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      Exome-wide somatic mutation characterization of small bowel adenocarcinoma

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003–2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA ( TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes ( SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.

          Author summary

          Small bowel adenocarcinoma is a rare but aggressive disease with limited treatment options. Of gastrointestinal tumors, small bowel tumors account for 3%, of which around one third are adenocarcinomas. Due to the scarcity of evidence-based treatment recommendations there is a dire need for knowledge on the biology of these tumors. Here, we performed the first large exome sequencing effort of 106 small bowel adenocarcinomas from a Finnish population-based cohort to comprehensively characterize the genetic background of this tumor type. The set included tumors from all three small bowel segments allowing us to also compare the genetic differences between these subsets. We defined significantly mutated genes and frequently affected pathways, providing potential therapeutic targets, such as BRAF, ERBB2, ERBB3, ERBB4, PIK3CA, KRAS, ATM, ACVR2A, ACVR1B, BRCA2, and SMARCA4, for this disease.

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          Most cited references 31

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          Primer3Plus, an enhanced web interface to Primer3

          Here we present Primer3Plus, a new web interface to the popular Primer3 primer design program as an enhanced alternative for the CGI- scripts that come with Primer3. Primer3 consists of a command line program and a web interface. The web interface is one large form showing all of the possible options. This makes the interface powerful, but at the same time confusing for occasional users. Primer3Plus provides an intuitive user interface using present-day web technologies and has been developed in close collaboration with molecular biologists and technicians regularly designing primers. It focuses on the task at hand, and hides detailed settings from the user until these are needed. We also added functionality to automate specific tasks like designing primers for cloning or step-wise sequencing. Settings and designed primer sequences can be stored locally for later use. Primer3Plus supports a range of common sequence formats, such as FASTA. Finally, primers selected by Primer3Plus can be sent to an order form, allowing tight integration into laboratory ordering systems. Moreover, the open architecture of Primer3Plus allows easy expansion or integration of external software packages. The Primer3Plus Perl source code is available under GPL license from SourceForge. Primer3Plus is available at http://www.bioinformatics.nl/primer3plus.
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            Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.

            Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. Copyright © 2015, American Association for the Advancement of Science.
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              BRCA2 is required for homology-directed repair of chromosomal breaks.

              The BRCA2 tumor suppressor has been implicated in the maintenance of chromosomal stability through a function in DNA repair. In this report, we examine human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination. Using the I-SceI endonuclease to introduce a double-strand break at a specific chromosomal locus, we find that BRCA2 mutant cell lines are recombination deficient, such that homology-directed repair is reduced 6- to >100-fold, depending on the cell line. Thus, BRCA2 is essential for efficient homology-directed repair, presumably in conjunction with the Rad51 recombinase. We propose that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and, possibly, tumorigenesis, through lack of repair or misrepair of DNA damage.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: SoftwareRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Data curationRole: SoftwareRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                9 March 2018
                March 2018
                : 14
                : 3
                Affiliations
                [1 ] Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
                [2 ] Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
                [3 ] Department of Pathology, HUSLAB, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
                [4 ] Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
                [5 ] Faculty of Social Sciences, University of Tampere, Tampere, Finland
                [6 ] Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
                [7 ] Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland
                [8 ] Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
                Dana Farber Cancer Institute, UNITED STATES
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: LAA has received a lecture fee from Roche Oy.

                Article
                PGENETICS-D-17-01877
                10.1371/journal.pgen.1007200
                5871010
                29522538
                © 2018 Hänninen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 5, Tables: 1, Pages: 23
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002341, Academy of Finland;
                Award ID: 250345
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100006383, Syöpäjärjestöt;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100006306, Sigrid Juséliuksen Säätiö;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004012, Jane ja Aatos Erkon Säätiö;
                Award Recipient :
                Funded by: SYSCOL
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002341, Academy of Finland;
                Award ID: 295693
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002341, Academy of Finland;
                Award ID: 287665
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100008723, Suomen Lääketieteen Säätiö;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003756, Biomedicum Helsinki-säätiö;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004212, Päivikki ja Sakari Sohlbergin Säätiö;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007634, Ida Montinin Säätiö;
                Award Recipient :
                Funded by: The Gastroenterological Research Foundation
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100010129, Maud Kuistilan Muistosäätiö;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100006383, Syöpäjärjestöt;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100009067, K. Albin Johanssons Stiftelse;
                Award Recipient :
                This work was supported by grants from the Academy of Finland (Centre of Excellence in Cancer Genetics Research 2012–2017, no. 250345), the Finnish Cancer Society, the Sigrid Juselius Foundation, the Jane and Aatos Erkko Foundation, and SYSCOL (an EU FP7 Collaborative Project, no. 258236). Personal grants were received from the Academy of Finland (no. 295693 to NM and no. 287665 to NV). UAH received the following personal grants for this work: the Finnish Medical Society “Duodecim”, Biomedicum Helsinki Foundation, the Päivikki and Sakari Sohlberg Foundation, the Ida Montin Foundation, the Gastroenterological Research Foundation, the Maud Kuistila Memorial Foundation, Cancer Foundation Finland sr., and the K. Albin Johansson Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Mutation
                Nonsense Mutation
                Biology and Life Sciences
                Genetics
                Mutation
                Frameshift Mutation
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                Antigen-Presenting Cells
                Biology and Life Sciences
                Immunology
                Immune Cells
                Antigen-Presenting Cells
                Medicine and Health Sciences
                Immunology
                Immune Cells
                Antigen-Presenting Cells
                Biology and Life Sciences
                Genetics
                Mutation
                Point Mutation
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Colorectal Cancer
                Biology and Life Sciences
                Genetics
                Mutation
                Biology and Life Sciences
                Genetics
                Mutation
                Somatic Mutation
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Carcinomas
                Adenocarcinomas
                Custom metadata
                vor-update-to-uncorrected-proof
                2018-03-27
                Sequence data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under study accession number EGAS00001002559. Further information about EGA can be found on https://ega-archive.org "The European Genome-phenome Archive of human data consented for biomedical research" ( http://www.nature.com/ng/journal/v47/n7/full/ng.3312.html). Data are available on request upon publication from the EGA database by contacting the data access committee (DAC accession EGAC00001000649, dac-tumorgenomics@ 123456helsinki.fi ) assigned for this project. Data are restricted due to reasons of patient confidentiality.

                Genetics

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