Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia

Effect of drugs, peptide hormones and lipogenic precursors on the relative incorporation of [3H]H2O and carbon into hepatic cholesterol

AbstractMeasurement of the weight of desmosterol produced during its biosynthesis in the presence of tritiated water and triparanol has permitted a direct determination of the relative flux of carbon and tritium (the H/C ratio) into sterol in hepatocytes. The H/C ratio increased with time of incubation irrespective of the nutritional state of the donor animals. This increase was more marked in hepatocytes from starved animals. Pyruvate and lactate increased, and glucagon decreased, the sterol H/C ratio. Addition of pyruvate to incubations containing glucagon resulted in a 32–67% increase in the H/C ratio depending upon nutritional status. Insulin had no effect whilst (−)-hydroxycitrate decreased the ratio by 25%

Functional variants of the HMGA1 gene and type 2 diabetes mellitus.

CONTEXT: High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM). OBJECTIVE: To examine the association of HMGA1 gene variants with type 2 DM. DESIGN, SETTINGS, AND PARTICIPANTS: Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls. MAIN OUTCOME MEASURES: The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis. RESULTS: The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA. CONCLUSIONS: Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM