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OBJECTIVE: Patients with late life depression sometimes refuse to receive electroconvulsive therapy (ECT) owing to its adverse reactions. To alleviate patient's resistance, a novel ECT stimulation strategy named mixed-strategy ECT (msECT) was designed in which patients are administered conventional ECT during the first three sessions, followed by low energy stimulation during the subsequent sessions. However, whether low energy electrical stimulation in the subsequent stage of therapy affect its efficacy and reduce adverse reactions in patients with late life depression remains unknown. To explore differences between msECT and regular ECT(RECT) with respect to clinical efficacy and side effects. METHODS: This randomized, controlled trial was conducted from 2019 to 2021 on 60 patients with late life depression who were randomly assigned to two groups: RECT or msECT. A generalized estimating equation (GEE) was used to compare the two stimulation strategies regarding their efficacy and side effects on cognition. Chi-squared test was used to compare side effects in the two strategies. RESULTS: In the intent-to-treat group, the GEE model suggested no differences between-group difference in Hamilton Depression Rating Scale-17 score over time (Wald χ2=7.275, p=0.064), whereas the comparison of side effects in the two strategies favored msECT (Wald χ2=8.463, p=0.015) as fewer patients had adverse events during the second phase of treatment with msECT (χ2 =13.467, p=0.004). CONCLUSION: msECT presents its similar efficacy to RECT. msECT may have milder side effects on cognition.
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PURPOSE: Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. METHODS AND MATERIALS: Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. RESULTS: A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]). CONCLUSION: Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.
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Algoritmos , Antraciclinas , Neoplasias de la Mama , Terapia Neoadyuvante , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Antraciclinas/uso terapéutico , Antraciclinas/administración & dosificación , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , China/epidemiología , Adulto , Recombinación Homóloga , Mutación , Anciano , Variaciones en el Número de Copia de ADN , Proteína BRCA1/genéticaRESUMEN
For a wide range of chronic autoimmune and inflammatory diseases in both adults and children, synthetic glucocorticoids (GCs) are one of the most effective treatments. However, besides other adverse effects, GCs inhibit bone mass at multiple levels, and at different ages, especially in puberty. Although extensive studies have investigated the mechanism of GC-induced osteoporosis, their target cell populations still be obscure. Here, our data show that the osteoblast subpopulation among Gli1+ metaphyseal mesenchymal progenitors (MMPs) is responsive to GCs as indicated by lineage tracing and single-cell RNA sequencing experiments. Furthermore, the proliferation and differentiation of Gli1+ MMPs are both decreased, which may be because GCs impair the oxidative phosphorylation(OXPHOS) and aerobic glycolysis of Gli1+ MMPs. Teriparatide, as one of the potential treatments for GCs in bone mass, is sought to increase bone volume by increasing the proliferation and differentiation of Gli1+ MMPs in vivo. Notably, our data demonstrate teriparatide ameliorates GC-caused bone defects by targeting Gli1+ MMPs. Thus, Gli1+ MMPs will be the potential mesenchymal progenitors in response to diverse pharmaceutical administrations in regulating bone formation.
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Glucocorticoides , Células Madre Mesenquimatosas , Osteoporosis , Animales , Ratones , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones Endogámicos C57BL , Osteoblastos/metabolismo , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteoporosis/inducido químicamente , Osteoporosis/metabolismo , Osteoporosis/patología , Teriparatido/farmacología , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/genéticaRESUMEN
Injectable antibacterial and osteoinductive hydrogels have received considerable attention for promoting bone regeneration owing to their versatile functionalities. However, a current hydrogel with antibacterial, osteoinductive, and antioxidant properties by a facile method for periodontitis treatment is still missing. To overcome this issue, we designed an injectable hydrogel system (GPM) composed of gelatin, Ti3C2Tx MXene nanosheets, and poly-l-lysine using a simple enzymatic cross-linking technique. Physicochemical characterization demonstrated that the GPM hydrogel matrix exhibited excellent stability, moderate tissue adhesion ability, and good mechanical behavior. The GPM hydrogels significantly inhibited the growth of Porphyromonas gingivalis, scavenged reactive oxygen species, attenuated inflammatory responses, and enhanced bone tissue regeneration. Intriguingly, the arrangement of the junctional epithelium, alveolar bone volume, and alveolar bone height in the GPM-treated periodontal disease group recovered to that of the healthy group. Therefore, our injectable hydrogel system with versatile functions may serve as an excellent tissue scaffold for the treatment of periodontitis.
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Periodontitis , Humanos , Nanogeles , Especies Reactivas de Oxígeno , Periodontitis/tratamiento farmacológico , Hidrogeles/farmacología , Hidrogeles/química , Antibacterianos/farmacologíaRESUMEN
Urine-based testing is promising for noninvasive diagnosis of urothelial carcinoma (UC) but has suboptimal sensitivity for early-stage tumors. Herein, we developed a multitarget urine tumor DNA test, UI-Seek, for UC detection and evaluated its clinical feasibility. The prediction model was developed in a retrospective cohort (n = 382), integrating assays for FGFR3 and TERT mutations and aberrant ONECUT2 and VIM methylation to generate a UC-score. The test performance was validated in a double-blinded, multicenter, prospective trial (n = 947; ChiCTR2300076543) and demonstrated a sensitivity of 91.37% and a specificity of 95.09%. The sensitivity reached 75.81% for low-grade Ta tumors and exceeded 93% in high-grade Ta and higher stages (T1 to T4). Simultaneous identification of both bladder and upper urinary tract tumors was enabled with sensitivities exceeding 90%. No significant confounding effects were observed regarding benign urological diseases or non-UC malignancies. The test showed improved sensitivities over urine cytology, the NMP22 test, and UroVysion FISH alongside comparable specificities. The single-target accuracy was greater than 98% as confirmed by Sanger sequencing. Post-surgery UC-score decreased in 97.7% of subjects. Overall, UI-Seek demonstrated robust performance and considerable potential for the early detection of UC.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/orina , Estudios Retrospectivos , Estudios Prospectivos , Sensibilidad y Especificidad , Resultado del Tratamiento , ADN , Biomarcadores de Tumor/genética , Factores de Transcripción , Proteínas de HomeodominioRESUMEN
Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1, and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern, and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy, and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR, and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant metastasis-free survival and event-free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population.
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Neoplasias Óseas , Osteosarcoma , Humanos , Variaciones en el Número de Copia de ADN/genética , Osteosarcoma/genética , Genómica , Factores de Riesgo , Mutación/genética , Neoplasias Óseas/genéticaRESUMEN
BACKGROUND: The mutational pattern of homologous recombination repair (HRR)-associated gene alterations in Chinese urothelial carcinoma (UC) necessitates comprehensive sequencing efforts, and the clinical implications of HRR gene mutations in UC remain to be elucidated. MATERIALS AND METHODS: We delineated the mutational landscape of 343 Chinese UC patients from West China Hospital and 822 patients from The Cancer Genome Atlas (TCGA) using next-generation sequencing (NGS). Data from 182 metastatic UC patients from MSK-IMPACT cohort were used to assess the association between HRR mutations and immunotherapy efficacy. Comprehensive transcriptomic analysis was performed to explore the impact of HRR mutations on tumor immune microenvironment. RESULTS: Among Chinese UC patients, 34% harbored HRR gene mutations, with BRCA2, ATM, BRCA1, CDK12, and RAD51C being the most prevalently mutated genes. Mutational signatures contributing to UC differed between patients with and without HRR mutations. Signature 22 for exposure to aristolochic acid was only observed in Chinese UC patients. The presence of HRR mutations was correlated with higher tumor mutational burden, neoantigen burden, and PD-L1 expression. Importantly, patients with HRR mutations exhibited significantly improved prognosis following immunotherapy compared to those without HRR mutations. CONCLUSIONS: Our findings provide valuable insights into the genomic landscape of Chinese UC patients and underscore the molecular rationale for utilizing immunotherapy in UC patients with HRR mutations.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Reparación del ADN por Recombinación , Genes cdc , Mutación , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Homologous recombination (HR) repair (HRR) has been indicated to be a biomarker for immunotherapy, chemotherapy, and poly-ADP ribose polymerase inhibitors inhibitors (PARPis). Nonetheless, their molecular correlates in upper tract urothelial carcinoma (UTUC) have not been well studied. This study aimed to explore the molecular mechanism and tumor immune profile of HRR genes and the relevance of their prognostic value in patients with UTUC. MATERIALS AND METHODS: One hundred and ninety-seven tumors and matched blood samples from Chinese UTUC were subjected to next-generation sequencing. A total of 186 patients from The Cancer Genome Atlas were included. Comprehensive analysis was performed. RESULTS: In Chinese patients with UTUC, 5.01% harbored germline HRR gene mutations, and 1.01% had Lynch syndrome-related genes. A total of 37.6% (74/197) of patients carried somatic or germline HRR gene mutations. There was marked discrepancy in the mutation landscapes, genetic interactions, and driver genes between the HRR-mut cohorts and HRR-wt cohorts. Aristolochic acid signatures and defective DNA mismatch repair signatures only existed in individuals in the HRR-mut cohorts. Inversely, the unknown signature (signature A) and signature SBS55 only existed in patients in the HRR-wt cohorts. HRR gene mutations regulated immune activities by NKT cells, plasmacytoid dendritic cells, hematopoietic stem cell, and M1 macrophages. In patients with local recurrence, patients with HRR gene mutations had poorer DFS rates than patients with wild-type HRR genes. CONCLUSIONS: Our results imply that the detection of HRR gene mutations can predict recurrence in patients with UC. In addition, this study provides a path to explore the role of HRR-directed therapies, including PARPis, chemotherapy, and immunotherapy.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/genética , Reparación del ADN por Recombinación , Mutación , PronósticoRESUMEN
Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative effects on normal cells, and chemotherapeutic drugs, such as platinum, can lead to multidrug resistance in tumor cells. Herein, this work reports a new bioinspired tumor-targeting and enzyme-activatable cell-material interface system based on DDDEEK-pY-phenylboronic acid (SAP-pY-PBA) conjugates. Using this tandem-activation system, this work selectively regulates the alkaline phosphatase (ALP) triggered anchoring and aggregation of SAP-pY-PBA conjugates on the cancer cell surface and the subsequent formation of the supramolecular hydrogel. This hydrogel layer can efficiently kill osteosarcoma cells by enriching calcium ions from tumor cells and forming a dense hydroxyapatite layer. Owing to the novel antitumor mechanism, this strategy neither hurts normal cells nor causes multidrug resistance in tumor cells, thereby showing an enhanced tumor treatment effect than the classical antitumor drug, doxorubicin (DOX). The outcome of this research demonstrates a new antitumor strategy based on a bioinspired enzyme-responsive biointerface combining supramolecular hydrogels with biomineralization.
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Neoplasias Óseas , Osteosarcoma , Niño , Humanos , Adolescente , Biomineralización , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Hidrogeles/farmacología , Neoplasias Óseas/tratamiento farmacológico , BiomarcadoresRESUMEN
PURPOSE: The 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85-90%, with a 10-15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL. METHODS: We enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ2-square test or Fisher's exact test for categorical variables. RESULTS: A total of 381 gene mutations were identified in 66 different genes in 152/219 patients. PIK3R1 mutation was more common in infants (P = 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P < 0.001). NRAS, PTPN11, FLT3, and KMT2D mutations were more common in patients who did not carry the fusion genes (all P < 0.050). PTEN mutation was significantly associated with high-risk ALL patients (P = 0.011), while NOTCH1 mutation was common in middle-risk ALL patients (P = 0.039). Patients with ETV6 or PHF6 mutations were less sensitive to steroid treatment (P = 0.033, P = 0.048, respectively). CONCLUSION: This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.
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Pueblos del Este de Asia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Lactante , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Mutación , Factores de Transcripción/genética , Genómica , PronósticoRESUMEN
Current methods for the early detection and minimal residual disease (MRD) monitoring of urothelial carcinoma (UC) are invasive and/or possess suboptimal sensitivity. We developed an efficient workflow named urine tumor DNA multidimensional bioinformatic predictor (utLIFE). Using UC-specific mutations and large copy number variations, the utLIFE-UC model was developed on a bladder cancer cohort (n = 150) and validated in The Cancer Genome Atlas (TCGA) bladder cancer cohort (n = 674) and an upper tract urothelial carcinoma (UTUC) cohort (n = 22). The utLIFE-UC model could discriminate 92.8% of UCs with 96.0% specificity and was robustly validated in the BLCA_TCGA and UTUC cohorts. Furthermore, compared to cytology, utLIFE-UC improved the sensitivity of bladder cancer detection (p < 0.01). In the MRD cohort, utLIFE-UC could distinguish 100% of patients with residual disease, showing superior sensitivity compared to cytology (p < 0.01) and fluorescence in situ hybridization (FISH, p < 0.05). This study shows that utLIFE-UC can be used to detect UC with high sensitivity and specificity in patients with early-stage cancer or MRD. The utLIFE-UC is a cost-effective, rapid, high-throughput, noninvasive, and promising approach that may reduce the burden of cystoscopy and blind surgery.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/patología , Hibridación Fluorescente in Situ/métodos , Variaciones en el Número de Copia de ADN , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , ADN , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: TP53 mutations are frequent in non-small cell lung cancer (NSCLC). Different categories of TP53 mutations may be associated with survival in advanced NSCLC, but their effect on prognosis is diverse. To date, a comprehensive comparison of the relationship between different classes of TP53 alterations and survival in advanced NSCLC has rarely been performed. Moreover, the prognostic significance of a novel approach called the evolutionary action of TP53 (EAp53) in advanced NSCLC is unclear. METHODS: A total of 210 patients with NSCLC harboring TP53 mutation data were enrolled. Genomic and clinical data for the Memorial Sloan Kettering Cancer Center (MSKCC) cohort with advanced NSCLC were obtained from cBioPortal. Relationship between clinical characteristics and TP53 mutations was performed by Fisher's exact test or χ2 test. Overall survival (OS) analysis was evaluated using Kaplan-Meier method and Cox proportional hazards regression model. RESULTS: TP53 mutations were identified in 51.4% of NSCLC patients and were mainly located in exons 5, 7, and 8. The distribution patterns of missense and truncating mutations of TP53 were remarkably different. Among patients with advanced NSCLC who never received immune checkpoint inhibitor treatments, EAp53 high-risk mutations were significantly associated with poor OS in both our cohort and the MSKCC cohort. Moreover, marked differences were observed in the mutational landscape between patients with EAp53 high-risk mutations (HR group) and other patients (OT group). The HR group displayed higher mutation frequencies in the RTK, cell cycle, and DNA damage repair (DDR) pathways than the OT group. In addition, the tumor mutation burden in the HR group was significantly higher than that in the OT group. CONCLUSIONS: This study provided important insights into the molecular-clinical profile of TP53-mutated NSCLC patients. Moreover, the data revealed that EAp53 high-risk mutations were an independent prognostic factor for worse OS in advanced NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Mutación , Proteína p53 Supresora de Tumor/genética , Pronóstico , Análisis de SupervivenciaRESUMEN
Background: Colorectal cancer (CRC) is one of the most prevalent malignances worldwide. However, CRC with situs inversus totalis (SCRC) is extremely rare, and molecular characterization of this disease has never been investigated. Methods: Tumor tissue samples from 8 patients with SCRC and 33 CRC patients without situs inversus totalis (NSCRC) were subjected to multigene next-generation sequencing. Results: The most frequently mutated genes in SCRC were APC, TP53, CHEK2, MDC1, GNAQ, KRAS, and SMAD4. A high frequency of SCRC tumors had mutations in DNA damage repair genes. Single amino acid substitutions in the DNA damage repair genes caused by continuous double base substitution was identified in the majority of this population. Furthermore, mutational profiles showed notable differences between the SCRC and NSCRC groups. In particular, CHEK2, MDC1, GNAQ, SMAD4, BRCA1, HLA-B, LATS2, and NLRC5 mutations were more frequently observed in SCRC patients. The mutation loci distributions of KRAS in the SCRC cohort differed from that of the NSCRC cohort. Additionally, differences in the targeted genomic profiles and base substitution patterns were observed between the two groups. Conclusions: These findings comprehensively revealed a molecular characterization of SCRC, which will contribute to the development of personalized therapy and improved clinical management of SCRC patients.
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The tumor mutational burden (TMB) calculated by whole-exome sequencing (WES) is a promising biomarker for the response to immune checkpoint inhibition (ICIs) in solid tumors. However, WES is not feasible in the routine clinical setting. In addition, the characteristics of the TMB in Chinese urothelial carcinoma (UC) are unclear. The aim of this study was to demonstrate the reliability of an Acornmed 808 panel and analyze the characteristics of the TMB in Chinese UC. An Acornmed 808 panel was designed and virtually validated using UC data from the cancer genome atlas (TCGA). Comprehensive analysis of sequencing and clinical data was performed to explore the characteristics of the TMB for 143 Chinese UC patients. Compared to the TMB calculated with random 808-, 500-, and 250-gene panels, the TMB calculated with the Acornmed 808 panel was closer to that calculated by WES. There were marked disparities in the mutational landscape and TMB between Chinese and TCGA UC data. The TMB was negatively associated with copy number variation (CNV). In contrast, the TMB was positive correlation with numbers of mutated DDR genes. Exposure to aristolochic acid signature was observed only in the TMB-high groups. The Acornmed 808 panel is a clinically practical method to assess the TMB. The TMB was associated with the DDR gene status and CNV counts and might be a biomarker for further stratification of UC patients. The study suggested that patients with high TMB may have a unique carcinogenic mechanism.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/genética , China/epidemiología , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Mutación , Reproducibilidad de los Resultados , Carga Tumoral/genética , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
BACKGROUND: Renal cell carcinoma (RCC) is a disease of genomic alterations, of which the complete panorama helps in facilitating molecular-guided therapy. Germline mutation profiles and associated somatic and clinical characteristics remains unexplored in Chinese RCC patients. METHODS: We retrospectively profiled the germline and somatic mutations of 322 unselected RCC patients using a panel consisting of 808 cancer-related genes. We categorized patients into three groups based on germline mutation status and compared the somatic mutation spectrum among different groups. RESULTS: Approximately one out of ten (9.9%) RCC patients were identified to carry pathogenic/likely pathogenic (P/LP) germline variants (PGVs), of which 3.7% were variants in syndromic RCC-associated genes and 6.2% were other cancer-predisposition genes. The most common PGV was found in VHL (2.2%), followed by FH, TSC2, ATM, BRCA1, NBN, and BLM (0.6% each). Young patients (≤46 years) were more likely to harbor PGVs. Variants in syndromic RCC-associated genes were predominant identified in young patients, while variants in other cancer-predisposition genes were found in patients >46 years more frequently. Furthermore, 39.3% (11/28) of patients carrying PGVs were detected to have somatic "second hit" events. Germline and somatic sequencing, including microsatellite instability (MSI) status analysis, provided potentially actionable therapeutic targets in 17.1% of patients in the whole cohort. CONCLUSIONS: Our results revealed that approximately 10% of RCC patients carried clinically significant germline mutations. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing in RCC population.
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BACKGROUND: Approximately 30% of Chinese individuals with cytogenetically normal acute myeloid leukemia (CN-AML) have biallelic CEBPA (biCEBPA) mutations. The prognosis and optimal therapy for these patients are controversial in clinical practice. METHODS: In this study, we performed targeted region sequencing of 236 genes in 158 individuals with this genotype and constructed a nomogram model based on leukemia-free survival (LFS). Patients were randomly assigned to a training cohort (N =111) and a validation cohort (N =47) at a ratio of 7:3. Risk stratification was performed by the prognostic factors to investigate the risk-adapted post-remission therapy by Kaplan-Meier method. RESULTS: At least 1 mutated gene other than CEBPA was identified in patients and mutation number was associated with LFS (61.6% vs. 39.0%, P =0.033), survival (85.6% vs. 62.9%, P =0.030) and cumulative incidence of relapse (CIR) (38.4% vs. 59.5%, P =0.0496). White blood cell count, mutations in CFS3R, KMT2A and DNA methylation related genes were weighted to construct a nomogram model and differentiate two risk subgroups. Regarding LFS, low-risk patients were superior to the high-risk (89.3% vs. 33.8%, P <0.001 in training cohort; 87.5% vs. 18.2%, P =0.009 in validation cohort). Compared with chemotherapy, allogenic hematopoietic stem cell transplantation (allo-HSCT) improved 5-year LFS (89.6% vs. 32.6%, P <0.001), survival (96.9% vs. 63.6%, P =0.001) and CIR (7.2% vs. 65.8%, P <0.001) in high-risk patients but not low-risk patients (LFS, 77.4% vs. 88.9%, P =0.424; survival, 83.9% vs. 95.5%, P =0.173; CIR, 11.7% vs. 11.1%, P =0.901). CONCLUSIONS: Our study indicated that biCEBPA mutant-positive CN-AML patients could be further classified into two risk subgroups by four factors and allo-HSCT should be recommended for high-risk patients as post-remission therapy. These data will help physicians refine treatment decision-making in biCEBPA mutant-positive CN-AML patients.
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BACKGROUND: The aim of the study was to validate the diagnostic role of circulating tumor DNA (ctDNA) in genetics aberration on the basis of next-generation sequencing (NGS) in pediatric acute myeloid leukemia (AML). METHODS: Bone marrow (BM) and peripheral blood (PB) were collected from 20 AML children at the time of initial diagnosis, and a ctDNA sample was isolated from PB. Detection of mutation was performed on ctDNA, BM, and peripheral blood mononuclear cell (PBMC) by NGS based on a 185-gene panel. RESULTS: Among 185 genes sequenced by the NGS platform, a total of 82 abnormal genes were identified in 20 patients. Among them, 61 genes (74.39%) were detected in ctDNA, PBMC, and BM samples, while 11 (13.41%) genes were found only in ctDNA and 4 (4.88%) were detected only in the BM sample, and 2 (2.44%) were detected only in PBMC. A total of 239 mutations were detected in three samples, while 209 in ctDNA, 180 in bone marrow, and 184 in PBMC. One hundred sixty-four mutations in ctDNA were shared by matched BM samples, and the median variant allelic frequency (VAF) of these mutations was 41.34% (range, 0.55% to 99.96%) and 44.36% (range, 0.56% to 99.98%) in bone marrow and ctDNA. It was found that 65.79% (75/114) of mutations with clinical significance were detected in three samples, with 9 mutations detected both in ctDNA and BM, and 2 mutations detected both in PBMC and BM. The consistency of mutations with clinical significance between ctDNA and BM was 77.06% (84/109). Among the 84 mutations with clinical significance detected in both sources, the concordance of VAF assessment by both methods was high (R2 = 0.895). CONCLUSION: This study demonstrates that ctDNA was a reliable sample in pediatric AML and can be used for mutation detection. Consistency analysis showed that ctDNA can mirror the genomic information from BM. In addition, a subset of mutations was exclusively detected in ctDNA. These data support the fact that monitoring ctDNA with next-generation sequencing-based assays can provide more information about gene mutations to guide precision treatment in pediatric AML.
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Small bowel adenocarcinoma (SBA) is a rare malignancy with a poor prognosis and limited treatment options. Despite prior studies, molecular characterization of this disease is not well defined, and little is known regarding Chinese SBA patients. In this study, we conducted multigene next-generation sequencing and 16S ribosomal RNA gene sequencing on samples from 76 Chinese patients with surgically resected primary SBA. Compared with colorectal cancer and Western SBA cohorts, a distinctive genomic profile was revealed in Chinese SBA cohorts. According to the levels of clinical actionability to targetable alterations stratified by OncoKB system, 75% of patients harbored targetable alterations, of which ERBB2, BRCA1/2, and C-KIT mutations were the most common targets of highest-level actionable alterations. In DNA mismatch repair-proficient (pMMR) patients, significant associations between high tumor mutational burden and specific genetic alterations were identified. Moreover, KRAS mutations/TP53 wild-type/nondisruptive mutations (KRASmut /TP53wt/non-dis ) were independently associated with an inferior recurrence-free survival (hazard ratio [HR] = 4.21, 95% confidence interval [CI] = 1.94-9.14, P < .001). The bacterial profile revealed Proteobacteia, Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Cyanobacteria were the most common phyla in SBA. Furthermore, patients were clustered into three subgroups based on the relative abundance of bacterial phyla, and the distributions of the subgroups were significantly associated with the risk of recurrence stratified by TP53 and KRAS mutations. In conclusion, these findings provided a comprehensive molecular basis for understanding SBA, which will be of great significance in improving the treatment strategies and clinical management of this population.
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Adenocarcinoma/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Intestinales/genética , Intestino Delgado , ARN Ribosómico 16S/genética , Adenocarcinoma/microbiología , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , China , Reparación de la Incompatibilidad de ADN , Supervivencia sin Enfermedad , Neoplasias Duodenales/genética , Neoplasias Duodenales/microbiología , Neoplasias Duodenales/mortalidad , Femenino , Microbioma Gastrointestinal , Genes BRCA1 , Genes BRCA2 , Genes p53 , Genes ras , Humanos , Neoplasias del Íleon/genética , Neoplasias del Íleon/microbiología , Neoplasias del Íleon/mortalidad , Neoplasias Intestinales/microbiología , Neoplasias Intestinales/mortalidad , Intestino Delgado/microbiología , Neoplasias del Yeyuno/genética , Neoplasias del Yeyuno/microbiología , Neoplasias del Yeyuno/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-kit/genética , Receptor ErbB-2/genéticaRESUMEN
Teriparatide is the most widely prescribed bone anabolic drug in the world, but its cellular targets remain incompletely defined. The Gli1+ metaphyseal mesenchymal progenitors (MMPs) are a main source for osteoblasts in postnatal growing mice, but their potential response to teriparatide is unknown. Here, by lineage tracing, we show that teriparatide stimulates both proliferation and osteoblast differentiation of MMPs. Single-cell RNA sequencing reveals heterogeneity among MMPs, including an unexpected chondrocyte-like osteoprogenitor (COP). COP expresses the highest level of Hedgehog (Hh) target genes and the insulin-like growth factor 1 receptor (Igf1r) among all cell clusters. COP also expresses Pth1r and further upregulates Igf1r upon teriparatide treatment. Inhibition of Hh signaling or deletion of Igf1r from MMPs diminishes the proliferative and osteogenic effects of teriparatide. The study therefore identifies COP as a teriparatide target wherein Hh and insulin-like growth factor (Igf) signaling are critical for the osteoanabolic response in growing mice.