4 results on '"Wenan Chen"'
Search Results
2. The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21
- Author
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Qingsong Gao, Sarra L Ryan, Ilaria Iacobucci, Pankaj S Ghate, Ruth E Cranston, Claire J Schwab, Abdelrahman H. Elsayed, Lei Shi, Stanley B Pounds, Shaohua Lei, Pradyumna Baviskar, Deqing Pei, Cheng Cheng, Matthew Bashton, Paul B Sinclair, David R Bentley, Mark Ross, Zoya Kingsbury, Terena James, Kathryn G Roberts, Meenakshi Devidas, Yiping Fan, Wenan Chen, Ti-Cheng Chang, Gang Wu, Andrew J. Carroll, Nyla A. Heerema, Virginia Valentine, Marcus B Valentine, Wenjian Yang, Jun J. Yang, Anthony V Moorman, Christine J Harrison, and Charles G. Mullighan
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remain incompletely understood. Here, using integrated whole genome and transcriptome sequencing of 124 iAMP21-ALL patients, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL according to patterns of copy number alteration and structural variation. This large dataset enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which are differentially expressed compared to non-iAMP21-ALL cases, and including multiple genes implicated in the pathogenesis of acute leukemia: CHAF1B, DYRK1A, ERG, HMGN1 and RUNX1. Using multimodal single cell genomic profiling, including single cell whole genome sequencing of two cases, we documented clonal heterogeneity and genomic evolution, formally demonstrating that acquisition of the iAMP21-chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.
- Published
- 2023
3. Rare Deleterious TCF3 Germline Variants and Predisposition to Acute Lymphoblastic Leukemia in Children
- Author
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Carolin Escherich, Wenan Chen, Satoshi Miyamoto, Yui Namikawa, Wenjian Yang, David T. Teachey, Zhenhua Li, Elizabeth A. Raetz, Eric C Larsen, Meenakshi Devidas, Paul L. Martin, W Paul Bowman, Gang Wu, Ching-Hon Pui, Stephen P. Hunger, Masatoshi Takagi, Jun J. Yang, and Mignon L. Loh
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
4. Precision Medicine for Sickle Cell Disease through Whole Genome Sequencing
- Author
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Andrew Thrasher, Jeffrey D. Lebensburger, Pavel Sumazin, Winfred C. Wang, Akshay Sharma, Wenan Chen, Nidal Boulos, Yutaka Yasui, Ti-Cheng Chang, Lance E. Palmer, Donald Yergeau, Michael Rusch, Heather L. Mulder, Yadav Sapkota, Celeste Rosencrance, Gang Wu, Jinghui Zhang, Martha Villavicencio, Michael R. DeBaun, Wenjian Bi, Jason R. Hodges, Jane S. Hankins, Mitchell J. Weiss, James R. Downing, Shuoguo Wang, Shawn Levy, John Easton, Amanda M. Brandow, Jeremie H. Estepp, Yong Cheng, Vivien A. Sheehan, Guolian Kang, Evadnie Rampersaud, and Xing Tang
- Subjects
Immunology ,Cell ,Merkel cell polyomavirus ,02 engineering and technology ,Computational biology ,Disease ,01 natural sciences ,Biochemistry ,Medicine ,Whole genome sequencing ,biology ,business.industry ,010401 analytical chemistry ,Cell Biology ,Hematology ,021001 nanoscience & nanotechnology ,Precision medicine ,medicine.disease ,biology.organism_classification ,Sickle cell anemia ,0104 chemical sciences ,medicine.anatomical_structure ,0210 nano-technology ,business ,Vaso-occlusive crisis ,Imputation (genetics) - Abstract
Although sickle cell disease (SCD) is a monogenic disorder, the severity and specific organ dysfunction and failure are strongly influenced by genetic modifiers. Rapid identification of all modifiers in patients and well-phenotyped cohorts will better define the impact of relevant variants on clinical status, inform disease biology, and identify new therapeutic strategies. We created the Sickle Genome Project (SGP), a whole genome sequencing (WGS) strategy, to define genomic variation and modifiers of SCD. We performed WGS on 871 African American SCD patients from St. Jude Children's Research Hospital who participated in the Sickle Cell Clinical Research and Intervention Program (SCCRIP, Hankins et al. Pediatr Blood Cancer, 2018) and Texas Children's Hospital Hematology Center (TCHC). We developed robust pipelines for accurate detection of single nucleotide polymorphisms (SNPs), identification of structural variants and data retrieval/sharing via the St. Jude Cloud platform (to be described elsewhere). Notable findings include: 1) Confirmed associations of common genetic modifiers with SCD phenotypes, including levels of fetal hemoglobin (BCL11A, HBS1L-MYB, HBB), bilirubin (UGT1A1), and microalbuminuria (APOL1). Additional associations approaching genome-wide significance require further investigation, including replication in independent samples. 2) Improved determination of the SCD modifier α-thalassemia. The most common α-thalassemia mutations in SCD are 3.7 kb or 4.2 kb deletions (-α3.7 and -α4.2 alleles), which arose from recombination between homologous HBA1 and HBA2 genes and are difficult to map using standard WGS reads. Three independent crossover events are described for -α3.7 and one for -α4.2 in SCD cohorts. We developed a novel approach to identify α-globin gene deletions by local de novo assembly of WGS data and coverage depth analysis. We identified 5 -α3.7 alleles (frequencies 0.77-32.12%) and 7 -α4.2 alleles (frequencies 0.19-5.77%). Collectively, the frequency of all -α alleles was 57%, reflecting at least 12 distinct recombination events, greatly exceeding previously published counts. These findings better define the evolution of α-globin genes to allow improved understanding of their regulation and influence on SCD. 3) Characterization of β0-thalassemia alleles. Mutations in the extended β-globin locus influence SCD phenotypes. Five SGP patients had large β-globin (HBB) deletions associated with elevated fetal hemoglobin, which ameliorates symptoms of SCD. Twenty-three patients had HbSβ0-thalassemia, which reduces the severity of some SCD phenotypes. Overall, 48.6% (18/37) of patients clinically designated as HbSβ0 -thalassemia had no identified β-thalassemia mutation. Moreover, 4/680 patients (0.6%) designated HbSS were identified to be β0-thalassemia heterozygotes. The MCV, RBC and %HbA2 distributions overlapped substantially in correct vs. incorrect genotype assignments. Improved discrimination of HbSβ0 vs HbSS genotypes by WGS will better define associated phenotype differences to impact clinical care. 4) Determination of a genetic variant linked to vaso-occlusive crisis (VOC). Previously, a single GWAS study linked rs3115229, located 63.7 kb 5′ upstream of the KIAA1109 gene, with VOC at borderline significance (P = 5.63 × 10−8) (Chaturvedi et al, Blood 130, 2017). Using WGS data for 327 SGP participants (HbSS or HbSβ0-thalassemia) enrolled in the SCCRIPP study, we found strong association (p = 7 x 10-5) between the onset of VOC and a 4-SNP diplotype within an adjacent LD block of the KIAA1109-TENR-IL2-IL21 region (chr4: 122.8Mb - 123.8Mb) which has been previously associated with numerous inflammatory disorders. We validated this association using imputed genome-wide array data in an independent group of SCD patients (Sleep and Asthma Cohort, n= 181 patients, p = 0.05) (Cohen et al, Ann Am Thorac Soc, 2016). This works provides confirmation that the region surrounding KIAA1109 is associated with pain crisis in SCD. Our studies provide new information on the genomic architecture of SCD patients and delineate a consolidated approach for future applications of precision medicine. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Research Funding; NCQA: Consultancy; bluebird bio: Consultancy. Estepp:Global Blood Therapeutics: Consultancy, Research Funding; ASH Scholar: Research Funding; NHLBI: Research Funding; Daiichi Sankyo: Consultancy.
- Published
- 2018
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