Fifty-seven PROC patients were recruited.Forty-three patients with matched tumor and plasma samples were analyzed via both a tumor-informed ctDNA assay(TICA)and a tumor-uninformed ctDNA assay(TUCA)profiling TP53 mutations and CNA.The TUCA algorithm was optimized based on TICA results.Fourteen patients without matched tumor tissues were used just for TUCA analysis.Results:A ctDNA decrease of≥80%from baseline or ctDNA negativity during treatment detected by the TICA(defined as favorable TICA changes)strategy before the third cycle predicted the best overall response,with 81.8%sensitivity and 84.6%specificity.The TUCA strategy was defined as a combination of TP53 mutations and CNA changes.A favorable TUCA change before the third cycle predicted the best overall response,with 90.0%sensitivity and 63.2%specificity.In 12 patients without clinical benefit,the median lead time to detect drug resistance from TUCA to the Response Evaluation Criteria in Solid Tumors was 86.0 days.Patients with favorable ctDNA changes(n=15)detected by TUCA before the third cycle had a median progression-free survival of 9.2 months,versus 3.6 months in those without(n=34)(HR:2.88;95%CI 1.56-5.30;log-rank p=0.0008).Conclusions:Similar to TICA,ctDNA changes detected by TUCA combined with TP53 mutations and CNA could predict treatment response and prognosis in PROC patients without requiring tumor tissues.展开更多
基金supported by Zhongnanshan Medical Foundation of Guangdong Province(No.ZNSXS-20240108 to Anping Xu).
文摘Objectives:The tumorigenic progression of Lung adenocarcinoma(LUAD),the predominant NSCLC subtype,is predominantly driven by co-occurring mutations in KRAS proto-oncogene(KRAS)/Tumor protein p53(TP53).However,their impact on tumor microenvironment(TME)heterogeneity,particularly neutrophil dynamics,remains poorly understood.This present study aims to elucidate how KRAS/TP53 mutations reprogram the TME and develop a neutrophil-centric prognostic signature for LUAD.Methods:Leveraging single-cell RNA sequencing data and transcriptome data,neutrophil subpopulations were identified using Seurat and CellChat R packages,with trajectory analysis via Monocle2 R package.High-dimensional weighted gene co-expression network analysis(hdWGCNA),univariate Cox regression,and least absolute shrinkage and selection operator(LASSO)regression analyses were employed to generate a prognostic signature.Functional validation included Ras homolog family member V(RHOV)knockdown in A549/H1299 cells using siRNA,were assessed by cell counting kit 8(CCK8)assay,wound healing assay,and transwell assay.Results:KRAS/TP53-mutated LUAD exhibited increased neutrophil infiltration,particularly IS MUT subtypes with enhanced OSM/CALCR/IL-1 signaling.A five-gene prognostic signature(MS4A1,ANLN,FAM83A,RHOV,KRT6A)stratified patients into high-and low-risk groups with divergent overall survival in the TCGA-LUAD cohort(p<0.0001).AUCs achieved 0.73,0.70,and 0.66 at 1-,3-,and 5-year,respectively.External validation in immunotherapy cohorts(IMvigor210,GSE78220)confirmed the fine predictive capability of the prognostic signature in predicting treatment response.An integrated prognostic nomogram combining clinicopathological features and risk score further improved its clinical utility.Pseudotime analysis found that RHOV was essential for the growth of lung epithelial cells.RHOV knockdown significantly reduced the proliferation,migration,and invasion capabilities of A549/H1299 cells in vitro.Conclusion:KRAS/TP53 mutations may drive neutrophil heterogeneity in the TME of LUAD,addressing prognostic and therapeutic value.The five-gene signature and RHOV targeting offer translational relevance for risk stratification and therapy.These findings bridge genomic alterations with TME remodeling,advancing precision oncology in LUAD.
基金supported by the National Natural Science Foundation of China(32171131,32371013,82071429,82471274,and 32371181)Shandong Province Natural Science Foundation(2021ZDSYS11,ZR2019ZD31,and ZR2022MC098)the Taishan Scholars Construction Project.
文摘Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
基金supported by the National Natural Science Foun-dation of China(grant numbers 81974483 and 82072589)the ChineseSocietyofClinicalOncology-HengruiCancerResearch Fund(Y-HR2020QN-0946).
文摘As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.
基金supported by the grants from the Chinese Academy of Medical Sciences(CAMS)Initiative for InnovativeMedicine(CAMS-12 M-1-010,2017-I2M-3-004)the National Natural Science Foundation of China(81874122).
文摘Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2(HER2)-targeted therapy in breast cancer remains controversial.In the present study,we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA(ctDNA)from breast cancer patients in China.Methods:We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients withmetastatic breast cancer.TP53 mutations were detected by target region capture-based next-generation sequencing.The relationship between TP53 mutation status and disease-free survival(DFS)was analyzed in 444 patientswithmetastatic breast cancer.Moreover,the relationship between TP53 mutation status and progression-free survival(PFS)was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy.Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups,and the log-rank test was used to compare the curves.A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95%confidence intervals(CIs)associated with the DFS and PFS.Results:Among the 804 investigated patients,431(53.6%)patients harbored TP53 mutations.TP53 mutations were differentially distributed among different molecular subtypes of breast cancer(P<0.05).Patients with TP53 mutations had a shorter DFS than those with wild-type TP53(hazard ratio=1.32,95%CI=1.09-1.61,P=0.005).TP53 mutations in exons 5-8 were associated with worse outcome(hazard ratio=1.50,95%CI=1.11-2.03,P=0.009).However,TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received firstline trastuzumab-based therapy(P=0.966).Interestingly,in the taxane combination group,patients with TP53 mutations exhibited longer PFS than those without TP53 mutations(hazard ratio=0.08,95%CI=0.02-0.30,P<0.001).However,in the nontaxane combination group,patients with TP53 mutations displayed shorter PFS than those with wild-type TP53(hazard ratio=4.84,95%CI=1.60-14.66,P=0.005).Conclusions:TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.
基金Supported by Guangdong Yiyang Healthcare Charity Foundation,No.JZ2022014.
文摘BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers little benefit to individuals.AIM To investigate the clinical outcomes of TP53 and CDH1 mutations in GC.METHODS In this study,202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected.A total of 490 genes were identified using target capture.Through t-test and Wilcoxon rank-sum test,somatic mutations,microsatellite instability,and clinical statistics,including overall survival,were detected,compared,and calculated.RESULTS The mutation rates of 32 genes,including TP53,SPEN,FAT1,and CDH1 exceeded 10%.TP53 mutations had a slightly lower overall occurrence rate(33%).The TP53 mutation rate was significantly higher in advanced stages(stage Ⅲ/Ⅳ)than that in early stages(stage Ⅰ/Ⅱ)(P<0.05).In contrast,CDH1 mutations were significantly associated with diffuse GC.TP53 is related to poor prognosis of advanced-stage tumors;nevertheless,CDH1 corresponds to a diffuse type of cancer.TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms.CONCLUSION Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.
文摘BACKGROUND The diagnosis and etiology of multiple primary malignant neoplasms(MPMNs)are difficult to establish.Here,we report a case of heterochronic triple primary malignancies with gastric cancer,nasopharyngeal squamous cell cancer,and then rectal cancer.CASE SUMMARY The patient was first diagnosed with gastric cancer at the age of 33 in 2014 and underwent distal gastrectomy and gastrojejunostomy and six cycles of adjuvant chemotherapy.Three years later,he was diagnosed with nasopharyngeal cancer and treated with radical chemoradiotherapy in 2017.Recently,a mass in the middle of the rectum was resected and reported as ulcerative,moderately to poorly differentiated adenocarcinoma.Research on the etiology of MPMNs showed that Epstein-Barr virus(EBV)infection may be the cause of gastric cancer and nasopharyngeal squamous cell cancer since these two primary lesions were positive for transcripts of EBV-encoded ribonucleic acid using an in situ hybridization EBV-encoded ribonucleic acid probe in formalin-fixed,paraffinembedded tissue.The cause of rectal cancer may be due to a somatic mutation of tumor protein 53 gene in exon 8(c.844C>T,p.Arg282Trp)through highthroughput sequencing for the rectal cancer.Appropriate standard therapy for each primary cancer was administered,and the patient has no evidence of cancer disease to date.CONCLUSION To our knowledge,this is the first report on heterochronic triple primary malignancies whose cause may be associated with EBV infection and tumor protein 53 genetic mutations.The etiological research may not only elucidate the cause of MPMN but also has implications in clinical management.
基金the National Natural Science Foundation of China(Nos.21976155,81802881,and 81773016)the Zhejiang Provincial Natural Science Foundation of China(No.LY18C060001)+1 种基金the Fundamental Research Funds for the Central Universitiesthe Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(No.2019-I2M-5-044),China。
文摘This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors(ICIs)by conducting systematic literature search in electronic databases up to May 31,2021.The main outcomes including overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and durable clinical benefit(DCB)were correlated with tumor genomic features.A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies.The Kirsten rat sarcoma viral oncogene homolog G12C(KRAS^(G12C))mutation combined with tumor protein P53(TP53)mutation revealed the promising efficacy of ICI therapy in these patients.Furthermore,patients with epidermal growth factor receptor(EGFR)classical activating mutations(including EGFRL858Rand EGFRΔ19)exhibited worse outcomes to ICIs in OS(adjusted hazard ratio(HR),1.40;95%confidence interval(CI),1.01-1.95;P=0.0411)and PFS(adjusted HR,1.98;95%CI,1.49-2.63;P<0.0001),while classical activating mutations with EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min OS(adjusted HR,0.96;95%CI,0.48-1.94;P=0.9157)or PFS(adjusted HR,0.72;95%CI,0.39-1.35;P=0.3050).Of note,for patients harboring the Usher syndrome type-2A(USH2A)missense mutation,correspondingly better outcomes were observed in OS(adjusted HR,0.52;95%CI,0.32-0.82;P=0.0077),PFS(adjusted HR,0.51;95%CI,0.38-0.69;P<0.0001),DCB(adjusted odds ratio(OR),4.74;95%CI,2.75-8.17;P<0.0001),and ORR(adjusted OR,3.45;95%CI,1.88-6.33;P<0.0001).Our findings indicated that,USH2A missense mutations and the KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed the opposite role in the ICI therapy among lung cancer patients.Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.
基金Supported by The Lishui Science and Technology Planing Projects,No.2020SJZC048.
文摘BACKGROUND High-grade B-cell lymphoma(HGBL)is an unusual malignancy that includes myelocytomatosis viral oncogene(MYC),B-cell lymphoma-2(BCL-2),and/or BCL-6 rearrangements,termed double-hit or triple-hit lymphomas,and HGBL-not otherwise specific(HGBL-NOS),which are morphologically characteristic of HGBL but lack MYC,BCL-2,or BCL-6 rearrangements.HGBL is partially transformed by follicular lymphoma and other indolent lymphoma,with few cases of marginal zone lymphoma(MZL)transformation.HGBL often has a poor prognosis and intensive therapy is currently mainly advocated,but there is no good treatment for these patients who cannot tolerate chemotherapy.CASE SUMMARY We reported a case of MZL transformed into HGBL-NOS with TP53 mutation and terminal deoxynucleotidyl transferase expression.Gene analysis revealed the gene expression profile was identical in the pre-and post-transformed tissues,suggesting that the two diseases are homologous,not secondary tumors.The chemotherapy was ineffective and the side effect was severe,so we tried combination therapy including venetoclax and obinutuzumab.The patient tolerated treatment well,and reached partial response.The patient had recurrence of hepatocellular carcinoma and died of multifunctional organ failure.He survived for 12 months after diagnosis.CONCLUSION Venetoclax combined with obinutuzumab might improve the survival in some HGBL patients,who are unsuitable for chemotherapy.
基金supported by the National Key Research and Development Program of China(No.2022YFC3401000 to Zitong Zhao)the National Natural Science Foundation of China(No.82173332 to Yongmei Song,No.82272909 to Guiying Wang)+2 种基金the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(No.2023-I2M-2-004 to Yongmei Song,China)the Hebei Province Natural Innovation Group Program(No.H2022206355 to Guiying Wang,China)the Hebei Province Central Guide Local Science and Technology Special Project(No.236Z7757G to Guiying Wang,China).
文摘Approximately 60%of colorectal cancer(CRC)patients exhibit TP53 mutations,which are strongly associated with tumor progression,chemotherapy resistance,and an unfavorable prognosis.However,targeting p53 has historically been challenging,and currently,there are no approved p53-based therapeutics for clinical use worldwide.In this study,we discovered that ubiquitin carboxyl terminal hydrolase L3(UCHL3)plays a crucial role in high-level glycolysis,enhanced stem-like properties,and 5-fluorouracil(5-FU)chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilizeα-enolase(ENO1)protein.Notably,we identified a newly Food and Drug Administration(FDA)-approved drug,pacritinib,that potently suppresses UCHL3 expression by blocking the janus kinase 2(JAK2)–signal transducer and activator of transcription 3(STAT3)pathway in TP53-mutant CRC.Furthermore,Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC.Our findings suggest that targeting the JAK2–STAT3–UCHL3–ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC.Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.
文摘TO THE EDITORAlthough the incidence of gastric cancer has declined somewhat in recent years, it remains one of the most common cancers worldwide[1], and is the most common cancer in East Asian countries such as Korea and Japan[2].In terms of the genetics of gastric cancer, mutations in CDH1 (E-cadberin) have been associated with hereditary diffuse gastric cancer (HDGC). The first germline mutation in CDH1 was reported in a large Maori HDGC family[1],with subsequent corroborations in Western and Asian HDGC families[3-5], CDH1 mutations are believed to be associated with up to 50% of HDGC families[5], but have not been linked with sporadic or intestinal types of gastric cancer[5].
基金supported by the National Key R&D Program of China(Grant No.2016YFC13037040)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(Grant No.2022-RC310-08).
文摘Background:To assess whether changes in TP53 mutations and copy number alterations(CNA)in plasma circulating tumor DNA(ctDNA)can predict treatment response and prognosis in platinum-resistant recurrent ovarian cancer(PROC)patients.Methods:Fifty-seven PROC patients were recruited.Forty-three patients with matched tumor and plasma samples were analyzed via both a tumor-informed ctDNA assay(TICA)and a tumor-uninformed ctDNA assay(TUCA)profiling TP53 mutations and CNA.The TUCA algorithm was optimized based on TICA results.Fourteen patients without matched tumor tissues were used just for TUCA analysis.Results:A ctDNA decrease of≥80%from baseline or ctDNA negativity during treatment detected by the TICA(defined as favorable TICA changes)strategy before the third cycle predicted the best overall response,with 81.8%sensitivity and 84.6%specificity.The TUCA strategy was defined as a combination of TP53 mutations and CNA changes.A favorable TUCA change before the third cycle predicted the best overall response,with 90.0%sensitivity and 63.2%specificity.In 12 patients without clinical benefit,the median lead time to detect drug resistance from TUCA to the Response Evaluation Criteria in Solid Tumors was 86.0 days.Patients with favorable ctDNA changes(n=15)detected by TUCA before the third cycle had a median progression-free survival of 9.2 months,versus 3.6 months in those without(n=34)(HR:2.88;95%CI 1.56-5.30;log-rank p=0.0008).Conclusions:Similar to TICA,ctDNA changes detected by TUCA combined with TP53 mutations and CNA could predict treatment response and prognosis in PROC patients without requiring tumor tissues.
