Abstract
Chromothripsis is detectable in 20–30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study we interrogate 752 ...NDMM patients using whole genome sequencing (WGS) to investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC = 0.90) and can be used identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC = 0.97) and an independent series of 34 NDMM (AUC = 0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.
High sodium intake is known to increase blood pressure and is difficult to measure in epidemiologic studies.
We examined the effect of sodium intake on metabolites within the DASH (Dietary Approaches ...to Stop Hypertension Trial)-Sodium Trial to further our understanding of the biological effects of sodium intake beyond blood pressure.
The DASH-Sodium Trial randomly assigned individuals to either the DASH diet (low in fat and high in protein, low-fat dairy, and fruits and vegetables) or a control diet for 12 wk. Participants within each diet arm received, in random order, diets containing high (150 nmol or 3450 mg), medium (100 nmol or 2300 mg), and low (50 nmol or 1150 mg) amounts of sodium for 30 d (crossover design). Fasting blood samples were collected at the end of each sodium intervention. We measured 531 identified plasma metabolites in 73 participants at the end of their high- and low-sodium interventions and in 46 participants at the end of their high- and medium-sodium interventions (
= 119). We used linear mixed-effects regression to model the relation between each log-transformed metabolite and sodium intake. We also combined the resulting
values with Fisher's method to estimate the association between sodium intake and 38 metabolic pathways or groups.
Six pathways were associated with sodium intake at a Bonferroni-corrected threshold of 0.0013 (e.g., fatty acid, food component or plant, benzoate, γ-glutamyl amino acid, methionine, and tryptophan). Although 82 metabolites were associated with sodium intake at a false discovery rate ≤0.10, only 4-ethylphenylsufate, a xenobiotic related to benzoate metabolism, was significant at a Bonferroni-corrected threshold (
< 10
). Adjustment for coinciding change in blood pressure did not substantively alter the association for the top-ranked metabolites.
Sodium intake is associated with changes in circulating metabolites, including gut microbial, tryptophan, plant component, and γ-glutamyl amino acid-related metabolites. This trial was registered at clinicaltrials.gov as NCT00000608.
Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon-producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell ...neoplasm (BPDCN), and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia. The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here, we characterize patients with AML with pDC expansion (pDC-AML), which we observe in ∼5% of AML cases. pDC-AMLs often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, as well as originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells toward pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.
Pernicious anemia (PA) is a risk factor for gastric cancer. Other autoimmune conditions may also contribute.
In a case-control study, we evaluated 47 autoimmune conditions among 39,125 gastric ...cancers and 200,000 cancer-free controls.
Six conditions were associated with increased gastric cancer risk (range of adjusted odds ratios: 1.28-1.93, P < 0.05): PA, membranous nephropathy, primary biliary cirrhosis, pure red cell aplasia, primary sclerosing cholangitis, and Graves disease. PA was associated with 8 other autoimmune conditions (adjusted odds ratios: 1.57-4.54, P < 0.05).
Autoimmune conditions associated with gastric cancer or PA may reflect effects of autoimmune gastritis or other carcinogenic pathways.
We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and ...cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) ≥1.5 K/mcL, hemoglobin ≥12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx <15 months significantly decreased the likelihood of t-MN. The average AUC was 0.88. We stratified our cohort by bone metastasis and by findings on peripheral smear. In both the subset without bone metastasis (n=159) and in the cohort with no blasts or dysplastic cells on peripheral smear (n=96) our variables had similar effects on the risk of t-MN. Among the 47 patients with bone metastasis, an ANC ≥1.5 K/mcL was the only variable associated with a decreased risk of t-MN. Our findings show that in patients with BC and unexplained cytopenias, clinical and laboratory parameters can predict t-MN and assist clinicians in determining the timing of a BMBx.
Two recent metabolomic analyses found serum lipid, energy, and other metabolites related to aggressive prostate cancer risk up to 20 years prior to diagnosis.
We conducted a serum metabolomic ...investigation of prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that included annual serum total prostate-specific antigen measurement and digital rectal examination. This nested study included 380 cases diagnosed post-screening and 380 controls individually matched to cases on age, race, study centre, and blood-collection date (median time to diagnosis, 10 years (range 4.4-17 years)). Sera were analysed on a high-resolution accurate mass platform of ultrahigh-performance liquid and gas chromatography/mass spectroscopy that identified 695 known metabolites. Logistic regression conditioned on the matching factors estimated odds ratios (OR) and 95% confidence intervals of risk associated with an 80th percentile increase in the log-metabolite signal.
Twenty-seven metabolites were associated with prostate cancer at P<0.05. Pyroglutamine, gamma-glutamylphenylalanine, phenylpyruvate, N-acetylcitrulline, and stearoylcarnitine showed the strongest metabolite-risk signals (ORs=0.53, 0.51, 0.46, 0.58, and 1.74, respectively; 0.001⩽P⩽0.006). Findings were similar for aggressive disease (peptide chemical class, P=0.03). None of the P-values were below the threshold of Bonferroni correction, however.
A unique metabolomic profile associated with post-screening prostate cancer is identified that differs from that in a previously studied, unscreened population.
Abstract
Tobacco use, hypertension, hyperglycemia, overweight, and inactivity are leading causes of overall and cardiovascular disease (CVD) mortality worldwide, yet the relevant metabolic ...alterations responsible are largely unknown. We conducted a serum metabolomic analysis of 620 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985–2013). During 28 years of follow-up, there were 435 deaths (197 CVD and 107 cancer). The analysis included 406 known metabolites measured with ultra-high-performance liquid chromatography/mass spectrometry–gas chromatography/mass spectrometry. We used Cox regression to estimate mortality hazard ratios for a 1-standard-deviation difference in metabolite signals. The strongest associations with overall mortality were N-acetylvaline (hazard ratio (HR) = 1.28; P < 4.1 × 10−5, below Bonferroni statistical threshold) and dimethylglycine, 7-methylguanine, C-glycosyltryptophan, taurocholate, and N-acetyltryptophan (1.23 ≤ HR ≤ 1.32; 5 × 10−5 ≤ P ≤ 1 × 10−4). C-Glycosyltryptophan, 7-methylguanine, and 4-androsten-3β,17β-diol disulfate were statistically significantly associated with CVD mortality (1.49 ≤ HR ≤ 1.62, P < 4.1 × 10−5). No metabolite was associated with cancer mortality, at a false discovery rate of <0.1. Individuals with a 1-standard-deviation higher metabolite risk score had increased all-cause and CVD mortality in the test set (HR = 1.4, P = 0.05; HR = 1.8, P = 0.003, respectively). The several serum metabolites and their composite risk score independently associated with all-cause and CVD mortality may provide potential leads regarding the molecular basis of mortality.
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