In recent years, cancer genome sequencing and other high-throughput studies of cancer genomes have generated many notable discoveries. In this review, Novel genomic alteration mechanisms, such as chromothripsis (chromosomal crisis) and kataegis (mutation storms), and their implications for cancer are discussed. Genomic alterations spur cancer genome evolution. Thus, the relationship between cancer clonal evolution and cancer stems cells is commented. The key question in cancer biology concerns how these genomic alterations support cancer development and metastasis in the context of biological functioning. Thus far, efforts such as pathway analysis have improved the understanding of the functional contributions of genetic mutations and DNA copy number variations to cancer development, progression and metastasis. However, the known pathways correspond to a small fraction, plausibly 5-10%, of somatic mutations and genes with an altered copy number. To develop a comprehensive understanding of the function of these genomic alterations in cancer, an integrative network framework is proposed and discussed. Finally, the challenges and the directions of studying cancer omic data using an integrative network approach are commented.
In cancer research, high-throughput profiling has been extensively conducted. In recent studies, the integrative analysis of data on multiple cancer patient groups/subgroups has been conducted. Such analysis has the potential to reveal the genomic commonality as well as difference across groups/subgroups. However, in the existing literature, methods with a special attention to the genomic commonality and difference are very limited. In this study, a novel estimation and marker selection method based on the sparse boosting technique is developed to address the commonality/difference problem. In…
Rapid advancements in collection and dissemination of multi-platform molecular and genomics data has resulted in enormous opportunities to aggregate such data in order to understand, prevent, and treat human diseases. While significant improvements have been made in multi-omic data integration methods to discover biological markers and mechanisms underlying both prognosis and treatment, the precise cellular functions governing these complex mechanisms still need detailed and data-driven de-novo evaluations. We propose a framework called Functional Integrative Bayesian Analysis of High-dimensio…
Genome-wide analysis of distributions of densities of long-range interactions of human chromosomes with each other, nucleoli, nuclear lamina, and binding sites of chromatin state regulatory proteins, CTCF and STAT1, identifies non-random highly correlated patterns of density distributions along the chromosome length for all these features. Marked co-enrichments and clustering of all these interactions are detected at discrete genomic regions on selected chromosomes, which are located within pericentromeric heterochromatin and designated Centromeric Regions of Interphase Chromatin Homing (CENTR…
The phenotypic consequences of individual mutations are modulated by the wild type genetic background in which they occur.Although such background dependence is widely observed, we do not know whether general patterns across species and traits exist, nor about the mechanisms underlying it. We also lack knowledge on how mutations interact with genetic background to influence gene expression, and how this in turn mediates mutant phenotypes. Furthermore, how genetic background influences patterns of epistasis remains unclear. To investigate the genetic basis and genomic consequences of genetic ba…
The rapid growth of cancer genome structural information provides an opportunity for a better understanding of the mutational mechanisms of genomic alterations in cancer and the forces of selection that act upon them. Here we test the evidence for two major forces, spatial chromosome structure and purifying (or negative) selection, that shape the landscape of somatic copy-number alterations (SCNAs) in cancer1. Using a maximum likelihood framework we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by th…
A variety of genome-wide profiling techniques are available to probe complementary aspects of genome structure and function. Integrative analysis of heterogeneous data sources can reveal higher-level interactions that cannot be detected based on individual observations. A standard integration task in cancer studies is to identify altered genomic regions that induce changes in the expression of the associated genes based on joint analysis of genome-wide gene expression and copy number profiling measurements. In this review, we provide a comparison among various modeling procedures for integrati…
The vast amount of sequencing data presently available allow the scientific community to explore a range of genetic variables that may drive and progress cancer. A myriad of predictive tools has been proposed, allowing researchers and clinicians to compare and prioritize driver genes and mutations and their relative pathogenicity. However, there is little consensus on the computational approach or a golden standard for comparison. Hence, benchmarking the different tools depends highly on the input data, indicating that overfitting is still a massive problem. One of the solutions is to limit th…
Brigham and Women’s Hospital（布莱根妇女医院）；Harvard Medical School（哈佛医学院）；Broad Institute of Harvard and MIT（哈佛-麻省理工学院博德研究所）；Dana-Farber Cancer Institute（丹娜-法伯癌症研究所）；Harvard University（哈佛大学）
The rapidly emerging field of deep learning-based computational pathology has demonstrated promise in developing objective prognostic models from histology whole slide images. However, most prognostic models are either based on histology or genomics alone and do not address how histology and genomics can be integrated to develop joint image-omic prognostic models. Additionally identifying explainable morphological and molecular descriptors from these models that govern such prognosis is of interest. We used multimodal deep learning to integrate gigapixel whole slide pathology images, RNA-seq a…
The biological significance of genomic features is often context-dependent. We present CruzDB, a fast and intuitive programmatic interface to the UCSC genome browser that facilitates integrative analyses of diverse local and remotely hosted datasets. We showcase the syntax of CruzDB using miRNA-binding sites as examples, and further demonstrate its utility with 3 novel biological discoveries. First, we find that while exons replicate early, introns tend to replicate late, suggesting a complex replication pattern in gene regions. Second, variants associated with cognitive functions map to lincR…
Module network inference is an established statistical method to reconstruct co-expression modules and their upstream regulatory programs from integrated multi-omics datasets measuring the activity levels of various cellular components across different individuals, experimental conditions or time points of a dynamic process. We have developed Lemon-Tree, an open-source, platform-independent, modular, extensible software package implementing state-of-the-art ensemble methods for module network inference. We benchmarked Lemon-Tree using large-scale tumor datasets and showed that Lemon-Tree algor…
In the genomic analysis, it is significant while challenging to identify markers associated with cancer outcomes or phenotypes. Based on the biological mechanisms of cancers and the characteristics of datasets as well, this paper proposes a novel integrative interaction approach under the semiparametric model, in which the genetic factors and environmental factors are included as the parametric and nonparametric components, respectively. The goal of this approach is to identify the genetic factors and gene-gene interactions associated with cancer outcomes, and meanwhile, estimate the nonlinear…
Modern DNA sequencing technologies enable geneticists to rapidly identify genetic variation among many human genomes. However, isolating the minority of variants underlying disease remains an important, yet formidable challenge for medical genetics. We have developed GEMINI (GEnome MINIng), a flexible software package for exploring all forms of human genetic variation. Unlike existing tools, GEMINI integrates genetic variation with a diverse and flexible set of genome annotations (e.g., dbSNP, ENCODE, UCSC, ClinVar, KEGG) into a unified database to facilitate interpretation and data exploratio…
Dana Farber Cancer Institute（丹娜-法伯癌症研究所）；Harvard Medical School（哈佛医学院）；Broad Institute of MIT and Harvard（麻省理工学院和哈佛大学博德研究所）；ETH Zurich（苏黎世联邦理工学院）；SIB Swiss Institute of Bioinformatics（瑞士生物信息学研究所）
Identifying subgroups and properties of cancer biopsy samples is a crucial step towards obtaining precise diagnoses and being able to perform personalized treatment of cancer patients. Recent data collections provide a comprehensive characterization of cancer cell data, including genetic data on copy number alterations (CNAs). We explore the potential to capture information contained in cancer genomic information using a novel topology-based approach that encodes each cancer sample as a persistence diagram of topological features, i.e., high-dimensional voids represented in the data. We find t…
Motivation: We introduce TRONCO (TRanslational ONCOlogy), an open-source R package that implements the state-of-the-art algorithms for the inference of cancer progression models from (epi)genomic mutational profiles. TRONCO can be used to extract population-level models describing the trends of accumulation of alterations in a cohort of cross-sectional samples, e.g., retrieved from publicly available databases, and individual-level models that reveal the clonal evolutionary history in single cancer patients, when multiple samples, e.g., multiple biopsies or single-cell sequencing data, are ava…
Johannes Kepler University（约翰内斯·开普勒大学）；Software Competence Center Hagenberg（哈根贝格软件能力中心）；Children’s Cancer Research Institute（儿童癌症研究所）
Diagnosis and risk stratification of cancer and many other diseases require the detection of genomic breakpoints as a prerequisite of calling copy number alterations (CNA). This, however, is still challenging and requires time-consuming manual curation. As deep-learning methods outperformed classical state-of-the-art algorithms in various domains and have also been successfully applied to life science problems including medicine and biology, we here propose Deep SNP, a novel Deep Neural Network to learn from genomic data. Specifically, we used a manually curated dataset from 12 genomic single …
Phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via two mechanistically distinct pathways of creation of divergent regulatory DNA sequences
Understanding the origin of infectious diseases provides scientifically based rationales for implementing public health measures that may help to avoid or mitigate future epidemics. The recent ancestors of a pandemic virus provide invaluable information about the set of minimal genomic alterations that transformed a zoonotic agent into a full human pandemic. Since the first confirmed cases of the H1N1 pandemic virus in the spring of 2009, several hypotheses about the strain's origins have been proposed. However, how, where, and when it first infected humans is still far from clear. The only wa…
European Bioinformatics Institute（欧洲生物信息学研究所）；Wellcome Trust Sanger Institute（维康桑格研究所）；Massachusetts General Hospital Cancer Center（麻省总医院癌症中心）
Predicting the response of a specific cancer to a therapy is a major goal in modern oncology that should ultimately lead to a personalised treatment. High-throughput screenings of potentially active compounds against a panel of genomically heterogeneous cancer cell lines have unveiled multiple relationships between genomic alterations and drug responses. Various computational approaches have been proposed to predict sensitivity based on genomic features, while others have used the chemical properties of the drugs to ascertain their effect. In an effort to integrate these complementary approach…
Cancers follow a clonal Darwinian evolution, with fitter subclones replacing more quiescent cells, ultimately giving rise to macroscopic disease. High-throughput genomics provides the opportunity to investigate these processes and determine specific genetic alterations driving disease progression. Genomic sampling of a patient's cancer provides a molecular history, represented by a phylogenetic tree. Cohorts of patients represent a forest of related phylogenetic structures. To extract clinically relevant information, one must represent and statistically compare these collections of trees. We p…
Studies into the statistical properties of biological networks have led to important biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable a…
The increasing availability of sequencing data of cancer samples is fueling the development of algorithmic strategies to investigate tumor heterogeneity and infer reliable models of cancer evolution. We here build up on previous works on cancer progression inference from genomic alteration data, to deliver two distinct Cytoscape-based applications, which allow to produce, visualize and manipulate cancer evolution models, also by interacting with public genomic and proteomics databases. In particular, we here introduce cyTRON, a stand-alone Cytoscape app, and cyTRON/JS, a web application which …
Genomic alterations lead to cancer complexity and form a major hurdle for a comprehensive understanding of the molecular mechanisms underlying oncogenesis. In this review, we describe the recent advances in studying cancer-associated genes from a systems biological point of view. The integration of known cancer genes onto protein and signaling networks reveals the characteristics of cancer genes within networks. This approach shows that cancer genes often function as network hub proteins which are involved in many cellular processes and form focal nodes in the information exchange between many…
The genomic evolution inherent to cancer relates directly to a renewed focus on the voluminous next generation sequencing (NGS) data, and machine learning for the inference of explanatory models of how the (epi)genomic events are choreographed in cancer initiation and development. However, despite the increasing availability of multiple additional -omics data, this quest has been frustrated by various theoretical and technical hurdles, mostly stemming from the dramatic heterogeneity of the disease. In this paper, we build on our recent works on "selective advantage" relation among driver mutat…
Horizontal gene transfer is an important factor in bacterial evolution that can act across species boundaries. Yet, we know little about rate and genomic targets of cross-lineage gene transfer, and about its effects on the recipient organism's physiology and fitness. Here, we address these questions in a parallel evolution experiment with two Bacillus subtilis lineages of 7% sequence divergence. We observe rapid evolution of hybrid organisms: gene transfer swaps ~12% of the core genome in just 200 generations, and 60% of core genes are replaced in at least one population. By genomics, transcri…
A central goal in cancer genomics is to identify the somatic alterations that underpin tumor initiation and progression. This task is challenging as the mutational profiles of cancer genomes exhibit vast heterogeneity, with many alterations observed within each individual, few shared somatically mutated genes across individuals, and important roles in cancer for both frequently and infrequently mutated genes. While commonly mutated cancer genes are readily identifiable, those that are rarely mutated across samples are difficult to distinguish from the large numbers of other infrequently mutate…
Cancer progression is driven by a small number of genetic alterations accumulating in a neoplasm. These few driver alterations reside in a cancer genome alongside tens of thousands of other mutations that are widely believed to have no role in cancer and termed passengers. Many passengers, however, fall within protein coding genes and other functional elements and can possibly have deleterious effects on cancer cells. Here we investigate a potential of mildly deleterious passengers to accumulate and alter the course of neoplastic progression. Our approach combines evolutionary simulations of c…
Recent studies of cancer somatic mutation profiles seek to identify mutations for targeted therapy in personalized medicine. Analysis of profiles, however, is not trivial, as each profile is heterogeneous and there are multiple confounding factors that influence the cause-and-effect relationships between cancer genes such as cancer (sub)type, biological processes, total number of mutations, and non-linear mutation interactions. Moreover, cancer is biologically redundant, i.e., distinct mutations can result in the alteration of similar biological processes, so it is important to identify all po…
Somatic mutations in cancer cells affect various genomic elements disrupting important cell functions. In particular, mutations in DNA binding sites recognized by transcription factors can alter regulator binding affinities and expression of target genes. A number of promoter mutations have been linked with an increased risk of cancer, mutations in binding sites of selected transcription factors have been found under positive selection. However, negative selection of mutations in coding regions is elusive and significance of negative selection in non-coding regions remains controversial. Here …
