8,953 research outputs found
Computational Cancer Biology: An Evolutionary Perspective
ISSN:1553-734XISSN:1553-735
Predictive genomics: A cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data
We discuss a cancer hallmark network framework for modelling
genome-sequencing data to predict cancer clonal evolution and associated
clinical phenotypes. Strategies of using this framework in conjunction with
genome sequencing data in an attempt to predict personalized drug targets, drug
resistance, and metastasis for a cancer patient, as well as cancer risks for a
healthy individual are discussed. Accurate prediction of cancer clonal
evolution and clinical phenotypes will have substantial impact on timely
diagnosis, personalized management and prevention of cancer.Comment: 5 figs, related papers, visit lab homepage:
http://www.cancer-systemsbiology.org, Seminar in Cancer Biology, 201
Inferring clonal evolution of tumors from single nucleotide somatic mutations
High-throughput sequencing allows the detection and quantification of
frequencies of somatic single nucleotide variants (SNV) in heterogeneous tumor
cell populations. In some cases, the evolutionary history and population
frequency of the subclonal lineages of tumor cells present in the sample can be
reconstructed from these SNV frequency measurements. However, automated methods
to do this reconstruction are not available and the conditions under which
reconstruction is possible have not been described.
We describe the conditions under which the evolutionary history can be
uniquely reconstructed from SNV frequencies from single or multiple samples
from the tumor population and we introduce a new statistical model, PhyloSub,
that infers the phylogeny and genotype of the major subclonal lineages
represented in the population of cancer cells. It uses a Bayesian nonparametric
prior over trees that groups SNVs into major subclonal lineages and
automatically estimates the number of lineages and their ancestry. We sample
from the joint posterior distribution over trees to identify evolutionary
histories and cell population frequencies that have the highest probability of
generating the observed SNV frequency data. When multiple phylogenies are
consistent with a given set of SNV frequencies, PhyloSub represents the
uncertainty in the tumor phylogeny using a partial order plot. Experiments on a
simulated dataset and two real datasets comprising tumor samples from acute
myeloid leukemia and chronic lymphocytic leukemia patients demonstrate that
PhyloSub can infer both linear (or chain) and branching lineages and its
inferences are in good agreement with ground truth, where it is available
Learning mutational graphs of individual tumour evolution from single-cell and multi-region sequencing data
Background. A large number of algorithms is being developed to reconstruct
evolutionary models of individual tumours from genome sequencing data. Most
methods can analyze multiple samples collected either through bulk multi-region
sequencing experiments or the sequencing of individual cancer cells. However,
rarely the same method can support both data types.
Results. We introduce TRaIT, a computational framework to infer mutational
graphs that model the accumulation of multiple types of somatic alterations
driving tumour evolution. Compared to other tools, TRaIT supports multi-region
and single-cell sequencing data within the same statistical framework, and
delivers expressive models that capture many complex evolutionary phenomena.
TRaIT improves accuracy, robustness to data-specific errors and computational
complexity compared to competing methods.
Conclusions. We show that the application of TRaIT to single-cell and
multi-region cancer datasets can produce accurate and reliable models of
single-tumour evolution, quantify the extent of intra-tumour heterogeneity and
generate new testable experimental hypotheses
INVESTIGATING INVASION IN DUCTAL CARCINOMA IN SITU WITH TOPOGRAPHICAL SINGLE CELL GENOME SEQUENCING
Synchronous Ductal Carcinoma in situ (DCIS-IDC) is an early stage breast cancer invasion in which it is possible to delineate genomic evolution during invasion because of the presence of both in situ and invasive regions within the same sample. While laser capture microdissection studies of DCIS-IDC examined the relationship between the paired in situ (DCIS) and invasive (IDC) regions, these studies were either confounded by bulk tissue or limited to a small set of genes or markers. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS), which combines laser-catapulting with single cell DNA sequencing to measure genomic copy number profiles from single tumor cells while preserving their spatial context. We applied TSCS to sequence 1,293 single cells from 10 synchronous DCIS patients. We also applied deep-exome sequencing to the in situ, invasive and normal tissues for the DCIS-IDC patients. Previous bulk tissue studies had produced several conflicting models of tumor evolution. Our data support a multiclonal invasion model, in which genome evolution occurs within the ducts and gives rise to multiple subclones that escape the ducts into the adjacent tissues to establish the invasive carcinomas. In summary, we have developed a novel method for single cell DNA sequencing, which preserves spatial context, and applied this method to understand clonal evolution during the transition between carcinoma in situ to invasive ductal carcinoma
Modeling cumulative biological phenomena with Suppes-Bayes Causal Networks
Several diseases related to cell proliferation are characterized by the
accumulation of somatic DNA changes, with respect to wildtype conditions.
Cancer and HIV are two common examples of such diseases, where the mutational
load in the cancerous/viral population increases over time. In these cases,
selective pressures are often observed along with competition, cooperation and
parasitism among distinct cellular clones. Recently, we presented a
mathematical framework to model these phenomena, based on a combination of
Bayesian inference and Suppes' theory of probabilistic causation, depicted in
graphical structures dubbed Suppes-Bayes Causal Networks (SBCNs). SBCNs are
generative probabilistic graphical models that recapitulate the potential
ordering of accumulation of such DNA changes during the progression of the
disease. Such models can be inferred from data by exploiting likelihood-based
model-selection strategies with regularization. In this paper we discuss the
theoretical foundations of our approach and we investigate in depth the
influence on the model-selection task of: (i) the poset based on Suppes' theory
and (ii) different regularization strategies. Furthermore, we provide an
example of application of our framework to HIV genetic data highlighting the
valuable insights provided by the inferred
Computational strategies for dissecting the high-dimensional complexity of adaptive immune repertoires
The adaptive immune system recognizes antigens via an immense array of
antigen-binding antibodies and T-cell receptors, the immune repertoire. The
interrogation of immune repertoires is of high relevance for understanding the
adaptive immune response in disease and infection (e.g., autoimmunity, cancer,
HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the
quantitative and molecular-level profiling of immune repertoires thereby
revealing the high-dimensional complexity of the immune receptor sequence
landscape. Several methods for the computational and statistical analysis of
large-scale AIRR-seq data have been developed to resolve immune repertoire
complexity in order to understand the dynamics of adaptive immunity. Here, we
review the current research on (i) diversity, (ii) clustering and network,
(iii) phylogenetic and (iv) machine learning methods applied to dissect,
quantify and compare the architecture, evolution, and specificity of immune
repertoires. We summarize outstanding questions in computational immunology and
propose future directions for systems immunology towards coupling AIRR-seq with
the computational discovery of immunotherapeutics, vaccines, and
immunodiagnostics.Comment: 27 pages, 2 figure
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