Pedigree Investigation, Clinical Characteristics and Prognosis Analysis of Hematological Disease Patients with Germline TET2 Mutation

2021 ◽  
Author(s):  
Xia Wu ◽  
Jili Deng ◽  
Nanchen Zhang ◽  
Xiaoyan Liu ◽  
Xue Zheng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Clinical Characteristics ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Gene Mutations ◽  
Peripheral Blood Cell ◽  
Common Mutation ◽  
Tet2 Mutation ◽  
Family Aggregation

Abstract Background: More and more germline gene mutations have been discovered in hematological malignances with the development of next gene sequencing (NGS). Tet methylcytosine dioxygenase 2 (TET2) is one of the most common mutation genes in hematological neoplasms. We aimed to analyzed whether germline TET2 mutation has a family aggregation or is a tumor predisposition gene. Further we compared its impact with somatic TET2 mutation in hematological diseases.Methods: A total cohort of 103 hematological patients with TET2 mutation were included from December 2016 to December 2019. Data were extracted from hematology department of West China Hospital of Sichuan University. Bone marrow (BM) or peripheral blood (PB) as somatic DNA origin to be detected by next-generation sequencing (NGS), and nails and hairs as germline DNA origin to be detected by Sanger sequencing, respectively. Further, we compared the clinical characteristics between the patients with germline and somatic TET2 mutation.Results: 103 patients were included, including 33 (32.03%) patients with germline TET2 mutation and 70 (67.97%) patients with somatic TET2 mutation. Variant allele frequency (VAF) of germline TET2 mutation was more stable in our study, ranging from 40% to 55% and mutation sites were more concentrated. Patients with germline TET2 mutation were younger with median age 48 (range, 16-82) (P=0.0078). Further, patients with germline TET2 mutation were mainly myelodysplastic syndromes (MDS) (n=13, 39.4%), while patients with somatic TET2 mutation were acute myeloid leukemia (AML) (n=28, 40.0%) (P=0.0003). Germline TET2 mutation affected the distribution of peripheral blood cell count and the proportion in bone marrow (P<0.05). Germline TET2 mutation was a poor prognosis factor in MDS patients via univariate analysis (HR=5.3, 95%CI: 0.89-32.2, P=0.0209), but not in multivariate analysis by Cox regression model (P=0.062).Conclusions: Some family members were asymptomatic carriers, which indicated germline TET2 mutation might have a family aggregation. More importantly, TET2 gene may be a predisposition gene of hematological malignant when the other gene mutations as the second hit. The VAF of germline TET2 mutation is more stable. At the same time, the germline TET2 mutation may be an adverse factor for the MDS patients.

Correlation Between Changes of Pelvic Bone Marrow Fat Content and Hematological Toxicity in Concurrent Chemoradiotherapy for Cervical Cancer

2021 ◽  
Author(s):  
Cong Wang ◽  
Xiaohang Qin ◽  
Guanzhong Gong ◽  
Lizhen Wang ◽  
Ya Su ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Bone Marrow ◽  
Blood Cell ◽  
Peripheral Blood ◽  
Concurrent Chemoradiotherapy ◽  
Peripheral Blood Cell ◽  
Fat Content ◽  
Pelvic Bone ◽  
Cell Counts ◽  
Blood Cell Counts

Abstract Objectives: To quantify the pelvic bone marrow (PBM) fat content changes receiving different radiation doses of concurrent chemoradiotherapy for cervical cancer and to determine association with peripheral blood cell counts. Methods: Fifty-four patients were prospectively collected. Patients underwent MRI iterative decomposition of water and fat with echo asymmetrical and least squares estimation (IDEAL IQ) scanning at RT-Pre, RT mid-point, RT end, and six months. The changes in proton density fat fraction (PDFF%) at 5–10 Gy, 10–15 Gy, 15–20 Gy, 20–30 Gy, 30–40 Gy, 40–50 Gy, and >50 Gy doses were analyzed. Spearman’s rank correlations were performed between peripheral blood cell counts versus the differences in PDFF% at different dose gradients before and after treatment. Results: The lymphocytes (ALC) nadirs appeared at the midpoint of radiotherapy, which was only 27.6% of RT-Pre; the white blood cells (WBC), neutrophils (ANC), and platelets (PLT) nadirs appeared at the end of radiotherapy which was 52.4%, 65.1%, and 69.3% of RT-Pre, respectively. At RT mid-point and RT-end, PDFF% increased by 46.8% and 58.5%, respectively. Six months after radiotherapy, PDFF% decreased by 4.71% under 5–30 Gy compared to RT-end; while it still increased by 55.95% compared to RT-Pre. There was a significant positive correlation between PDFF% and ANC nadirs at 5–10 Gy (r = 0.62, P = 0.006), and correlation was observed between PDFF% and ALC nadirs at 5–10 Gy (r = 0.554, P = 0.017). Conclusion: MRI IDEAL IQ imaging was a non-invasive approach to evaluate and track the changes of PBM fat content with concurrent chemoradiotherapy for cervical cancer. The limitation of low-dose bone marrow irradiation volume in cervical cancer concurrent chemoradiotherapy should be paid more attention.

scholarly journals Chromosome Studies in Normal and Leukemic Rats

Blood ◽  
1964 ◽  
Vol 23 (5) ◽  
pp. 564-571 ◽  
Author(s):  
G. DOWD ◽  
K. DUNN ◽  
WILLIAM C. MOLONEY
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Species Differences ◽  
Peripheral Blood Cell ◽  
Myelogenous Leukemia ◽  
Peripheral Blood Cells ◽  
X Ray ◽  
Normal Rat

Abstract 1. Adequate chromosome preparations were obtained in 70 per cent of normal rat peripheral blood cell cultures. However, cultures of peripheral blood cells from leukemic rats were almost universally unsuccessful. 2. In x-ray- and 3MCA-induced leukemias direct bone marrow preparations provided adequate metaphases in eight of 12 cases. Failures were attributed in four cases to scanty material obtained from fibrotic marrows. 3. No consistent chromosome abnormalities, such as those reported in human myelogenous leukemia, were found in these leukemic rats. However, the series of cases is small, and species differences and other factors may have influenced the results of these studies.

scholarly journals Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell–Replete Haploidentical Donor Transplantation Using Post-Transplant Cyclophosphamide

2017 ◽  
Vol 35 (26) ◽  
pp. 3002-3009 ◽  
Author(s):  
Asad Bashey ◽  
Mei-Jie Zhang ◽  
Shannon R. McCurdy ◽  
Andrew St. Martin ◽  
Trevor Argall ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Peripheral Blood ◽  
Cox Regression ◽  
The United States ◽  
Platelet Recovery ◽  
Post Transplant ◽  
Transplant Outcomes ◽  
Prospective Comparison ◽  
Mobilized Peripheral Blood

Purpose T-cell–replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28-day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up.

Detection of Nucleophosmin Gene Mutations in Plasma from Patients with Acute Myeloid Leukemia: Clinical Significance and Implications.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2855-2855
Author(s):  
Wanlong Ma ◽  
Xi Zhang ◽  
Iman Jilani ◽  
Farhad Ravandi ◽  
Elihu Estey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Leukemic Cells ◽  
Striking Difference ◽  
Plasma Dna ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Nucleotides insertion in the nucleophosphamin (NPM1) gene has been reported in about one third of patients with acute myeloid leukemia (AML). Multiple studies showed that the presence of NPM1 mutations associated with better outcome in patients with AML. Studies reported to date have analyzed leukemic cells obtained from bone marrow or peripheral blood. We tested for mutations in the NPM1 gene using peripheral blood plasma and compared results with clinical outcome from a single institution. Analyzing plasma from 98 newly diagnosed patient with AML showed NPM1 mutation in 24 (23%) of patient while only one (4%) of 28 previously untreated patients with myelodysplastic syndrome (MDS) showed NPM1 mutation. Compared with peripheral blood cells, 2 (8%) of the 24 positive patients were negative by cells; none were positive by cells and negative by plasma. Most of the mutations detected (45%) were in patients with FAB classification M2, M4 and M5. In addition to the reported 4 bp insertion, we also detected 4 bp deletion in one patient in cells and plasma. Patients with NPM1 mutation had a significantly higher white blood cell count (P = 0.0009) and a higher blast count in peripheral blood (P = 0.002) and in bone marrow (P = 0.002). Blasts in patients with NPM1 mutant expressed lower levels of HLA-DR (P = 0.005), CD13 (P = 0.02) and CD34 (P < 0.0001), but higher CD33 levels (P = 0.0004). Patients with NPM1 mutation appear to have better chance of responding to standard therapy (P = 0.06). Event free survival of patients with NPM1 mutation was longer (P = 0.056) than in patients with intermediate cytogenetic abnormalities. The most striking difference in survival was in patients who required >35 days to respond to therapy (Figure). Survival was significantly longer in patients with NPM1 mutation requiring >35 days to respond (P = 0.027). This data not only support that NPM1 plays a significant role in the biology and clinical behavior of AML, but also show that plasma DNA is enriched with leukemia-specific DNA and is a reliable source for testing. Figure Figure

The Prognostic Role of Jagged-1 Protein Expression In Acute Myeloid Leukemia Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2726-2726 ◽  
Author(s):  
Agnieszka Wierzbowska ◽  
Agnieszka Pluta ◽  
Konrad Stepka ◽  
Magdalena Czemerska ◽  
Barbara Cebula-Obrzut ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Protein Expression ◽  
Hodgkin Lymphoma ◽  
Peripheral Blood ◽  
Univariate Analysis ◽  
Response To Treatment ◽  
Notch 1 ◽  
Hematopoietic Stem

Abstract Abstract 2726 Objectives: Jagged-1 is a member of the Delta/Serrate/Lag-2 (DSL) family of proteins that are ligands for Notch receptors. Aberrant Jagged-1/Notch-1 signaling is posited to promote the development of AML by inducing excessive self-renewal with a concomitant block in cell differentiation. Moreover, Notch-1 signaling has been identified as a critical factor involved in the maintenance of a pool of self-renewing hematopoietic stem cells (HSC) as well as AML stem cells. So far there were no reports on the clinical role of Notch-1 and Jagged-1 expression in AML. In this study we evaluated the expression of Jagged-1 and Notch-1 proteins in AML blasts and CD34+ peripheral blood stem cells (PBSC) collected during mobilization procedures before autologous stem cell transplantation. In addition, in AML patients we correlated the expression of both proteins with known prognostic factors and response to treatment. Methods: The expression of Notch-1 and Jagged-1 proteins was examined in leukemic blasts isolated from bone marrow or peripheral blood of 53 de novo AML patients with median age 57 years (range 21–82). CD34+ collected from 13 lymphoma patients (11 multiple myeloma, 1 Hodgkin lymphoma, 1 non-Hodgkin lymphoma) with median age 57 (range 21–69 years) served as a control. All measurements were carried out using multi-colour flow cytometry. In parallel, the isotype controls were performed for all measurements. Protein expression was assessed as a percentage of Notch-1 and Jagged-1 positive cells. The cut-off 20% was used to subdivide patients into “low-expressers” and “high-expressers” group. Results: We found that the median expression of Jagged-1 was significantly higher in AML blasts (18,2%; range 0,9–62,4%) as compared to CD34+ PBSC (3,0%; range 0,9–21%); p<0.0001. In contrast, the expression of Notch-1 in AML patients (median 1,4%; range 0,1–24,8%) was lower than in the control CD34+ cells (median 3,85%; range 0,7–16%); p<0.004. There was no correlation between Jagged-1 and Notch-1 protein expression in both AML blasts and PBSC. Jagged-1 expression was significantly higher in AML patients with WBC ≤20G/L (median 21,2%) compared to group with WBC >20 G/L (median 9,85%); p<0.004. Consequently, we found the significant negative correlation between Jagged-1 expression and WBC count (p<0.02). Patients with good-risk karyotype according to SWOG classification showed significantly higher expression of Jagged-1 protein as compared to intermediate and poor risk group (medians 21,8% vs. 11,5% respectively; p< 0.02). Thirty two out of 53 AML patients received standard induction chemotherapy with daunorubicine and cytarabine (“3+7”), 21/53 received non-intensive therapy. Nineteen (61%) of intensively treated patients achieved complete remission (CR). We observed that the CR rate in “high-expressers” of Jagged-1 was significantly higher than in the “low-expressers” group (80% vs. 43% respectively; p=0.04). Additionally, a good karyotype and a high expression of Jagged-1 protein were the only factors associated with higher probability of CR (p=0.05, p<0.01, respectively) in univariate analysis. There was no statistical association between the Notch-1 expression and response to treatment, karyotype or tumour size associated risk factors as: WBC, percentage of leukemic blasts in bone marrow and LDH. Moreover, no correlations between Notch-1 and CD34 expression as well as Notch-1 and differentiation markers (CD13, CD14, CD15, CD33) expressions in AML blasts were found. Conclusions: Jagged-1 protein is highly expressed in AML blasts and correlates with better response to standard chemotherapy, favorable karyotype and lower WBC in AML patients. These data clearly demonstrate an important role of Jagged-1 in AML biology. A better understanding of autonomous Jadded-1 signaling in AML may create new options for therapeutic interventions in AML. Disclosures: Robak: Johnson & Johnson: Research Funding.

scholarly journals Bioinformatics Analysis Reveals an Association Between Cancer Cell Stemness, Gene Mutations, and the Immune Microenvironment in Stomach Adenocarcinoma

2020 ◽  
Vol 11 ◽  
Author(s):  
Zaisheng Ye ◽  
Miao Zheng ◽  
Yi Zeng ◽  
Shenghong Wei ◽  
Yi Wang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Clinical Characteristics ◽  
Prognostic Model ◽  
Cox Regression ◽  
Tumor Therapy ◽  
Gene Mutations ◽  
The Cancer Genome Atlas ◽  
Prognostic Models ◽  
Immune Microenvironment ◽  
Stomach Adenocarcinoma

Cancer stem cells (CSCs), characterized by infinite proliferation and self-renewal, greatly challenge tumor therapy. Research into their plasticity, dynamic instability, and immune microenvironment interactions may help overcome this obstacle. Data on the stemness indices (mRNAsi), gene mutations, copy number variations (CNV), tumor mutation burden (TMB), and corresponding clinical characteristics were obtained from The Cancer Genome Atlas (TCGA) and UCSC Xena Browser. Tumor purity and infiltrating immune cells in stomach adenocarcinoma (STAD) tissues were predicted using the ESTIMATE R package and CIBERSORT method, respectively. Differentially expressed genes (DEGs) between the high and low mRNAsi groups were used to construct prognostic models with weighted gene co-expression network analysis (WGCNA) and Lasso regression. The association between cancer stemness, gene mutations, and immune responses was evaluated in STAD. A total of 6,739 DEGs were identified between the high and low mRNAsi groups. DEGs in the brown (containing 19 genes) and blue (containing 209 genes) co-expression modules were used to perform survival analysis based on Cox regression. A nine-gene signature prognostic model (ARHGEF38-IT1, CCDC15, CPZ, DNASE1L2, NUDT10, PASK, PLCL1, PRR5-ARHGAP8, and SYCE2) was constructed from 178 survival-related DEGs that were significantly related to overall survival, clinical characteristics, tumor microenvironment immune cells, TMB, and cancer-related pathways in STAD. Gene correlation was significant across the prognostic model, CNVs, and drug sensitivity. Our findings provide a prognostic model and highlight potential mechanisms and associated factors (immune microenvironment and mutation status) useful for targeting CSCs.

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