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  1. Article ; Online: How many samples are needed to infer truly clonal mutations from heterogenous tumours?

    Opasic, Luka / Zhou, Da / Werner, Benjamin / Dingli, David / Traulsen, Arne

    BMC cancer

    2019  Volume 19, Issue 1, Page(s) 403

    Abstract: Background: Modern cancer treatment strategies aim to target tumour specific genetic (or epigenetic) alterations. Treatment response improves if these alterations are clonal, i.e. present in all cancer cells within tumours. However, the identification ... ...

    Abstract Background: Modern cancer treatment strategies aim to target tumour specific genetic (or epigenetic) alterations. Treatment response improves if these alterations are clonal, i.e. present in all cancer cells within tumours. However, the identification of truly clonal alterations is impaired by the tremendous intra-tumour genetic heterogeneity and unavoidable sampling biases.
    Methods: Here, we investigate the underlying causes of these spatial sampling biases and how the distribution and sizes of biopsies in sampling protocols can be optimised to minimize such biases.
    Results: We find that in the ideal case, less than a handful of samples can be enough to infer truly clonal mutations. The frequency of the largest sub-clone at diagnosis is the main factor determining the accuracy of truncal mutation estimation in structured tumours. If the first sub-clone is dominating the tumour, higher spatial dispersion of samples and larger sample size can increase the accuracy of the estimation. In such an improved sampling scheme, fewer samples will enable the detection of truly clonal alterations with the same probability.
    Conclusions: Taking spatial tumour structure into account will decrease the probability to misclassify a sub-clonal mutation as clonal and promises better informed treatment decisions.
    MeSH term(s) Algorithms ; Cell Count ; Clone Cells/metabolism ; Genetic Heterogeneity ; Humans ; Models, Theoretical ; Mutation ; Neoplasms/genetics ; Neoplasms/pathology
    Language English
    Publishing date 2019-04-29
    Publishing country England
    Document type Journal Article
    ISSN 1471-2407
    ISSN (online) 1471-2407
    DOI 10.1186/s12885-019-5597-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Book ; Online ; Thesis: Sampling Strategies in Evolving Cancer

    Opasic, Luka [Verfasser] / Traulsen, Arne [Akademischer Betreuer] / von der Schulenburg, Hinrich [Gutachter]

    From Mathematical Models to Clinical Application

    2020  

    Author's details Luka Opasic ; Gutachter: Hinrich von der Schulenburg ; Betreuer: Arne Traulsen
    Keywords Naturwissenschaften ; Science
    Subject code sg500
    Language English
    Publisher Universitätsbibliothek Kiel
    Publishing place Kiel
    Document type Book ; Online ; Thesis
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  3. Article ; Online: Pleomorphic Variants of

    Čorak, Nina / Anniko, Sirli / Daschkin-Steinborn, Christina / Krey, Viktoria / Koska, Sara / Futo, Momir / Široki, Tin / Woichansky, Innokenty / Opašić, Luka / Kifer, Domagoj / Tušar, Anja / Maxeiner, Horst-Günter / Domazet-Lošo, Mirjana / Nicolaus, Carsten / Domazet-Lošo, Tomislav

    International journal of molecular sciences

    2023  Volume 24, Issue 6

    Abstract: ... ...

    Abstract Borreliella
    MeSH term(s) Animals ; Humans ; Bacterial Proteins/metabolism ; Borrelia burgdorferi/genetics ; Borrelia burgdorferi/metabolism ; Lyme Disease/genetics ; Mammals/metabolism ; Transcriptome
    Chemical Substances Bacterial Proteins
    Language English
    Publishing date 2023-03-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24065594
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine.

    Röcken, Christoph / Amallraja, Anu / Halske, Christine / Opasic, Luka / Traulsen, Arne / Behrens, Hans-Michael / Krüger, Sandra / Liu, Anne / Haag, Jochen / Egberts, Jan-Hendrik / Rosenstiel, Philip / Meißner, Tobias

    Genome medicine

    2021  Volume 13, Issue 1, Page(s) 177

    Abstract: Background: Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression ... ...

    Abstract Background: Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC.
    Methods: The study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was performed using samples form 45 primary tumors and 3 lymph node metastases (range 3-10 tumor samples/patient) of the discovery cohort.
    Results: In total, the discovery cohort harbored 16,537 non-synonymous mutations. Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. Of the non-synonymous mutations, 53-91% were not present in each patient's sample; 399 genes harbored 2-4 different non-synonymous mutations in the same patient; 175 genes showed copy number variations, the majority being heterogeneous, including CD274 (PD-L1). Multi-sample tree-based analyses provided evidence for branched evolution being most complex in a microsatellite instable GC. The analysis of the mode of evolution showed a high degree of heterogeneity in deviation from neutrality within each tumor. We found evidence of parallel evolution and evolutionary trajectories: different mutations of SMAD4 aligned with different subclones and were found only in TP53 mutant GCs.
    Conclusions: Neutral and non-neutral somatic evolution shape the mutational landscape in GC along its lateral expansions. It leads to complex spatial intratumoral heterogeneity, where lymph node metastases may stem from different areas of the primary tumor, synchronously. Our findings may have profound effects on future patient management. They illustrate the risk of mis-interpreting tumor genetics based on single-sample analysis and open new avenues for an evolutionary classification of GC, i.e., the discovery of distinct evolutionary trajectories which can be utilized for precision medicine.
    MeSH term(s) Adenocarcinoma/genetics ; Aged ; Aged, 80 and over ; B7-H1 Antigen ; Clonal Evolution ; Cohort Studies ; DNA Copy Number Variations ; Evolution, Molecular ; Exome ; Genetic Heterogeneity ; Humans ; Lymphatic Metastasis ; Middle Aged ; Mutation ; Phylogeny ; Precision Medicine/methods ; Sequence Analysis, DNA ; Smad4 Protein/genetics ; Stomach Neoplasms/genetics ; Tumor Suppressor Protein p53/genetics ; Exome Sequencing
    Chemical Substances B7-H1 Antigen ; CD274 protein, human ; SMAD4 protein, human ; Smad4 Protein ; TP53 protein, human ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2021-11-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2484394-5
    ISSN 1756-994X ; 1756-994X
    ISSN (online) 1756-994X
    ISSN 1756-994X
    DOI 10.1186/s13073-021-00975-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Embryo-Like Features in Developing Bacillus subtilis Biofilms.

    Futo, Momir / Opašić, Luka / Koska, Sara / Čorak, Nina / Široki, Tin / Ravikumar, Vaishnavi / Thorsell, Annika / Lenuzzi, Maša / Kifer, Domagoj / Domazet-Lošo, Mirjana / Vlahoviček, Kristian / Mijakovic, Ivan / Domazet-Lošo, Tomislav

    Molecular biology and evolution

    2020  Volume 38, Issue 1, Page(s) 31–47

    Abstract: Correspondence between evolution and development has been discussed for more than two centuries. Recent work reveals that phylogeny-ontogeny correlations are indeed present in developmental transcriptomes of eukaryotic clades with complex ... ...

    Abstract Correspondence between evolution and development has been discussed for more than two centuries. Recent work reveals that phylogeny-ontogeny correlations are indeed present in developmental transcriptomes of eukaryotic clades with complex multicellularity. Nevertheless, it has been largely ignored that the pervasive presence of phylogeny-ontogeny correlations is a hallmark of development in eukaryotes. This perspective opens a possibility to look for similar parallelisms in biological settings where developmental logic and multicellular complexity are more obscure. For instance, it has been increasingly recognized that multicellular behavior underlies biofilm formation in bacteria. However, it remains unclear whether bacterial biofilm growth shares some basic principles with development in complex eukaryotes. Here we show that the ontogeny of growing Bacillus subtilis biofilms recapitulates phylogeny at the expression level. Using time-resolved transcriptome and proteome profiles, we found that biofilm ontogeny correlates with the evolutionary measures, in a way that evolutionary younger and more diverged genes were increasingly expressed toward later timepoints of biofilm growth. Molecular and morphological signatures also revealed that biofilm growth is highly regulated and organized into discrete ontogenetic stages, analogous to those of eukaryotic embryos. Together, this suggests that biofilm formation in Bacillus is a bona fide developmental process comparable to organismal development in animals, plants, and fungi. Given that most cells on Earth reside in the form of biofilms and that biofilms represent the oldest known fossils, we anticipate that the widely adopted vision of the first life as a single-cell and free-living organism needs rethinking.
    MeSH term(s) Bacillus subtilis/cytology ; Bacillus subtilis/physiology ; Biofilms ; Biological Evolution
    Language English
    Publishing date 2020-08-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 998579-7
    ISSN 1537-1719 ; 0737-4038
    ISSN (online) 1537-1719
    ISSN 0737-4038
    DOI 10.1093/molbev/msaa217
    Database MEDical Literature Analysis and Retrieval System OnLINE

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