Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis

The Origin and Evolution of Mutations in Acute Myeloid Leukemia

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

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at.10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer. © 2012 Macmillan Publishers Limited. All rights reserved

Integrated genomic analyses of ovarian carcinoma

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.National Institutes of Health (U.S.) (Grant U54HG003067)National Institutes of Health (U.S.) (Grant U54HG003273)National Institutes of Health (U.S.) (Grant U54HG003079)National Institutes of Health (U.S.) (Grant U24CA126543)National Institutes of Health (U.S.) (Grant U24CA126544)National Institutes of Health (U.S.) (Grant U24CA126546)National Institutes of Health (U.S.) (Grant U24CA126551)National Institutes of Health (U.S.) (Grant U24CA126554)National Institutes of Health (U.S.) (Grant U24CA126561)National Institutes of Health (U.S.) (Grant U24CA126563)National Institutes of Health (U.S.) (Grant U24CA143882)National Institutes of Health (U.S.) (Grant U24CA143731)National Institutes of Health (U.S.) (Grant U24CA143835)National Institutes of Health (U.S.) (Grant U24CA143845)National Institutes of Health (U.S.) (Grant U24CA143858)National Institutes of Health (U.S.) (Grant U24CA144025)National Institutes of Health (U.S.) (Grant U24CA143866)National Institutes of Health (U.S.) (Grant U24CA143867)National Institutes of Health (U.S.) (Grant U24CA143848)National Institutes of Health (U.S.) (Grant U24CA143843)National Institutes of Health (U.S.) (Grant R21CA135877

Finishing the euchromatic sequence of the human genome

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

Genome remodelling in a basal-like breast cancer metastasis and xenograft

Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour

Prahistoric mining at Krasne Siolo (Belarus) and environmental changes

Krasne Siolo is situated about 60 km south-east from Grodno and about 12 km north from Wołkowysk in Grodno district, in Ros River valley (Fig. 1.). Prehistoric flint mines in area of glaciodislocated chalk in Krasne Siolo were discovered in 1924 by Z. Szmit and later were investigated by N.N. Gurina (1976), M.M. Czarniauski and others (1996). Rescue researches included only small area of two major prehistoric exploitation fields which were destroyed by exploitation of chalk since 1914 (Fig. 3). During researches in 'chalk tongues' about 700 hundred main shafts were documented and dug up (classified as pits and niche mines). Near shafts flint workshops and multicultural sites were located which served as a settlement for the miners and as a place where the raw material was processed. Main users of flint mines were Neolithic societies of Globular Amphora Culture and Corde Ware Culture. The beginning of the flint usage from Krasne Siolo can be dated to Final Palaeolithic (Tanged Points Cultures) and the end of mining activity falls probably in the Early Bronze Age. Exploratory region of Krasne Siolo is situated just few kilometers westward from in detail examined section of Zlewianka valley near Piaski. In palynological diagrams there are lack of changes in vegetation cover caused by development of the center of flint mining in region of the Krasne Siolo in period of settlement by the Globular Amphora and Corde Ware Culture population

Origin and neotectonic activity of a local Andine trench in the light of studiem of deformation in lacustrine sediments of the Río Colca valley (Peru)

Na obwodzie doliny Rio Colca (uformowanej w osadach jeziornych) w Andach Środkowych (Peru) znajdują się uskoki, których bieg jest zgodny z kształtem tej doliny. Zbadano je w miejscowościach Madrigal, Coporaque, Chivay i Maca, gdzie mają cechy uskoków zrzutowych, zarówno normalnych, jak i odwróconych. Ich geometryczne parametry wskazują, że dolina jest tektonicznym zapadliskiem, a uskoki są jego brzegiem. Porównano ich układ z teoretycznymi modelami geotektonicznymi (ryc. 10A-C). Widoczna krzywizna i nachylenie powierzchni uskoków są obecnie tylko fragmentami pełnego kształtu uskoków, co nie pozwala jednoznacznie ustalić jaką formę ma całe zapadlisko i który z modeli jest właściwy. Stwierdzono natomiast, że są to uskoki młode, ponieważ deformują osady czwartorzędowe. Ich powstanie jest związane z intensywnym wypiętrzaniem Andów. Jest możliwe, że nawiązują do układu uskoków starszych i są ich przedłużeniem w młodszym piętrze strukturalnym.Tectonic faults run along the margins of the Río Colca valley (incised in lacustrine sediments) in the Central Andes of Peru. The faults were studied at localities Madrigal, Coporaque, Chivay and Maca, where they have characteristics of normal and reverse dip-slip faults. Their geometrical parameters indicate that the valley is a graben bounded by the studied faults. The fault pattern has been compared with theoretical geotectonic models (Fig. 10A- C). As the visible curvatures and slopes of the fault surfaces are representative only for their exposed fragments, they are not sufficient for unanimous recognition of the graben form and for the selection of the proper model. It has been ascertained that the faults are young, because they deform Quaternary sediments. It is possible that they are linked to the older faults and are their continuation in the younger structural stage

Quaternary evolution of Valley and Canyon of Rio Colca - report from geomorphological studies done in 2006 year

Kartowanie geomorfologiczne wykonano w Dolinie Colca pomiędzy Chivay i Madrigal (30 km) oraz w Kanionie Colca powyżej Canco (trzy przekroje). Zarówno Dolina jak i Kanion mają założenia tektoniczne. W Dolinie Colca wyraźnie wyodrębniają się trzy odcinki z odmiennym zestawem form i procesów modelujących dno i zbocza. Okresowe blokowanie odpływu przez osuwiska (Dolina Colca) i potoki lawowe (Kanion) powodowało powstawanie jezior zaporowych. Współczesna dolina rzeki Colca powstała w środkowym plejstocenie wskutek kaptażu przez ciek należący do zlewiska Oceanu Spokojnego bezodpływowego systemu śródgórskich rowów tektonicznych, zajętego u schyłku pliocenu i w dolnym plejstocenie przez jezioro wypełniane pyłami wulkanicznymi. Kaptaż nastąpił w miejscu uwarunkowanym tektonicznie, na zrzuconym skrzydle uskoku i linii tektonicznej. Brak odmłodzenia profilu podłużnego w Dolinie Colca związany jest z młodym wiekiem kaptażu, ruchami neotektonicznymi, a także przeciążeniem rzeki koluwiami bezpośrednio powyżej miejsca kaptażu.Geomorphological mapping was carried out in Colca Valley between Chivay and Madrigal (section of 30 km length) and in Colca Canyon upstream of Canco (three cross sections). Both the valley and the canyon are conditioned by tectonic structures. Three sections with different morphology and processes modelling bottom and sides of the valley could be distinguished in the Colca Valley. A water-course was periodically obstructed by landslides (Colca Valley) or lava flows (Colca Canyon) and dam lakes occurred. The recent Colca Valley is a result of the Middle Pleistocene capture of endorheic system of intermountain grabens by a river which belongs to the Pacific Ocean drainage basin. Lake filling by volcanic ashes occurred in these grabens in the end of Pliocene and the beginning of Quater-nary. Capture happened in tectonically determined place on downthrow at block and fracture line. A lack of rejuvenation of longitudinal profile of the Colca Valley can result from young age of capture, neotectonic movements and also river overloading by colluvia directly upstream of the capture place