ONCO-MS11

Mathematical Oncology: From methodological studies to clinical applications

Wednesday, June 16 at 02:15am (PDT)
Wednesday, June 16 at 10:15am (BST)
Wednesday, June 16 06:15pm (KST)

SMB2021 Follow Tuesday (Wednesday) during the "MS11" time block.

Note: this minisymposia has multiple sessions. The second session is MS12-ONCO (click here).

Saskia Haupt (Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Germany), Vincent Heuveline (Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Germany), Matthias Kloor (Department of Applied Tumor Biology (ATB), Institute of Pathology, University Hospital Heidelberg, Germany)

Description:

While the understanding of cancer development has dramatically increased during the last years, key questions with immediate implications for clinical management and prevention strategies remain still unanswered. In the framework of the mini-symposium, we will present current research work in Mathematical Oncology addressing these challenges. Talks range from mathematical analyses and methodological studies to medical and clinical applications with a strong focus on interdisciplinary collaborations and diversity.

Calum Gabbutt

(Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom (UK))

"Reconstructing Contemporary Human Stem Cell Dynamics with Oscillatory Molecular Clocks"

Cell histories can be reconstructed from their genomes by analysing ‘molecular clocks’ that accumulate heritable changes through time. Commonly used clocks, such as the accumulation of single nucleotide variants, change slowly over decades, recording cell dynamics that occur at the longer timescale of the change accumulation rate. Studies within mouse have revealed that normal colon epithelium is maintained by a pool of multipotent stem-cells which undergo neutral competition and inevitably drift towards monoclonality. Here we develop a new method that can measure contemporary human adult cell dynamics with rapidly oscillating CpG DNA methylation. Ongoing (de)methylation causes switching between 0, 50 and 100% methylation at each CpG locus in a diploid cell – the clock ‘tick-tocks’ back-and-forth like a pendulum. In polyclonal cell populations, these oscillator states are unsynchronized between cells, hence the average oscillator methylation is randomly distributed about 50%. However, any clonal expansion will synchronize the oscillator clocks resulting in clonal populations that have characteristic “W-shaped” distributions (methylation peaks at 0, 50 and 100%), approximating the methylation of the progenitor cell. The precise shape of the W-distribution is determined by the underlying dynamics of cell growth and replacement. We show how to identify appropriate oscillators from standard methylation array data (Illumina EPIC) and develop a mathematical modelling framework to quantitatively measure stem cell dynamics from these data. We apply our method to measure stem cell dynamics in individual human intestinal crypt and endometrial gland populations, and test whether these tissues have different stem cell dynamics using a hierarchical Bayesian model.

Toni Seppälä

(Helsinki University Hospital and University of Helsinki, Finland)

"Organoids and cell-free DNA in cancer precision medicine"

It is generally believed that earlier diagnosis of a cancer recurrence might improve the outcome. Postoperative minimal residual disease (MRD) very deterministically predicts future recurrence after curative surgery, but the preliminary evidence suggests that the prognosis of a recurring cancer may be improved by timely chemotherapy. Patients are always followed up for years to detect cancer recurrences using clinical examinations and blood tests that are not optimal by sensitivity or specificity. In case of a recurrence seen in imaging, chemotherapy is usually initiated. Selection of chemotherapy regimen between multiple options is usually based on expected tolerability of toxicity and failure of earlier choices. Tools to aid decision-making in these challenging clinical situations are required, and precision medicine holds great promise in delivering for the unmet need. Applications detecting bloodstream cell-free DNA have been developed to support diagnostics of MRD. Patient-derived organoid technology enables individualized cell culture from each tumor. Organoids may serve as a clinical tool to guide traditional primary tumor NGS, and facilitate in vitro response prediction to therapy. Data-intensive models for tumor microenvironment co-culture and combination pharmacotyping are needed.

Vincent Jonchere

(INSERM Sorbonne Université, UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer et SIRIC, France)

"Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability"

Background & Aims Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study. Methods We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients. Results Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1–7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis. Conclusions The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation.

Johannes Witt

(Department of Applied Tumor Biology (ATB), Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany)

"Analyzing the influence of HLA class I genotype on cancer immunoediting"

Already in early stages of tumorigenesis, transformed cells are recognized and attacked by the immune system, leading to the elimination of precancerous cell clones. This process depends on the generation of neoantigens, which determine the immunogenicity of tumor cells. Highly immunogenic cancer cells are counterselected during tumor evolution, constituting a Darwinian selection process. In microsatellite-unstable (MSI) cancer, a high load of neoantigens accumulates due to frameshift mutations in coding microsatellites. The immunogenicity of frameshift peptides (FSP) depends on the presentation of cleaved peptides on the cell surface by human leucocyte antigen (HLA) molecules. Endogenously produced peptides are preferentially presented by HLA class I molecules. Among the HLA class I genes, HLA-A, -B and -C play the most prominent role in the immune response. Due to amino acid substitutions in the peptide-binding region, each HLA molecule is characterized by a specific repertoire of peptides that can be presented. Analyzing a single nucleotide polymorphism at the 5’-end of exon 2 of the HLA-A gene, we divided a set of 75 MSI colorectal cancer samples into two groups: samples possessing at least one HLA-A*02 allele and samples without any HLA-A*02 allele. For both constellations, we developed scores estimating the probability that at least one FSP-derived peptide is presented on the cell surface by a HLA-A molecule (OLLA,G2, OLLA,GN). We observed an inverse correlation between the predicted immunogenicity of 41 FSP and the mutation frequency, which may reflect a selection pressure exerted by the immune system. However, this correlation is not group-specific, indicating that the immunogenicity of FSP is potentially not only determined by the HLA type. With increasing length l of FSP, the number of possible FSP-derived peptides increases. Thus, the likelihood rises that at least one of them fits a random HLA molecule. For both the HLA-A*02 and the Non-HLA-A*02 group, we observed a negative correlation between l and the mutation frequency. Our predictions imply that HLA diversity may determine the likelihood of FSP recognition and therefore immune recognition of tumor cells.

Hosted by SMB2021 Follow

Virtual conference of the Society for Mathematical Biology, 2021.