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  1. Article ; Online: Examining clustered somatic mutations with SigProfilerClusters.

    Bergstrom, Erik N / Kundu, Mousumy / Tbeileh, Noura / Alexandrov, Ludmil B

    Bioinformatics (Oxford, England)

    2022  Volume 38, Issue 13, Page(s) 3470–3473

    Abstract: Motivation: Clustered mutations are found in the human germline as well as in the genomes of cancer and normal somatic cells. Clustered events can be imprinted by a multitude of mutational processes, and they have been implicated in both cancer ... ...

    Abstract Motivation: Clustered mutations are found in the human germline as well as in the genomes of cancer and normal somatic cells. Clustered events can be imprinted by a multitude of mutational processes, and they have been implicated in both cancer evolution and development disorders. Existing tools for identifying clustered mutations have been optimized for a particular subtype of clustered event and, in most cases, relied on a predefined inter-mutational distance (IMD) cutoff combined with a piecewise linear regression analysis.
    Results: Here, we present SigProfilerClusters, an automated tool for detecting all types of clustered mutations by calculating a sample-dependent IMD threshold using a simulated background model that takes into account extended sequence context, transcriptional strand asymmetries and regional mutation densities. SigProfilerClusters disentangles all types of clustered events from non-clustered mutations and annotates each clustered event into an established subclass, including the widely used classes of doublet-base substitutions, multi-base substitutions, omikli and kataegis. SigProfilerClusters outputs non-clustered mutations and clustered events using standard data formats as well as provides multiple visualizations for exploring the distributions and patterns of clustered mutations across the genome.
    Availability and implementation: SigProfilerClusters is supported across most operating systems and made freely available at https://github.com/AlexandrovLab/SigProfilerClusters with an extensive documentation located at https://osf.io/qpmzw/wiki/home/.
    Supplementary information: Supplementary data are available at Bioinformatics online.
    MeSH term(s) Humans ; Software ; Mutation ; Neoplasms/genetics ; Genome
    Language English
    Publishing date 2022-05-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btac335
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Metastatic colorectal adenocarcinoma tumor purity assessment from whole exome sequencing data.

    Tbeileh, Noura / Timmerman, Luika / Mattis, Aras N / Toriguchi, Kan / Kasai, Yosuke / Corvera, Carlos / Nakakura, Eric / Hirose, Kenzo / Donner, David B / Warren, Robert S / Karelehto, Eveliina

    PloS one

    2023  Volume 18, Issue 4, Page(s) e0271354

    Abstract: Tumors rich in stroma are associated with advanced stage and poor prognosis in colorectal adenocarcinoma (CRC). Abundance of stromal cells also has implications for genomic analysis of patient tumors as it may prevent detection of somatic mutations. As ... ...

    Abstract Tumors rich in stroma are associated with advanced stage and poor prognosis in colorectal adenocarcinoma (CRC). Abundance of stromal cells also has implications for genomic analysis of patient tumors as it may prevent detection of somatic mutations. As part of our efforts to interrogate stroma-cancer cell interactions and to identify actionable therapeutic targets in metastatic CRC, we aimed to determine the proportion of stroma embedded in hepatic CRC metastases by performing computational tumor purity analysis based on whole exome sequencing data (WES). Unlike previous studies focusing on histopathologically prescreened samples, we used an unbiased in-house collection of tumor specimens. WES from CRC liver metastasis samples were utilized to evaluate stromal content and to assess the performance of three in silico tumor purity tools, ABSOLUTE, Sequenza and PureCN. Matching tumor derived organoids were analyzed as a high purity control as they are enriched in cancer cells. Computational purity estimates were compared to those from a histopathological assessment conducted by a board-certified pathologist. According to all computational methods, metastatic specimens had a median tumor purity of 30% whereas the organoids were enriched for cancer cells with a median purity estimate of 94%. In line with this, variant allele frequencies (VAFs) of oncogenes and tumor suppressor genes were undetectable or low in most patient tumors, but higher in matching organoid cultures. Positive correlation was observed between VAFs and in silico tumor purity estimates. Sequenza and PureCN produced concordant results whereas ABSOLUTE yielded lower purity estimates for all samples. Our data shows that unbiased sample selection combined with molecular, computational, and histopathological tumor purity assessment is critical to determine the level of stroma embedded in metastatic colorectal adenocarcinoma.
    MeSH term(s) Humans ; Exome Sequencing ; Mutation ; Exome/genetics ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Adenocarcinoma/genetics ; Liver Neoplasms/genetics
    Language English
    Publishing date 2023-04-06
    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.0271354
    Database MEDical Literature Analysis and Retrieval System OnLINE

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