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  1. Article ; Online: Mutational signatures association with replication timing in normal cells reveals similarities and differences with matched cancer tissues.

    Yaacov, Adar / Rosenberg, Shai / Simon, Itamar

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 7833

    Abstract: Mutational signatures' association with replication timing (RT) has been studied in cancer samples, but the RT distribution of somatic mutations in non-cancerous cells was only minimally explored. Here, we performed comprehensive analyses of mutational ... ...

    Abstract Mutational signatures' association with replication timing (RT) has been studied in cancer samples, but the RT distribution of somatic mutations in non-cancerous cells was only minimally explored. Here, we performed comprehensive analyses of mutational signatures in 2.9 million somatic mutations across multiple non-cancerous tissues, stratified by early and late RT regions. We found that many mutational processes are active mainly or solely in early RT, such as SBS16 in hepatocytes and SBS88 in the colon, or in late RT, such as SBS4 in lung and hepatocytes, and SBS18 across many tissues. The two ubiquitous signatures, SBS1 and SBS5, showed late and early bias, respectively, across multiple tissues and in mutations representing germ cells. We also performed a direct comparison with cancer samples in 4 matched tissue-cancer types. Unexpectedly, while for most signatures the RT bias was consistent in normal tissue and in cancer, we found that SBS1's late RT bias is lost in cancer.
    MeSH term(s) Humans ; Mutation ; Neoplasms/genetics ; DNA Replication Timing ; Colon ; Hepatocytes
    Language English
    Publishing date 2023-05-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-34631-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Both cell autonomous and non-autonomous processes modulate the association between replication timing and mutation rate.

    Vardi-Yaacov, Oriya / Yaacov, Adar / Rosenberg, Shai / Simon, Itamar

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 13143

    Abstract: Cancer somatic mutations are the product of multiple mutational and repair processes, some of which are tightly associated with DNA replication. Mutation rates (MR) are known to be higher in late replication timing (RT) regions, but different processes ... ...

    Abstract Cancer somatic mutations are the product of multiple mutational and repair processes, some of which are tightly associated with DNA replication. Mutation rates (MR) are known to be higher in late replication timing (RT) regions, but different processes can affect this association. Systematic analysis of the mutational landscape of 2787 tumors from 32 tumor types revealed that approximately one third of the tumor samples show weak association between replication timing and mutation rate. Further analyses revealed that those samples have unique mutational signatures and are enriched with mutations in genes involved in DNA replication, DNA repair and chromatin structure. Surprisingly, analysis of differentially expressed genes between weak and strong RT-MR association groups revealed that tumors with weak association are enriched with genes associated with cell-cell communication and the immune system, suggesting a non-autonomous response to DNA damage.
    MeSH term(s) Humans ; Mutation Rate ; Mutation ; DNA Repair/genetics ; DNA Damage/genetics ; Neoplasms/genetics ; Neoplasms/pathology ; DNA Replication/genetics ; Genome, Human
    Language English
    Publishing date 2023-08-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-39463-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Shared Cancer Dataset Analysis Identifies and Predicts the Quantitative Effects of Pan-Cancer Somatic Driver Variants.

    Landau, Jakob / Tsaban, Linoy / Yaacov, Adar / Ben Cohen, Gil / Rosenberg, Shai

    Cancer research

    2022  Volume 83, Issue 1, Page(s) 74–88

    Abstract: Driver mutations endow tumors with selective advantages and produce an array of pathogenic effects. Determining the function of somatic variants is important for understanding cancer biology and identifying optimal therapies. Here, we compiled a shared ... ...

    Abstract Driver mutations endow tumors with selective advantages and produce an array of pathogenic effects. Determining the function of somatic variants is important for understanding cancer biology and identifying optimal therapies. Here, we compiled a shared dataset from several cancer genomic databases. Two measures were applied to 535 cancer genes based on observed and expected frequencies of driver variants as derived from cancer-specific rates of somatic mutagenesis. The first measure comprised a binary classifier based on a binomial test; the second was tumor variant amplitude (TVA), a continuous measure representing the selective advantage of individual variants. TVA outperformed all other computational tools in terms of its correlation with experimentally derived functional scores of cancer mutations. TVA also highly correlated with drug response, overall survival, and other clinical implications in relevant cancer genes. This study demonstrates how a selective advantage measure based on a large cancer dataset significantly impacts our understanding of the spectral effect of driver variants in cancer. The impact of this information will increase as cancer treatment becomes more precise and personalized to tumor-specific mutations.
    Significance: A new selective advantage estimation assists in oncogenic driver identification and relative effect measurements, enabling better prognostication, therapy selection, and prioritization.
    MeSH term(s) Humans ; Computational Biology ; Mutation ; Neoplasms/genetics ; Oncogenes
    Language English
    Publishing date 2022-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-22-1038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Cancer Mutational Processes Vary in Their Association with Replication Timing and Chromatin Accessibility.

    Yaacov, Adar / Vardi, Oriya / Blumenfeld, Britny / Greenberg, Avraham / Massey, Dashiell J / Koren, Amnon / Adar, Sheera / Simon, Itamar / Rosenberg, Shai

    Cancer research

    2021  Volume 81, Issue 24, Page(s) 6106–6116

    Abstract: Cancer somatic mutations are the product of multiple mutational and repair processes, both of which are tightly associated with DNA replication. Distinctive patterns of somatic mutation accumulation, termed mutational signatures, are indicative of ... ...

    Abstract Cancer somatic mutations are the product of multiple mutational and repair processes, both of which are tightly associated with DNA replication. Distinctive patterns of somatic mutation accumulation, termed mutational signatures, are indicative of processes sustained within tumors. However, the association of various mutational processes with replication timing (RT) remains an open question. In this study, we systematically analyzed the mutational landscape of 2,787 tumors from 32 tumor types separately for early and late replicating regions using sequence context normalization and chromatin data to account for sequence and chromatin accessibility differences. To account for sequence differences between various genomic regions, an artificial genome-based approach was developed to expand the signature analyses to doublet base substitutions and small insertions and deletions. The association of mutational processes and RT was signature specific: Some signatures were associated with early or late replication (such as SBS7b and SBS7a, respectively), and others had no association. Most associations existed even after normalizing for genome accessibility. A focused mutational signature identification approach was also developed that uses RT information to improve signature identification; this approach found that SBS16, which is biased toward early replication, is strongly associated with better survival rates in liver cancer. Overall, this novel and comprehensive approach provides a better understanding of the etiology of mutational signatures, which may lead to improved cancer prevention, diagnosis, and treatment. SIGNIFICANCE: Many mutational processes associate with early or late replication timing regions independently of chromatin accessibility, enabling development of a focused identification approach to improve mutational signature detection.
    MeSH term(s) Biomarkers, Tumor/genetics ; Chromatin Assembly and Disassembly ; DNA Replication ; Genome, Human ; Humans ; Mutation ; Mutation Accumulation ; Neoplasms/genetics ; Neoplasms/pathology
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2021-10-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-21-2039
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: High throughput SARS-CoV-2 variant analysis using molecular barcodes coupled with next generation sequencing.

    Cohen-Aharonov, Lyora A / Rebibo-Sabbah, Annie / Yaacov, Adar / Granit, Roy Z / Strauss, Merav / Colodner, Raul / Cheshin, Ori / Rosenberg, Shai / Eavri, Ronen

    PloS one

    2022  Volume 17, Issue 6, Page(s) e0253404

    Abstract: The identification of SARS-CoV-2 variants across the globe and their implications on the outspread of the pandemic, infection potential and resistance to vaccination, requires modification of the current diagnostic methods to map out viral mutations ... ...

    Abstract The identification of SARS-CoV-2 variants across the globe and their implications on the outspread of the pandemic, infection potential and resistance to vaccination, requires modification of the current diagnostic methods to map out viral mutations rapidly and reliably. Here, we demonstrate that integrating DNA barcoding technology, sample pooling and Next Generation Sequencing (NGS) provide an applicable solution for large-population viral screening combined with specific variant analysis. Our solution allows high throughput testing by barcoding each sample, followed by pooling of test samples using a multi-step procedure. First, patient-specific barcodes are added to the primers used in a one-step RT-PCR reaction, amplifying three different viral genes and one human housekeeping gene (as internal control). Then, samples are pooled, purified and finally, the generated sequences are read using an Illumina NGS system to identify the positive samples with a sensitivity of 82.5% and a specificity of 97.3%. Using this solution, we were able to identify six known and one unknown SARS-CoV-2 variants in a screen of 960 samples out of which 258 (27%) were positive for the virus. Thus, our diagnostic solution integrates the benefits of large population and epidemiological screening together with sensitive and specific identification of positive samples including variant analysis at a single nucleotide resolution.
    MeSH term(s) COVID-19/diagnosis ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Pandemics ; SARS-CoV-2/genetics
    Language English
    Publishing date 2022-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0253404
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling.

    Ferrarotto, Renata / Mishra, Vasudha / Herz, Elad / Yaacov, Adar / Solomon, Oz / Rauch, Rami / Mondshine, Adi / Motin, Maria / Leibovich-Rivkin, Tal / Davis, Matti / Kaye, Joel / Weber, Christopher R / Shen, Le / Pearson, Alexander T / Rosenberg, Ari J / Chen, Xiangying / Singh, Alka / Aster, Jon C / Agrawal, Nishant /
    Izumchenko, Evgeny

    Cell death & disease

    2022  Volume 13, Issue 8, Page(s) 678

    Abstract: Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the ... ...

    Abstract Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.
    MeSH term(s) Amyloid Precursor Protein Secretases/metabolism ; Carcinoma, Adenoid Cystic/drug therapy ; Carcinoma, Adenoid Cystic/genetics ; Enzyme Inhibitors/pharmacology ; Humans ; Neoplasm Recurrence, Local ; Receptors, Notch/metabolism ; Salivary Gland Neoplasms/genetics ; Signal Transduction
    Chemical Substances Enzyme Inhibitors ; Receptors, Notch ; Amyloid Precursor Protein Secretases (EC 3.4.-)
    Language English
    Publishing date 2022-08-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-022-05133-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: High throughput SARS-CoV-2 variant analysis using molecular barcodes coupled with Next Generation Sequencing

    Cohen-Aharonov, Lyora A / Rebibo-Sabbah, Annie / Yaacov, Adar / Granit, Roy Z / Strauss, Merav / Colodner, Raul / Cheshin, Ori / Rosenberg, Shai / Eavri, Ronen

    medRxiv

    Abstract: The identification of SARS-CoV-2 variants across the globe and their implications on the outspread of the pandemic, infection potential and resistance to vaccination, requires modification of the current diagnostic methods to map out viral mutations ... ...

    Abstract The identification of SARS-CoV-2 variants across the globe and their implications on the outspread of the pandemic, infection potential and resistance to vaccination, requires modification of the current diagnostic methods to map out viral mutations rapidly and reliably. Here, we demonstrate that integrating DNA barcoding technology, sample pooling and Next Generation Sequencing (NGS) provide an applicable solution for large-population viral screening combined with specific variant analysis. Our solution allows high throughput testing by barcoding each sample, followed by pooling of test samples using a multi-step procedure. First, patient-specific barcodes are added to the primers used in a one-step RT-PCR reaction, amplifying three different viral genes and one human housekeeping gene (as internal control). Then, samples are pooled, purified and finally, the generated sequences are read using an Illumina NGS system to identify the positive samples with a sensitivity of 82.5% and a specificity of 97.3%. Using this solution, we were able to identify six known and one unknown SARS-CoV-2 variants in a screen of 960 samples out of which 258 (27%) were positive for the virus. Thus, our diagnostic solution integrates the benefits of large population and epidemiological screening together with sensitive and specific identification of positive samples including variant analysis at a single nucleotide resolution.
    Keywords covid19
    Language English
    Publishing date 2021-06-04
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2021.05.27.21257726
    Database COVID19

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