Search tips
Search criteria

Results 1-25 (124)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
more »
1.  Integrated Analysis of Germline and Somatic Variants in Ovarian Cancer 
Nature communications  2014;5:3156.
We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyze germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2, and PALB2. Additionally, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B, and MLL3). Evidence for loss of heterozygosity was found in 100% and 76% of cases with germline BRCA1 and BRCA2 truncations respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 237 candidate functional germline truncation and missense variants, including 2 pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK, and MLL pathways.
PMCID: PMC4025965  PMID: 24448499
2.  Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma 
Cell reports  2014;7(1):104-112.
Osteosarcoma is a neoplasm of mesenchymal origin with features of osteogenic differentiation. Patients with recurrent or metastatic disease have a very poor prognosis. To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue (obtained from 19 patients) in the discovery cohort as well as 14 samples from 13 patients in the validation cohort. Our results demonstrate that pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). Moreover, single nucleotide variations (SNVs) exhibit a pattern of localized hypermutation called “kataegis” in 50% of the tumors. Despite these regions of kataegis across the osteosarcoma genomes, we detected relatively few recurrent SNVs, and only when SVs were included did we identify the major pathways that are mutated in osteosarcoma. We identified p53 pathway lesions in all 19 patient’s tumors in the discovery cohort, 9 of which were translocations in the first intron of the TP53 gene, leading to gene inactivation. This mechanism of p53 gene inactivation is unique to osteosarcoma among pediatric cancers. In an additional cohort of 32 patients, TP53 gene alterations were identified in 29 of those tumors. Beyond TP53, the RB1, ATRX and DLG2 genes showed recurrent somatic alterations (SNVs and/or SVs) in 29–53% of the tumors. These data highlight the power of whole-genome sequencing in identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.
PMCID: PMC4096827  PMID: 24703847
3.  Clonal Architecture of Secondary Acute Myeloid Leukemia Defined by Single-Cell Sequencing 
PLoS Genetics  2014;10(7):e1004462.
Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions—the population frequency of individual clones, their genetic composition, and their evolutionary relationships—which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells.
Author Summary
Human cancers are genetically diverse populations of cells that evolve over the course of their natural history or in response to the selective pressure of therapy. In theory, it is possible to infer how this variation is structured into related populations of cells based on the frequency of individual mutations in bulk samples, but the accuracy of these models has not been evaluated across a large number of variants in individual cells. Here, we report a strategy for analyzing hundreds of variants within a single cell, and we apply this method to assess models of tumor clonality derived from bulk samples in three cases of leukemia. The data largely support the predicted population structure, though they suggest specific refinements. This type of approach not only illustrates the biological complexity of human cancer, but it also has the potential to inform patient management. That is, precise knowledge of which variants are present in which populations of cells may allow physicians to more effectively target combinations of mutations and predict how patients will respond to therapy.
PMCID: PMC4091781  PMID: 25010716
5.  Combination of BCL11A siRNA with vincristine increases the apoptosis of SUDHL6 cells 
B cell chronic lymphocytic leukemia/lymphoma 11 A (BCL11A) is associated with human B cell malignancy initiation. Our previous study has shown that downregulation of BCL11A mRNA by small interfering RNA (siRNA) is capable of inducing apoptosis in the SUDHL6 cell line. To further explore the effects of BCL11A siRNA on the enhanced cytotoxicity of a chemotherapeutic drug, we investigated the effects of BCL11A siRNA combined with vincristine (VCR) on SUDHL6 cell proliferation and apoptosis.
Chemically synthesized BCL11A siRNA was transfected into SUDHL6 cells using the HiPerFect Transfection Reagent in combination with VCR. Cell proliferation was measured by the CCK8 assay. The morphology of apoptotic cells was observed with Hoechst 33258 staining. The rate of cell apoptosis was determined by annexin V-fluorescein isothiocyanate/propidium iodide double staining using fluorescence-activated cell sorting (FACS) analysis.
After BCL11A siRNA plus VCR treatment, cell proliferation was significantly decreased in comparison with VCR or BCL11A siRNA treatment alone and negative control siRNA plus VCR treatment (P <0.05). The apoptotic rate of BCL11A siRNA plus VCR treated cells was significantly increased compared with BCL11A siRNA and VCR treatment alone and negative control siRNA plus VCR treatment (P <0.05).
The combination of BCL11A siRNA and VCR increases apoptosis in SUDHL6 cells. Our study implies that BCL11A siRNA in combination with VCR may be a useful approach for improving effective treatment for B cell lymphoma.
PMCID: PMC4086990  PMID: 24961604
BCL11A; small interfering RNA; vincristine; SUDHL6 cells; apoptosis
6.  Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis 
Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis.
We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections.
PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated.
We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ–induced gene expression, but we found impaired responses to IFN-γ restimulation.
Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ–mediated inflammation.
PMCID: PMC3746066  PMID: 23541320
Signal transducer and activator of transcription 1; IFN-γ; progressive multifocal leukoencephalopathy; Histoplasma capsulatum; Coccidioides immitis; thrush
7.  DGIdb - Mining the druggable genome 
Nature methods  2013;10(12):10.1038/nmeth.2689.
The Drug-Gene Interaction database (DGIdb) mines existing resources that generate hypotheses about how mutated genes might be targeted therapeutically or prioritized for drug development. It provides an interface for searching lists of genes against a compendium of drug-gene interactions and potentially druggable genes. DGIdb can be accessed at
PMCID: PMC3851581  PMID: 24122041
8.  Effusion cytology: an effective method for the diagnosis of pulmonary lymphangioleiomyomatosis 
Journal of Thoracic Disease  2014;6(5):E54-E57.
Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease. Chylous effusion is one of the most common clinical manifestations of LAM. Herein we present a 39-year-old female who presented progressive dyspnea on exertion and chylothorax. The chest computed tomography showed multiple thin-walled cysts in both lungs which suggesting LAM. The pleural effusion cytology plus with further immunocytochemistry confirmed the computed tomography diagnosis. Therefore, the LAM can be diagnosed by cytologic examination combined with conventional chest computed tomography and clinical manifestations, which can help some patients to avoid an invasive biopsy.
PMCID: PMC4015018  PMID: 24822126
Lymphangioleiomyomatosis (LAM); immunocytochemistry; cytology; diagnosis
9.  Anti-granulocyte-macrophage colony stimulating factor autoantibodies in patients with cryptococcal meningitis 
Cryptococcal meningitis has been described in immunocompromised patients as well as in those for whom no immune defect has been identified. GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryptococcal control.
We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in 4 current patients with cryptococcal meningitis, and identified and tested 103 archived plasma/CSF samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody containing plasmas to inhibit GM-CSF signaling.
We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis. Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified 7 HIV uninfected patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the 7 later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT-5 phosphorylation and MIP-1α production in normal PBMC. This effect was limited to their IgG fraction.
Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated pulmonary alveolar proteinosis.
PMCID: PMC3675663  PMID: 23509356
10.  Aerobic Sludge Granulation in a Full-Scale Sequencing Batch Reactor 
BioMed Research International  2014;2014:268789.
Aerobic granulation of activated sludge was successfully achieved in a full-scale sequencing batch reactor (SBR) with 50,000 m3 d−1 for treating a town's wastewater. After operation for 337 days, in this full-scale SBR, aerobic granules with an average SVI30 of 47.1 mL g−1, diameter of 0.5 mm, and settling velocity of 42 m h−1 were obtained. Compared to an anaerobic/oxic plug flow (A/O) reactor and an oxidation ditch (OD) being operated in this wastewater treatment plant, the sludge from full-scale SBR has more compact structure and excellent settling ability. Denaturing gradient gel electrophoresis (DGGE) analysis indicated that Flavobacterium sp., uncultured beta proteobacterium, uncultured Aquabacterium sp., and uncultured Leptothrix sp. were just dominant in SBR, whereas uncultured bacteroidetes were only found in A/O and OD. Three kinds of sludge had a high content of protein in extracellular polymeric substances (EPS). X-ray fluorescence (XRF) analysis revealed that metal ions and some inorganics from raw wastewater precipitated in sludge acted as core to enhance granulation. Raw wastewater characteristics had a positive effect on the granule formation, but the SBR mode operating with periodic feast-famine, shorter settling time, and no return sludge pump played a crucial role in aerobic sludge granulation.
PMCID: PMC4009315  PMID: 24822190
11.  Fever Burden Is an Independent Predictor for Prognosis of Traumatic Brain Injury 
PLoS ONE  2014;9(3):e90956.
To evaluate fever burden as an independent predictor for prognosis of traumatic brain injury (TBI).
This retrospective study involved 355 TBI patients with Glasgow Coma Scale (GCS) ≤14, who presented at the emergency department of our hospital between November 2010 and October 2012. At 6 months follow-up, patients were divided into 5 groups based on Glasgow Outcome Scale (GOS) and dichotomized to GOS score (high (4 to 5) vs. low (1 to 3)). The relationship between fever burden and GOS was assessed.
Fever burden increased as GOS scores decreased from 5 to 2, except for score 1 of GOS, which corresponded to a significant lower fever burden. Following dichotomization, patients in the high GOS group were younger, and showed less abnormal pupil reactivity (P<0.001), a higher median GCS score (P<0.001), and a lower median fever burden (P<0.001), compared with patients in the low GOS group. Univariate logistic regression analysis revealed that poor TBI prognosis was related to age, GCS, pupil reactivity, and fever burden (OR: 1.166 [95% CI: 1.117–1.217] P<0.0001). Multivariate logistic regression analysis identified fever burden as an independent predictor of poor prognosis after TBI (OR 1.098; 95% CI: 1.031–1.169; P = 0.003). These observations were confirmed by evaluation of the receiver operating characteristic (ROC) curve for fever burden (area under the curve [AUC] 0.73 [95% CI: 0.663–0.760]).
Fever burden might be an independent predictor for prognosis of TBI. High fever burden in the early stage of the disease course associated with TBI could increase the risk of poor prognosis.
PMCID: PMC3953326  PMID: 24626046
12.  Mutational landscape and significance across 12 major cancer types 
Nature  2013;502(7471):333-339.
The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known(forexample, mitogen-activatedprotein kinase, phosphatidylinositol-3-OH kinase,Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the numberof driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
PMCID: PMC3927368  PMID: 24132290
Nature genetics  2013;45(3):242-252.
The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole genome and exome sequencing of 40 cases, identified two subtypes that differ in severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras- and PI3K signaling pathways, and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
PMCID: PMC3919793  PMID: 23334668
14.  Activating HER2 mutations in HER2 gene amplification negative breast cancer 
Cancer discovery  2012;3(2):224-237.
Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.
PMCID: PMC3570596  PMID: 23220880
Genomics; Breast Cancer; Receptor Tyrosine Kinase; Oncogene
15.  Re-sequencing Expands Our Understanding of the Phenotypic Impact of Variants at GWAS Loci 
PLoS Genetics  2014;10(1):e1004147.
Genome-wide association studies (GWAS) have identified >500 common variants associated with quantitative metabolic traits, but in aggregate such variants explain at most 20–30% of the heritable component of population variation in these traits. To further investigate the impact of genotypic variation on metabolic traits, we conducted re-sequencing studies in >6,000 members of a Finnish population cohort (The Northern Finland Birth Cohort of 1966 [NFBC]) and a type 2 diabetes case-control sample (The Finland-United States Investigation of NIDDM Genetics [FUSION] study). By sequencing the coding sequence and 5′ and 3′ untranslated regions of 78 genes at 17 GWAS loci associated with one or more of six metabolic traits (serum levels of fasting HDL-C, LDL-C, total cholesterol, triglycerides, plasma glucose, and insulin), and conducting both single-variant and gene-level association tests, we obtained a more complete understanding of phenotype-genotype associations at eight of these loci. At all eight of these loci, the identification of new associations provides significant evidence for multiple genetic signals to one or more phenotypes, and at two loci, in the genes ABCA1 and CETP, we found significant gene-level evidence of association to non-synonymous variants with MAF<1%. Additionally, two potentially deleterious variants that demonstrated significant associations (rs138726309, a missense variant in G6PC2, and rs28933094, a missense variant in LIPC) were considerably more common in these Finnish samples than in European reference populations, supporting our prior hypothesis that deleterious variants could attain high frequencies in this isolated population, likely due to the effects of population bottlenecks. Our results highlight the value of large, well-phenotyped samples for rare-variant association analysis, and the challenge of evaluating the phenotypic impact of such variants.
Author Summary
Abnormal serum levels of various metabolites, including measures relevant to cholesterol, other fats, and sugars, are known to be risk factors for cardiovascular disease and type 2 diabetes. Identification of the genes that play a role in generating such abnormalities could advance the development of new treatment and prevention strategies for these disorders. Investigations of common genetic variants carried out in large sets of research subjects have successfully pinpointed such genes within many regions of the human genome. However, these studies often have not led to the identification of the specific genetic variations affecting metabolic traits. To attempt to detect such causal variations, we sequenced genes in 17 genomic regions implicated in metabolic traits in >6,000 people from Finland. By conducting statistical analyses relating specific variations (individually and grouped by gene) to the measures for these metabolic traits observed in the study subjects, we added to our understanding of how genotypes affect these traits. Our findings support a long-held hypothesis that the unique history of the Finnish population provides important advantages for analyzing the relationship between genetic variations and biomedically important traits.
PMCID: PMC3907339  PMID: 24497850
16.  Anatomy and transcript profiling of gynoecium development in female sterile Brassica napus mediated by one alien chromosome from Orychophragmus violaceus 
BMC Genomics  2014;15:61.
The gynoecium is one of the most complex organs of angiosperms specialized for seed production and dispersal, but only several genes important for ovule or embryo sac development were identified by using female sterile mutants. The female sterility in oilseed rape (Brassica napus) was before found to be related with one alien chromosome from another crucifer Orychophragmus violaceus. Herein, the developmental anatomy and comparative transcript profiling (RNA-seq) for the female sterility were performed to reveal the genes and possible metabolic pathways behind the formation of the damaged gynoecium.
The ovules in the female sterile Brassica napus with two copies of the alien chromosomes (S1) initiated only one short integument primordium which underwent no further development and the female gametophyte development was blocked after the tetrad stage but before megagametogenesis initiation. Using Brassica_ 95k_ unigene as the reference genome, a total of 28,065 and 27,653 unigenes were identified to be transcribed in S1 and donor B. napus (H3), respectively. Further comparison of the transcript abundance between S1 and H3 revealed that 4540 unigenes showed more than two fold expression differences. Gene ontology and pathway enrichment analysis of the Differentially Expressed Genes (DEGs) showed that a number of important genes and metabolism pathways were involved in the development of gynoecium, embryo sac, ovule, integuments as well as the interactions between pollen and pistil.
DEGs for the ovule development were detected to function in the metabolism pathways regulating brassinosteroid (BR) biosynthesis, adaxial/abaxial axis specification, auxin transport and signaling. A model was proposed to show the possible roles and interactions of these pathways for the sterile gynoecium development. The results provided new information for the molecular mechanisms behind the gynoecium development at early stage in B. napus.
PMCID: PMC3930543  PMID: 24456102
Brassica napus; Gynoecium; Ovule; Female sterility; Transcriptome
17.  Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts 
Cell reports  2013;4(6):10.1016/j.celrep.2013.08.022.
To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.
PMCID: PMC3881975  PMID: 24055055
18.  Pulmonary gangliocytic paraganglioma: a case report and review of the literature 
Gangliocytic paraganglioma (GP) is a rare histologic type of neuroendocrine tumors. We report a case of pulmonary GP in a 29-year-old male presenting with an asymptomatic endobronchial nodule. Grossly, the tumor showed a 4.0x3.8x3.5 cm well-defined nodule with yellowish cut surface. Microscopically, the tumor was composed of three distinct cellular types: epithelioid cells, ganglion-like cells and spindle cells. Meanwhile, transitional cells, having morphologic features between ganglion-like and epithelioid cells, were also presented. The epithelioid cells arranged in various morphologic architectures, including Zellballen, papillary, cystic and microcystic pattern. The epithelioid cells were positive for AE1/AE3, CAM 5.2, chromogranin A and synaptophysin. Ganglion-like cells showed immunoreactivity for chromogranin A and synaptophysin. A few ganglion-like cells were also positive for AE1/AE3 and/or CAM 5.2. The spindle cells were positive for S-100 protein and neurofilament. The transitional cells showed a similar immunohistochemical profile to the epithelioid cells. The authors believe stem cell theory is a reasonable explanation for the origin of GP. GP probably originate from some kind of mucosa associated stem cell which can differentiate into diverse cellular lineages.
PMCID: PMC3885502  PMID: 24427368
Gangliocytic paraganglioma; bronchial; histomorphology; immunohistochemistry; histogenesis
19.  Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas 
Nature genetics  2013;45(6):602-612.
The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs.
PMCID: PMC3727232  PMID: 23583981
20.  An inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia 
Cancer cell  2012;22(5):683-697.
To define the mutation spectrum in non-Down syndrome acute megkaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL leukemia samples. Our analysis identified a cryptic chromosome 16 inversion [inv(16)(p13.3q24.3)] in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.
PMCID: PMC3547667  PMID: 23153540
21.  Attomolar DNA detection with chiral nanorod assemblies 
Nature Communications  2013;4:2689.
Nanoscale plasmonic assemblies display exceptionally strong chiral optical activity. So far, their structural design was primarily driven by challenges related to metamaterials whose practical applications are remote. Here we demonstrate that gold nanorods assembled by the polymerase chain reaction into DNA-bridged chiral systems have promising analytical applications. The chiroplasmonic activity of side-by-side assembled patterns is attributed to a 7–9 degree twist between the nanorod axes. This results in a strong polarization rotation that matches theoretical expectations. The amplitude of the bisignate ‘wave’ in the circular dichroism spectra of side-by-side assemblies demonstrates excellent linearity with the amount of target DNA. The limit of detection for DNA using side-by-side assemblies is as low as 3.7 aM. This chiroplasmonic method may be particularly useful for biological analytes larger than 2–5 nm which are difficult to detect by methods based on plasmon coupling and ‘hot spots’. Circular polarization increases for inter-nanorod gaps between 2 and 20 nm when plasmonic coupling rapidly decreases. Reaching the attomolar limit of detection for simple and reliable bioanalysis of oligonucleotides may have a crucial role in DNA biomarker detection for early diagnostics of different diseases, forensics and environmental monitoring.
Nanoscale plasmonic assemblies are known to display exceptionally strong chiral optical activity. Here, the authors assemble gold nanorods into DNA-bridged chiral systems, and demonstrate their high efficiency for DNA detection at very low concentrations.
PMCID: PMC3826651  PMID: 24162144
22.  Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns 
The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss.
PMCID: PMC3861312  PMID: 24348793
newborn; hearing screening; gene screening; MassARRAY platform; mitochondrial 12S rRNA; GJB2 gene; SLC26A4 gene
23.  Effects of Zinc Supplementation on the Incidence of Mortality in Preschool Children: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2013;8(11):e79998.
Previous trials have shown that zinc supplementation can decrease the risk of diarrhea, pneumonia, and malaria in children; however, the effects of zinc supplementation on mortality remain unclear. This study aimed at evaluating the benefits and risks of zinc supplementation on both total mortality and cause-specific mortality.
Methodology and Principal Findings
We searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials in preschool children reporting total mortality or cause-specific mortality. Relative risk (RR) was used as a measure of the effect of zinc supplementation on the risk of mortality using a random effect model. Of the 1,520 identified articles, we included 8 trials reporting data on 87,854 children. Overall, zinc supplementation had no effect on total mortality (RR, 0.76; 95% CI: 0.56–1.04; P = 0.084), diarrhea-related mortality (RR, 0.80; 95% CI: 0.53–1.20; P = 0.276), pneumonia-related mortality (RR, 0.52; 95% CI: 0.11–2.39; P = 0.399), malaria-related mortality (RR, 0.90; 95% CI: 0.77–1.06; P = 0.196), or other causes of mortality (RR, 0.98; 95% CI: 0.67–1.44; P = 0.917). Subgroup analysis indicated that zinc supplementation was associated with a reduction in total mortality risk if the participants were boys, aged greater than 12 months, and the duration of the follow-up period was less than 12 months.
Zinc supplementation does not have an effect on total mortality, diarrhea-related mortality, pneumonia-related mortality, malaria-related mortality, or other causes of mortality. Subgroup analysis suggested that zinc supplementation can effectively reduce the risk of total mortality if the participants were boys, aged greater than 12 months, and the duration of the follow-up period was less than 12 months.
PMCID: PMC3823854  PMID: 24244591
24.  Comprehensive identification of mutational cancer driver genes across 12 tumor types 
Scientific Reports  2013;3:2650.
With the ability to fully sequence tumor genomes/exomes, the quest for cancer driver genes can now be undertaken in an unbiased manner. However, obtaining a complete catalog of cancer genes is difficult due to the heterogeneous molecular nature of the disease and the limitations of available computational methods. Here we show that the combination of complementary methods allows identifying a comprehensive and reliable list of cancer driver genes. We provide a list of 291 high-confidence cancer driver genes acting on 3,205 tumors from 12 different cancer types. Among those genes, some have not been previously identified as cancer drivers and 16 have clear preference to sustain mutations in one specific tumor type. The novel driver candidates complement our current picture of the emergence of these diseases. In summary, the catalog of driver genes and the methodology presented here open new avenues to better understand the mechanisms of tumorigenesis.
PMCID: PMC3788361  PMID: 24084849
25.  Prevalence and correlated factors of lifetime suicidal ideation in adults in Ningxia, China 
Shanghai Archives of Psychiatry  2013;25(5):287-294.
Compare the prevalence and associated factors of lifetime suicidal ideation, plans and attempts in the Hui and Han ethnic groups in the Ningxia Hui Autonomous Region of China.
Using a probability proportionate to size sampling method and villages (in rural areas) or neighborhoods (in urban areas) as primary sampling units, 5880 residents aged 18 and over were sampled. Face-to-face interviews were conducted using a computer-administered Chinese version of the World Health Organization’s Composite International Diagnostic Interview. Factors associated with self-reported lifetime suicidal ideation were identified using logistic regression models.
Of the 4789 (81.4%) persons who completed the survey, the lifetime prevalence of suicidal ideation, suicidal plans and suicide attempts were 5.30% (95% confidence interval [CI]=4.66-5.93%), 1.52% (CI=1.17-1.86%), and 0.77% (CI=0.52-1.02%), respectively. The age standardized rate of lifetime suicidal ideation and lifetime suicidal planning were significantly higher in the largely Muslim Hui ethnic group (n=1955) than in the largely atheist Han ethnic group (n=2834); the lifetime prevalence of suicide attempt was also higher in the Hui group, but only at the trend level (p=0.20). Factors independently associated with lifetime suicidal ideation were female gender (odds ratio [OR]=2.07), being divorced or widowed (OR=2.02), rural residence (OR=1.95), mood disorder in the prior year (OR=1.96), other mental disorder in the prior year (OR=2.99), and self-reported poor physical health in the prior year (OR=2.21). After adjustment for these factors, ethnicity was not independently associated with lifetime suicidal ideation, but stratified analyses by ethnic group found some differences in the factors associated with lifetime suicidal ideation between Hui and Han respondents.
Contrary to previous studies, we found that lifetime suicidal ideation was more common in a Muslim ethnic group than in a non-Muslim ethnic group of Ningxia, but this difference did not persist in the multivariate analysis after adjusting for gender, mental disorders and other factors.
PMCID: PMC4054571  PMID: 24991168

Results 1-25 (124)