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The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumor sample. By doing so, we can track tumor evolution and identify the spatial origins of cells resisting therapy.

Whole-genome sequencing of samples from seven subjects with secondary acute myeloid leukemia identified somatic mutations. These data, together with genotype analysis of the antecedent myelodysplastic syndromes (MDS), revealed the clonal evolution of MDS and secondary AML. The myelodysplastic syndromes, a heterogeneous group of diseases characterized by ineffective hematopoiesis, are the most common cause of acquired bone marrow failure in adults. 1 Secondary acute myeloid leukemia (AML) develops in approximately one third of persons with myelodysplastic syndromes. 2 Clinical discrimination between the myelodysplastic syndromes and secondary AML currently rests predominantly on cytomorphologic analysis, since patients with myelodysplastic syndromes have dysplastic hematopoiesis and a myeloblast count of less than 20%, whereas those with a myeloblast count of 20% or more have AML. Although considerable overlap exists between the spectrum of cytogenetic and molecular lesions seen in the two disorders, there . . .

The risk of disease progression among patients with myelodysplastic syndrome was higher among those in whom point mutations persisted in bone marrow at day 30 after allogeneic hematopoietic stem-cell transplantation than among those without these mutations.

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C , PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes ( ATM , BAP1 , BRCA1/2 , BRIP1 , FANCM , PALB2 and RAD51C/D ). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine. Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer. Here, Lu et al . analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.

Somatic mutations in spliceosome genes are detectable in ∼50% of patients with myelodysplastic syndromes (MDS). We hypothesize that cells harbouring spliceosome gene mutations have increased sensitivity to pharmacological perturbation of the spliceosome. We focus on mutant U2AF1 and utilize sudemycin compounds that modulate pre-mRNA splicing. We find that haematopoietic cells expressing mutant U2AF1(S34F), including primary patient cells, have an increased sensitivity to in vitro sudemycin treatment relative to controls. In vivo sudemycin treatment of U2AF1(S34F) transgenic mice alters splicing and reverts haematopoietic progenitor cell expansion induced by mutant U2AF1 expression. The splicing effects of sudemycin and U2AF1(S34F) can be cumulative in cells exposed to both perturbations—drug and mutation—compared with cells exposed to either alone. These cumulative effects may result in downstream phenotypic consequences in sudemycin-treated mutant cells. Taken together, these data suggest a potential for treating haematological cancers harbouring U2AF1 mutations with pre-mRNA splicing modulators like sudemycins. Spliceosome mutations occur in approximately 50% of patients with myelodysplastic syndromes. Here, the authors show that tumour cells harbouring the S34F mutation in the U2AF spliceosome gene is sensitive to compounds that further perturb the spliceosome.

The cure rates for precursor B-cell acute lymphoblastic leukemia (ALL) among children have improved, but the prognosis for older patients and children with relapsed disease remains poor. Risk stratification based on clinical features and disease characteristics can improve outcomes by enabling physicians to reduce the toxicity of therapy for patients with lower-risk disease and intensify therapy for patients with higher-risk disease. The negative prognosis associated with the t(9;22) translocation, which results in expression of the BCR–ABL1 activated kinase fusion protein, is attenuated by treatment that includes tyrosine kinase inhibitors, providing a paradigm for molecularly guided therapy in patients with precursor . . .

Timothy Graubert and colleagues report a high-resolution survey of copy number variation in mouse inbred strains and assess the impact of such variation on gene expression. They find that up to 26% of strain-dependent expression variation in hematopoietic stem/progenitor cells is associated with copy number variation. The extent to which differences in germline DNA copy number contribute to natural phenotypic variation is unknown. We analyzed the copy number content of the mouse genome to sub–10-kb resolution. We identified over 1,300 copy number variant regions (CNVRs), most of which are <10 kb in length, are found in more than one strain, and, in total, span 3.2% (85 Mb) of the genome. To assess the potential functional impact of copy number variation, we mapped expression profiles of purified hematopoietic stem and progenitor cells, adipose tissue and hypothalamus to CNVRs in cis . Of the more than 600 significant associations between CNVRs and expression profiles, most map to CNVRs outside of the transcribed regions of genes. In hematopoietic stem and progenitor cells, up to 28% of strain-dependent expression variation is associated with copy number variation, supporting the role of germline CNVs as key contributors to natural phenotypic variation in the laboratory mouse.

Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study 21 well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21 to 2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes, and many (47.5%) colocalize with previously mapped segmental duplications in the mouse genome. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits.

In patients who had a relapse of acute myeloid leukemia after allogeneic hematopoietic stem-cell transplantation, no characteristic genetic lesions were detected, but alterations in expression of genes related to immune function were noted, particularly down-regulation of major histocompatibility complex class II genes.

Decitabine produced responses in patients with acute myeloid leukemia or myelodysplastic syndromes who had cytogenetic abnormalities associated with a poor prognosis, including 21 of 21 patients with tumors that contained TP53 mutations. Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are clonal disorders of myeloid hematopoiesis. 1 Adult patients with AML who have karyotypes that are associated with unfavorable risk and older patients with AML (≥60 years of age) have poor outcomes, with a median survival of approximately 1 year. 2 , 3 Patients with AML and TP53 mutations tend to be older (median age, 61 to 67 years), and almost all have karyotypes that are associated with unfavorable risk; if they receive standard cytotoxic chemotherapy, these patients have especially poor outcomes (median survival, 4 to 6 months). 3 – 6 Decitabine (5-aza-2′-deoxycytidine) is commonly used as . . .