11 research outputs found

    Clonal architecture of secondary acute myeloid leukemia

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    BACKGROUND: The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. METHODS: We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. RESULTS: Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene. CONCLUSIONS: Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.

    Integrated genomic characterization of endometrial carcinoma

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    SummaryWe performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors

    The Origin and Evolution of Mutations in Acute Myeloid Leukemia

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    SummaryMost mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse

    Comprehensive molecular portraits of human breast tumours

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    This Article from the Cancer Genome Atlas consortium describes a multifaceted analysis of primary breast cancers in 825 people. Exome sequencing, copy number variation, DNA methylation, messenger RNA arrays, microRNA sequencing and proteomic analyses were performed and integrated to shed light on breast-cancer heterogeneity. Just three genes — TP53, PIK3CA and GATA3 — are mutated at greater than 10% frequency across all breast cancers. Many subtype-associated and novel mutations were identified, as well as two breast-cancer subgroups with specific signalling-pathway signatures. The analyses also suggest that much of the clinically observable plasticity and heterogeneity occurs within, and not across, the major subtypes of breast cancer

    Finishing the euchromatic sequence of the human genome

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    The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

    Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

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    Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

    Integrated genomic characterization of endometrial carcinoma

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    We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ~25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.National Institutes of Health (U.S.) (Grant 5U24CA143799-04)National Institutes of Health (U.S.) (Grant 5U24CA143835-04)National Institutes of Health (U.S.) (Grant 5U24CA143840-04)National Institutes of Health (U.S.) (Grant 5U24CA143843-04)National Institutes of Health (U.S.) (Grant 5U24CA143845-04)National Institutes of Health (U.S.) (Grant 5U24CA143848-04)National Institutes of Health (U.S.) (Grant 5U24CA143858-04)National Institutes of Health (U.S.) (Grant 5U24CA143866-04)National Institutes of Health (U.S.) (Grant 5U24CA143867-04)National Institutes of Health (U.S.) (Grant 5U24CA143882-04)National Institutes of Health (U.S.) (Grant 5U24CA143883-04)National Institutes of Health (U.S.) (Grant 5U24CA144025-04)National Institutes of Health (U.S.) (Grant U54HG003067-11)National Institutes of Health (U.S.) (Grant U54HG003079-10)National Institutes of Health (U.S.) (Grant U54HG003273-10

    Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

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    © 2014 Elsevier Inc. Recent genomic analyses of pathologically defined tumor types identify 'within-a-tissue' disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-oforigin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pancancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies
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