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  • 1
    Publication Date: 2013-05-03
    Description: We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and approximately 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704730/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704730/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cancer Genome Atlas Research Network -- Kandoth, Cyriac -- Schultz, Nikolaus -- Cherniack, Andrew D -- Akbani, Rehan -- Liu, Yuexin -- Shen, Hui -- Robertson, A Gordon -- Pashtan, Itai -- Shen, Ronglai -- Benz, Christopher C -- Yau, Christina -- Laird, Peter W -- Ding, Li -- Zhang, Wei -- Mills, Gordon B -- Kucherlapati, Raju -- Mardis, Elaine R -- Levine, Douglas A -- 5U24CA143799-04/CA/NCI NIH HHS/ -- 5U24CA143835-04/CA/NCI NIH HHS/ -- 5U24CA143840-04/CA/NCI NIH HHS/ -- 5U24CA143843-04/CA/NCI NIH HHS/ -- 5U24CA143845-04/CA/NCI NIH HHS/ -- 5U24CA143848-04/CA/NCI NIH HHS/ -- 5U24CA143858-04/CA/NCI NIH HHS/ -- 5U24CA143866-04/CA/NCI NIH HHS/ -- 5U24CA143867-04/CA/NCI NIH HHS/ -- 5U24CA143882-04/CA/NCI NIH HHS/ -- 5U24CA143883-04/CA/NCI NIH HHS/ -- 5U24CA144025-04/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50 CA098258/CA/NCI NIH HHS/ -- U24 CA143799/CA/NCI NIH HHS/ -- U24 CA143835/CA/NCI NIH HHS/ -- U24 CA143840/CA/NCI NIH HHS/ -- U24 CA143843/CA/NCI NIH HHS/ -- U24 CA143845/CA/NCI NIH HHS/ -- U24 CA143848/CA/NCI NIH HHS/ -- U24 CA143858/CA/NCI NIH HHS/ -- U24 CA143866/CA/NCI NIH HHS/ -- U24 CA143867/CA/NCI NIH HHS/ -- U24 CA143882/CA/NCI NIH HHS/ -- U24 CA143883/CA/NCI NIH HHS/ -- U24 CA144025/CA/NCI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- U54HG003067-11/HG/NHGRI NIH HHS/ -- U54HG003079-10/HG/NHGRI NIH HHS/ -- U54HG003273-10/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 May 2;497(7447):67-73. doi: 10.1038/nature12113.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636398" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/genetics ; Chromosome Aberrations ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; DNA Polymerase II/genetics ; DNA-Binding Proteins/genetics ; Endometrial Neoplasms/*classification/*genetics ; Exome/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genome, Human/*genetics ; Genomics ; Humans ; Ovarian Neoplasms/genetics ; Signal Transduction ; Transcription Factors/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-06-23
    Description: To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383766/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383766/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ellis, Matthew J -- Ding, Li -- Shen, Dong -- Luo, Jingqin -- Suman, Vera J -- Wallis, John W -- Van Tine, Brian A -- Hoog, Jeremy -- Goiffon, Reece J -- Goldstein, Theodore C -- Ng, Sam -- Lin, Li -- Crowder, Robert -- Snider, Jacqueline -- Ballman, Karla -- Weber, Jason -- Chen, Ken -- Koboldt, Daniel C -- Kandoth, Cyriac -- Schierding, William S -- McMichael, Joshua F -- Miller, Christopher A -- Lu, Charles -- Harris, Christopher C -- McLellan, Michael D -- Wendl, Michael C -- DeSchryver, Katherine -- Allred, D Craig -- Esserman, Laura -- Unzeitig, Gary -- Margenthaler, Julie -- Babiera, G V -- Marcom, P Kelly -- Guenther, J M -- Leitch, Marilyn -- Hunt, Kelly -- Olson, John -- Tao, Yu -- Maher, Christopher A -- Fulton, Lucinda L -- Fulton, Robert S -- Harrison, Michelle -- Oberkfell, Ben -- Du, Feiyu -- Demeter, Ryan -- Vickery, Tammi L -- Elhammali, Adnan -- Piwnica-Worms, Helen -- McDonald, Sandra -- Watson, Mark -- Dooling, David J -- Ota, David -- Chang, Li-Wei -- Bose, Ron -- Ley, Timothy J -- Piwnica-Worms, David -- Stuart, Joshua M -- Wilson, Richard K -- Mardis, Elaine R -- 3P50 CA68438/CA/NCI NIH HHS/ -- P30 CA091842/CA/NCI NIH HHS/ -- P30 CA091842-01/CA/NCI NIH HHS/ -- P50 CA068438/CA/NCI NIH HHS/ -- P50 CA068438-05/CA/NCI NIH HHS/ -- P50 CA094056/CA/NCI NIH HHS/ -- P50 CA094056-10/CA/NCI NIH HHS/ -- P50 CA94056/CA/NCI NIH HHS/ -- R01 CA095614/CA/NCI NIH HHS/ -- R01 CA095614-01A1/CA/NCI NIH HHS/ -- U01 CA114722/CA/NCI NIH HHS/ -- U01 CA114722-01/CA/NCI NIH HHS/ -- U10 CA076001/CA/NCI NIH HHS/ -- U10 CA076001-13/CA/NCI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003079-04/HG/NHGRI NIH HHS/ -- U54HG003079/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 10;486(7403):353-60. doi: 10.1038/nature11143.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Division of Oncology, Washington University, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722193" target="_blank"〉PubMed〈/a〉
    Keywords: Androstadienes/pharmacology/therapeutic use ; Antineoplastic Agents/pharmacology/therapeutic use ; Aromatase/*metabolism ; Aromatase Inhibitors/*therapeutic use ; Breast Neoplasms/*drug therapy/*genetics/metabolism/pathology ; DNA Repair ; Exome/genetics ; Exons/genetics ; Female ; Genetic Variation/genetics ; Genome, Human/*genetics ; Humans ; MAP Kinase Kinase 4/genetics ; MAP Kinase Kinase Kinase 1/genetics ; Mutation/genetics ; Nitriles/pharmacology/therapeutic use ; Receptors, Estrogen/metabolism ; Treatment Outcome ; Triazoles/pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-10-18
    Description: 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 (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/beta-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 number of 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927368/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927368/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kandoth, Cyriac -- McLellan, Michael D -- Vandin, Fabio -- Ye, Kai -- Niu, Beifang -- Lu, Charles -- Xie, Mingchao -- Zhang, Qunyuan -- McMichael, Joshua F -- Wyczalkowski, Matthew A -- Leiserson, Mark D M -- Miller, Christopher A -- Welch, John S -- Walter, Matthew J -- Wendl, Michael C -- Ley, Timothy J -- Wilson, Richard K -- Raphael, Benjamin J -- Ding, Li -- P01 CA101937/CA/NCI NIH HHS/ -- P01CA101937/CA/NCI NIH HHS/ -- R01 CA180006/CA/NCI NIH HHS/ -- R01 HG005690/HG/NHGRI NIH HHS/ -- R01CA180006/CA/NCI NIH HHS/ -- R01HG005690/HG/NHGRI NIH HHS/ -- U01 HG006517/HG/NHGRI NIH HHS/ -- U01HG006517/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54HG003079/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 Oct 17;502(7471):333-9. doi: 10.1038/nature12634.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Genome Institute, Washington University in St Louis, Missouri 63108, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24132290" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinogenesis/*genetics ; Cell Cycle/genetics ; Clone Cells/metabolism/pathology ; Cohort Studies ; DNA Repair/genetics ; Humans ; INDEL Mutation/genetics ; Mitogen-Activated Protein Kinases/genetics ; Models, Genetic ; Mutation/*genetics ; Neoplasms/*classification/*genetics/metabolism/pathology ; Oncogenes/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Point Mutation/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Survival Analysis ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Abstract: As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to approximately 100 x shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.
    Type of Publication: Journal article published
    PubMed ID: 26647970
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  • 5
    Publication Date: 2018-09-21
    Description: Genetic studies have identified recurrent somatic mutations in acute myeloid leukemia (AML) patients, including in the Wilms’ tumor 1 ( WT1 ) gene. The molecular mechanisms by which WT1 mutations contribute to leukemogenesis have not yet been fully elucidated. We investigated the role of Wt1 gene dosage in steady-state and pathologic hematopoiesis. Wt1 heterozygous loss enhanced stem cell self-renewal in an age-dependent manner, which increased stem cell function over time and resulted in age-dependent leukemic transformation. Wt1 -haploinsufficient leukemias were characterized by progressive genetic and epigenetic alterations, including those in known leukemia-associated alleles, demonstrating a requirement for additional events to promote hematopoietic transformation. Consistent with this observation, we found that Wt1 depletion cooperates with Flt3-ITD mutation to induce fully penetrant AML. Our studies provide insight into mechanisms of Wt1 -loss leukemogenesis and into the evolutionary events required to induce transformation of Wt1 -haploinsufficient stem/progenitor cells.
    Keywords: Hematopoiesis and Stem Cells
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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