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Author

Hua Shen

Other affiliations: Human Genome Sequencing Center
Bio: Hua Shen is an academic researcher from Baylor College of Medicine. The author has contributed to research in topics: Chromosome 19 & Chromosome 21. The author has an hindex of 5, co-authored 9 publications receiving 3035 citations. Previous affiliations of Hua Shen include Human Genome Sequencing Center.

Papers
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Journal ArticleDOI
Li Ding1, Gad Getz2, David A. Wheeler3, Elaine R. Mardis1, Michael D. McLellan1, Kristian Cibulskis2, Carrie Sougnez2, Heidi Greulich2, Heidi Greulich4, Donna M. Muzny3, Margaret Morgan3, Lucinda Fulton1, Robert S. Fulton1, Qunyuan Zhang1, Michael C. Wendl1, Michael S. Lawrence2, David E. Larson1, Ken Chen1, David J. Dooling1, Aniko Sabo3, Alicia Hawes3, Hua Shen3, Shalini N. Jhangiani3, Lora Lewis3, Otis Hall3, Yiming Zhu3, Tittu Mathew3, Yanru Ren3, Jiqiang Yao3, Steven E. Scherer3, Kerstin Clerc3, Ginger A. Metcalf3, Brian Ng3, Aleksandar Milosavljevic3, Manuel L. Gonzalez-Garay3, John R. Osborne1, Rick Meyer1, Xiaoqi Shi1, Yuzhu Tang1, Daniel C. Koboldt1, Ling Lin1, Rachel Abbott1, Tracie L. Miner1, Craig Pohl1, Ginger A. Fewell1, Carrie A. Haipek1, Heather Schmidt1, Brian H. Dunford-Shore1, Aldi T. Kraja1, Seth D. Crosby1, Christopher S. Sawyer1, Tammi L. Vickery1, Sacha N. Sander1, Jody S. Robinson1, Wendy Winckler2, Wendy Winckler4, Jennifer Baldwin2, Lucian R. Chirieac4, Amit Dutt2, Amit Dutt4, Timothy Fennell2, Megan Hanna4, Megan Hanna2, Bruce E. Johnson4, Robert C. Onofrio2, Roman K. Thomas5, Giovanni Tonon4, Barbara A. Weir4, Barbara A. Weir2, Xiaojun Zhao2, Xiaojun Zhao4, Liuda Ziaugra2, Michael C. Zody2, Thomas J. Giordano6, Mark B. Orringer6, Jack A. Roth, Margaret R. Spitz7, Ignacio I. Wistuba, Bradley A. Ozenberger8, Peter J. Good8, Andrew C. Chang6, David G. Beer6, Mark A. Watson1, Marc Ladanyi9, Stephen R. Broderick9, Akihiko Yoshizawa9, William D. Travis9, William Pao9, Michael A. Province1, George M. Weinstock1, Harold E. Varmus9, Stacey Gabriel2, Eric S. Lander2, Richard A. Gibbs3, Matthew Meyerson4, Matthew Meyerson2, Richard K. Wilson1 
23 Oct 2008-Nature
TL;DR: Somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B are found.
Abstract: Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.

2,615 citations

Journal ArticleDOI
TL;DR: OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.
Abstract: Background Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies.

271 citations

Journal ArticleDOI
01 Mar 2012-Nature
TL;DR: An empirical reconstruction of human MSY evolution is presented, in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection.
Abstract: This evolutionary decay was driven by a series of five ‘stratification’ events. Each event suppressed X–Y crossing over within a chromosome segment or ‘stratum’, incorporated that segment into the MSY and subjected its genes to the erosive forces that attend the absence of crossing over 2,6 . The last of these events occurred 30 million years ago, 5 million years before the human and Old World monkey lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome 7–10 , remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the Old World monkey lineage. To investigate this question, we sequenced the MSY of the rhesus macaque, an Old World monkey, and compared it to the human MSY. We discovered that during the last 25 million years MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. In the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 million years ago. Likewise, the rhesus MSY has not lost any older genes (from strata 1–4) during the past 25 million years, despite its major structural differences to the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection. The human Y chromosome no longer engages in crossing over with its once-identical partner, the X chromosome, except in its pseudoautosomal regions. During evolution, X–Y crossing over was suppressed in five different chromosomal regions at five different times, each probably resulting from an inversion in the Y chromosome 2,3 . Each of these regions of the Y chromosome then began its own individual course of degeneration, experiencing deletions and gene loss. Comparison of the present-day X and Y chromosomes enables identification of these five evolutionary ‘strata’ in the MSY (and X chromosome); their distinctive degrees of X–Y differentiation indicate their evolutionary ages 2,3 . The oldest stratum (stratum 1) dates back over 240 million years (Myr) 2 and is the most highly differentiated, and the youngest stratum (stratum 5) originated only 30 Myr ago and displays the highest X–Y nucleotide sequence similarity within the MSY 3 . The five strata and their respective decay processes, over tens to hundreds of millions of years of mammalian evolution, offer replicate experiments of nature from which to reconstruct the trajectories and kinetics of gene loss in the MSY. Only the human and chimpanzee MSYs had been sequenced before the present study, and they are separated by just 6 Myr of evolution. We decided to examine the MSY of a much more distant relative, the rhesus macaque (Macaca mulatta), to enable us to reconstruct gene loss and conservation in the MSY during the past 25 Myr. We sequenced the rhesus MSY using bacterial artificial chromosome (BAC) clones and the SHIMS (single-haplotype iterative mapping and sequencing) strategy that has previously been used in the human and chimpanzee MSYs 4,11–13 as well as in the chicken Z chromosome 5 . The resulting sequence is comprised of 11.0 megabases (Mb), is complete aside from three small gaps and has an error rate of about one nucleotide per Mb. We ordered and oriented the finished sequence contigs by fluorescence in situ hybridization and radiation hybrid mapping (Supplementary Figs 1–6, Supplementary Table 1, Supplemen

258 citations

Journal ArticleDOI
Donna M. Muzny1, Steven E. Scherer1, Rajinder Kaul2, Jing Wang3  +151 moreInstitutions (9)
27 Apr 2006-Nature
TL;DR: Using genomic sequence from chimpanzee and rhesus macaque, the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae are characterized and an evolutionary history of the inversion is proposed.
Abstract: After the completion of a draft human genome sequence1, the International Human Genome Sequencing Consortium has proceeded to finish2 and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B3. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.

59 citations

Journal ArticleDOI
16 Mar 2006-Nature
TL;DR: Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages.
Abstract: Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 45% of the human genome Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents

51 citations


Cited by
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04 Oct 2012-Nature
TL;DR: The 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.
Abstract: 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.

9,355 citations

Journal ArticleDOI
Ludmil B. Alexandrov1, Serena Nik-Zainal2, Serena Nik-Zainal3, David C. Wedge1, Samuel Aparicio4, Sam Behjati1, Sam Behjati5, Andrew V. Biankin, Graham R. Bignell1, Niccolo Bolli1, Niccolo Bolli5, Åke Borg2, Anne Lise Børresen-Dale6, Anne Lise Børresen-Dale7, Sandrine Boyault8, Birgit Burkhardt8, Adam Butler1, Carlos Caldas9, Helen Davies1, Christine Desmedt, Roland Eils5, Jorunn E. Eyfjord10, John A. Foekens11, Mel Greaves12, Fumie Hosoda13, Barbara Hutter5, Tomislav Ilicic1, Sandrine Imbeaud14, Sandrine Imbeaud15, Marcin Imielinsk15, Natalie Jäger5, David T. W. Jones16, David T. Jones1, Stian Knappskog17, Stian Knappskog11, Marcel Kool11, Sunil R. Lakhani18, Carlos López-Otín18, Sancha Martin1, Nikhil C. Munshi19, Nikhil C. Munshi20, Hiromi Nakamura13, Paul A. Northcott16, Marina Pajic21, Elli Papaemmanuil1, Angelo Paradiso22, John V. Pearson23, Xose S. Puente18, Keiran Raine1, Manasa Ramakrishna1, Andrea L. Richardson22, Andrea L. Richardson20, Julia Richter22, Philip Rosenstiel22, Matthias Schlesner5, Ton N. Schumacher24, Paul N. Span25, Jon W. Teague1, Yasushi Totoki13, Andrew Tutt24, Rafael Valdés-Mas18, Marit M. van Buuren25, Laura van ’t Veer26, Anne Vincent-Salomon27, Nicola Waddell23, Lucy R. Yates1, Icgc PedBrain24, Jessica Zucman-Rossi15, Jessica Zucman-Rossi14, P. Andrew Futreal1, Ultan McDermott1, Peter Lichter24, Matthew Meyerson20, Matthew Meyerson15, Sean M. Grimmond23, Reiner Siebert22, Elias Campo28, Tatsuhiro Shibata13, Stefan M. Pfister16, Stefan M. Pfister11, Peter J. Campbell29, Peter J. Campbell30, Peter J. Campbell3, Michael R. Stratton3, Michael R. Stratton31 
22 Aug 2013-Nature
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

7,904 citations

Journal ArticleDOI
TL;DR: Screening with the use of low-dose CT reduces mortality from lung cancer, as compared with the radiography group, and the rate of death from any cause was reduced.
Abstract: Background The aggressive and heterogeneous nature of lung cancer has thwarted efforts to reduce mortality from this cancer through the use of screening. The advent of low-dose helical computed tomography (CT) altered the landscape of lung-cancer screening, with studies indicating that low-dose CT detects many tumors at early stages. The National Lung Screening Trial (NLST) was conducted to determine whether screening with low-dose CT could reduce mortality from lung cancer. Methods From August 2002 through April 2004, we enrolled 53,454 persons at high risk for lung cancer at 33 U.S. medical centers. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732). Data were collected on cases of lung cancer and deaths from lung cancer that occurred through December 31, 2009. Results The rate of adherence to screening was more than 90%. The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results. The incidence of lung cancer was 645 cases per 100,000 person-years (1060 cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P=0.004). The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P=0.02). Conclusions Screening with the use of low-dose CT reduces mortality from lung cancer. (Funded by the National Cancer Institute; National Lung Screening Trial ClinicalTrials.gov number, NCT00047385.).

7,710 citations

Journal ArticleDOI
Debra A. Bell1, Andrew Berchuck2, Michael J. Birrer3, Jeremy Chien1  +282 moreInstitutions (35)
30 Jun 2011-Nature
TL;DR: It is reported 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.
Abstract: 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.

5,878 citations

01 Jun 2011
TL;DR: The Cancer Genome Atlas project has analyzed 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 as mentioned in this paper.
Abstract: 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.

5,609 citations