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Saverio Minucci, Giancarlo Pruneri, Luca Magnani and colleagues identify acquired CYP19A1 amplification as a mechanism of resistance to aromatase inhibitors in ERα metastatic breast cancer. Mechanistically, they show that CYP19A1 amplification results in increased aromatase activity and estrogen-independent ERα binding to target genes.
Franco Locatelli, Dirk Reinhardt, Marry van den Heuvel-Eibrink, C Michel Zwaan, Maarten Fornerod, Tanja Gruber and colleagues report whole-exome and transcriptome sequencing of acute megakaryoblastic leukemia from pediatric and adult patients without Down syndrome (non-DS-AMKL). They find that pediatric non-DS-AMKL can be divided into seven subgroups characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes.
Andrew Feinberg, Christine Iacobuzio-Donahue and colleagues describe the epigenomic reprogramming that occurs during pancreatic cancer progression. They also show that hematogenous metastases co-evolve a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP) and that oxPPP inhibition reverses chromatin reprogramming and blocks tumorigenic potential.
Ashlee Earl and colleagues analyze whole-genome sequences from 5,310 Mycobacterium tuberculosis isolates from five continents. They find that resistance to isoniazid arises before rifampicin resistance across all of the lineages, geographical regions and time periods.
Peter Campbell, Hartmut Döhner and colleagues present an analysis of genetic mutations and clinical information from 1,540 patients with acute myeloid leukemia, demonstrating the utility of clinical knowledge banks for personalized medicine. They show that use of their approach could reduce the number of hematopoietic cell transplants in patients with AML by up to 25% while maintaining survival rates.
Jens Lykke-Andersen, Frank Baas, Joseph Gleeson and colleagues report that mutations in the 3′ exonuclease TOE1 cause pontocerebellar hypoplasia type 7. They further show that these mutations result in the accumulation of incompletely processed small nuclear RNAs, leading to severe, early-onset neurodegeneration.
Christine Iacobuzio-Donahue and colleagues report a detailed analysis of whole-genome sequencing data from primary and metastatic tumors in four patients with pancreatic cancer. They find that in each patient primary tumors and metastases have identical mutations in known driver genes.
Jimmy Liu and colleagues perform genome-wide association by proxy (GWAX) in a large population cohort by replacing cases with their first-degree relatives. They apply GWAX to 12 common diseases and show its utility by identifying new risk loci for Alzheimer's disease, coronary artery disease and type 2 diabetes.
Michael Talkowski, David FitzPatrick, Erica Davis and colleagues report rare inherited or de novo missense variants in SMCHD1 in arhinia patients. Some of the same mutations in SMCHD1 are known to cause a phenotypically distinct muscular dystrophy disorder, FSHD2, and the distinct clinical features of the two disorders suggests that additional genes interact with SMCHD1 to cause arhinia.
James Lee, Kenneth Smith and colleagues report a within-cases genome-wide association analysis for Crohn's disease to identify genetic loci specifically associated with disease severity and outcome. They find four loci associated with prognosis, none of which is associated with susceptibility to Crohn's disease.
Nada Jabado, Jacek Majewski and colleagues identify mutations in multiple histone H3 genes causing recurrent p.Lys36Met alterations in head and neck squamous cell carcinomas. They show that tumors with these p.Lys36Met alterations correspond to a specific DNA methylation cluster along with tumors harboring previously described mutations in NSD1.
Carl Anderson, Jeffrey Barrett and colleagues use whole-genome sequencing and imputation to explore the genetic architecture of inflammatory bowel disease. They identify a low-frequency missense variant in ADCY7 that doubles risk of ulcerative colitis and detect a burden of very rare, damaging missense variants in known Crohn's disease risk genes.
Jeanne Amiel, Bernd Wollnik, Bruno Reversade and colleagues report de novo missense mutations in SMCHD1 in patients with Bosma arhinia microphthalmia syndrome (BAMS) and isolated arhinia. Mechanistic studies support a key role for SMCHD1 in nasal development and suggest that the mutations in patients may function via a gain-of-function mechanism.
Jeffrey Barrett, Carl Anderson and colleagues report the results of a large genome-wide association study of inflammatory bowel disease. They identify 25 new genome-wide significant loci, 3 of which contain integrin genes, and find that the associated variants at several of these loci are correlated with expression changes in response to immune stimulus.