We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.
BackgroundTriple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance.MethodsGenomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets.ResultsThrough gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76, and SYK) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC. CCNE1 and TPX2 were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC. CCNE1 amplification was associated with poor overall survival in patients with metastatic TNBC.ConclusionsCCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5290-4) contains supplementary material, which is available to authorized users.
Key Points• Notch1/DII4-mediated signals are normally suppressed by LRF, preventing HSCs from premature T-cell differentiation in the bone marrow.• Erythroblastic islands may have the capacity to regulate the fate and function of HSCs. IntroductionFor life-long hematopoiesis, most immature hematopoietic stem cells (HSCs), so-called long-term HSCs (LT-HSCs), remain dormant, but in response to hematopoietic stress, they actively cycle to generate multi-lineage blood cells without depleting the HSC pool. 1 These fate decisions are governed by intrinsic and extrinsic mechanisms. Relevant to extrinsic regulation, adult HSCs reside in a specialized microenvironment within the bone marrow (BM), the "niche," which is composed of multiple types of supporting cells that express membrane-bound and secreted factors. 2,3 Osteoblasts, endothelial cells, perivascular cells, mesenchymal stem cells, and glial cells have been proposed as components of the BM microenvironment. 3 These studies reveal how both self-renewal and quiescence of adult HSCs are maintained; however, how the balance between self-renewal and differentiation is regulated in the niche remains largely unknown.The highly conserved Notch signaling pathway regulates many cell-fate decisions and homeostasis in various organs. 4 In humans its dysregulation is associated with many types of cancer and inherited congenital anomalies. 4 There are 4 mammalian homologs of the Notch receptor (Notch 1-4) and 5 ligands: Delta-like-1, 3 and 4, which belong to the Delta ligand family, and Jagged-1 and 2, which belong to the Serrate family. 5 After ligand engagement, the intracellular domain of the Notch receptor (ICN) undergoes multiple proteolytic cleavages and translocates to the nucleus, where it binds the recombination signal-binding protein 1 for j (RBP-j, also known as CSL/CBF1) and mastermind-like coactivators (MAML1-3), and activates downstream targets, such as hairy and enhancer of split homologue-1 (Hes-1). 5 Notch is indispensable for the emergence of embryonic hematopoiesis 6 ; however, its role in adult HSC function is controversial. In addition, it is not completely understood at which HSC/progenitor stages Notch receptors are expressed and which Notch ligands are expressed in the BM microenvironment.LRF (for leukemia/lymphoma related factor), also known as Pokemon, ZBTB7a, FBI-1, and OCZF, is a POZ and Krüppel (POK)-type transcription factor with multiple functions in hematopoietic development, oncogenesis, and humoral immunity. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From inhibitors, which block Notch signaling, rescues aberrant lymphoid development, suggesting that Lrf antagonizes the Notch pathway at the HSC/progenitor level. 8 Furthermore, despite its cr...
Background. In this phase II clinical trial, we evaluated the efficacy of the non-anthracycline combination of carboplatin and nab-paclitaxel in early stage triple negative breast cancer (TNBC). Patients and Methods. Patients with newly diagnosed stage II-III TNBC (N=69) were treated with neoadjuvant carboplatin (AUC 6) every 28 days x 4 plus nab-paclitaxel (100 mg/m 2) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS). Results. Sixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events (AEs), including Grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were 32/67 (48%) pCR (RCB 0), 10/67 (15%) RCB I, 19/67 (28%) RCB II, 5/67 (7%) RCB III, and 1/67 (2%) progressed and had no surgery. Univariate analysis showed GSIS "immune-hot" and DNA repair defect (DRD) were associated with higher pCR with odds ratio of 4.62 (P=0.005) and 4.76 (P=0.03) respectively, and with RCB 0/I vs. RCB II/III with odds ratio 4.80 (P=0.01). "Immune-hot" GSIS was highly correlated with DRD status (P=0.03), TILs level (P<0.001), and TNBC molecular subtype (P<0.001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I vs. II/III with odds ratio 7.19 (95% CI 2.01-25.68, P=0.002) and 8.95 (95%. CI 2.09-38.23, P=0.003), respectively. Conclusions. The combination of carboplatin and nabpaclitaxel for early stage high risk TNBC showed manageable toxicity and encouraging anti-tumor activity. GSIS "immune-hot" signature is associated with higher pCR rate and RCB class 0/1. This study provides additional rationale for using non-anthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. The Oncologist 2020;9999:• • Implications for Practice: Platinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, "immune-hot" GeparSixto Immune Signature (GSIS) and DNA repair defect were associated with higher pCR and residual cancer burden class 0/1. The association of GSIS "immune-hot" signature with higher pCR holds promise for "de-escalating" neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.
Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P<0.01) among the patients with therapy-related disease. In mutational analysis, TP53 alteration was the most common abnormality in patients with therapy-related disease (n=18: 30%). Interestingly, the presence of mutations in TP53 or in any other of the high-risk genes (EZH2, ETV6, RUNX1, ASXL1: n=29: 48%) did not significantly affect either overall survival or relapse-free survival. Allogeneic stem-cell transplantation is, therefore, a curative treatment for patients with therapy-related myelodysplastic syndrome, conferring a similar long-term survival to that of patients with de novo disease despite higher-risk features. While TP53 alteration was the most common mutation in therapy-related myelodysplastic syndrome, the finding was not detrimental in our case-series.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.