Biology subjects

Satoru Miyano

Publications and source records attributed to Satoru Miyano.

4 recordsLinked to original sources

bioRxiv2016

phyC: Clustering cancer evolutionary trees

MotivationMulti-regional sequencing provides new opportunities to investigate genetic heterogeneity within or between common tumors from an evolutionary perspective. Several state-of-the-art methods have been proposed for reconstructing cancer sub-clonal evolutionary trees based on multi-regional sequencing data to develop models of cancer evolution. However, the methods developed thus far are not sufficient to characterize and interpret the diversity of cancer sub-clonal evolutionary trees.\n\nResultsWe propose a clustering method (phyC) for cancer sub-clonal evolutionary trees, in which sub-groups of the trees are identified based on topology and edge length attributes. For interpretation, we also propose a method for evaluating the diversity of trees in the clusters, which provides insight into the acceleration of sub-clonal expansion. Simulation showed that the proposed method can detect true clusters with sufficient accuracy. Application of the method to actual multi-regional sequencing data of clear cell renal carcinoma and non-small cell lung cancer allowed for the detection of clusters related to cancer type or phenotype.\n\nAvailabilityphyC is implemented with R(>=3.2.2) and is available from https://github.com/ymatts/phyC.\n\nContactymatsui@med.nagoya-u.ac.jp

Bioinformatics↗

bioRxiv2015

D3M: Detection of differential distributions of methylation levels

Motivation: DNA methylation is an important epigenetic modification related to a variety of diseases including cancers. We focus on the methylation data from Illuminas Infinium HumanMethylation450 BeadChip. One of the key issues of methylation analysis is to detect the differential methylation sites between case and control groups. Previous approaches describe data with simple summary statistics and kernel function, and then use statistical tests to determine the difference. However, a summary statistics-based approach cannot capture complicated underlying structure, and a kernel functions-based approach lacks interpretability of results.\n\nResults: We propose a novel method D3M, for detection of differential distribution of methylation, based on distribution-valued data. Our method can detect high-order moments, such as shapes of underlying distributions in methylation profiles, based on the Wasserstein metric. We test the significance of the difference between case and control groups and provide an interpretable summary of the results. The simulation results show that the proposed method achieves promising accuracy and shows favorable results compared with previous methods. Glioblastoma multiforme and lower grade glioma data from The Cancer Genome Atlas show that our method supports recent biological advances and suggests new insights.\n\nAvailability: R implemented code is freely available from\n\nhttps://github.com/ymatts/D3M/\n\nhttps://cran.r-project.org/package=D3M.\n\nContact: ymatsui@med.nagoya-u.ac.jp

Bioinformatics↗

bioRxiv2015

Cancer evolution simulation identifies possible principles underlying intratumor heterogeneity

Cancer arises from accumulation of somatic mutations and accompanying evolutionary selection for growth advantage. During the evolutionary process, an ancestor clone branches into multiple clones, yielding intratumor heterogeneity. However, principles underlying intratumor heterogeneity have been poorly understood. Here, to explore the principles, we built a cellular automaton model, termed the BEP model, which can reproduce the branching cancer evolution in silico. We then extensively searched for conditions leading to high intratumor heterogeneity by performing simulations with various parameter settings on a supercomputer. Our result suggests that multiple driver genes of moderate strength can shape subclonal structures by positive natural selection. Moreover, we found that high mutation rate and a stem cell hierarchy can contribute to extremely high intratumor heterogeneity, which is characterized by fractal patterns, through neutral evolution. Collectively, This study identified the possible principles underlying intratumor heterogeneity, which provide novel insights into the origin of cancer robustness and evolvability.

Cancer Biology↗

bioRxiv2015

A simple model-based approach to inferring and visualizing cancer mutation signatures

Recent advances in sequencing technologies have enabled the production of massive amounts of data on somatic mutations from cancer genomes. These data have led to the detection of characteristic patterns of somatic mutations or \"mutation signatures\" at an unprecedented resolution, with the potential for new insights into the causes and mechanisms of tumorigenesis.\n\nHere we present new methods for modelling, identifying and visualizing such mutation signatures. Our methods greatly simplify mutation signature models compared with existing approaches, reducing the number of parameters by orders of magnitude even while increasing the contextual factors (e.g. the number of flanking bases) that are accounted for. This improves both sensitivity and robustness of inferred signatures. We also provide a new intuitive way to visualize the signatures, analogous to the use of sequence logos to visualize transcription factor binding sites.\n\nWe illustrate our new method on somatic mutation data from urothelial carcinoma of the upper urinary tract, and a larger dataset from 30 diverse cancer types. The results illustrate several important features of our methods, including the ability of our new visualization tool to clearly highlight the key features of each signature, the improved robustness of signature inferences from small sample sizes, and more detailed inference of signature characteristics such as strand biases and sequence context effects at the base two positions 5 to the mutated site.\n\nThe overall framework of our work is based on probabilistic models that are closely connected with \"mixed-membership models\" which are widely used in population genetic admixture analysis, and in machine learning for document clustering. We argue that recognizing these relationships should help improve understanding of mutation signature extraction problems, and suggests ways to further improve the statistical methods.\n\nOur methods are implemented in an R package pmsignature (https://github.com/friend1ws/pmsignature) and a web application available at https://friend1ws.shinyapps.io/pmsignature_shiny/.\n\nAuthor SummarySomatic (non-inherited) mutations are acquired throughout our lives in cells throughout our body. These mutations can be caused, for example, by DNA replication errors or exposure to environmental mutagens such as tobacco smoke. Some of these mutations can lead to cancer.\n\nDifferent cancers, and even different instances of the same cancer, can show different distinctive patterns of somatic mutations. These distinctive patterns have become known as \"mutation signatures\". For example, C > A mutations are frequent in lung caners whereas C > T and CC > TT mutations are frequent in skin cancers. Each mutation signature may be associated with a specific kind of carcinogen, such as tobacco smoke or ultraviolet light. Identifying mutation signatures therefore has the potential to identify new carcinogens, and yield new insights into the mechanisms and causes of cancer,\n\nIn this paper, we introduce new statistical tools for tackling this important problem. These tools provide more robust and interpretable mutation signatures compared to previous approaches, as we demonstrate by applying them to large-scale cancer genomic data.

Bioinformatics↗