Topological Data Analysis of copy number alterations in cancer
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）
Stefan Groha, Caroline Weis, Alexander Gusev, Bastian Rieck
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 that this technique has the potential to extract meaningful low-dimensional representations in cancer somatic genetic data and demonstrate the viability of some applications on finding substructures in cancer data as well as comparing similarity of cancer types.
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…
Background: Regions with copy number variations (in germline cells) or copy number alteration (in somatic cells) are of great interest for human disease gene mapping and cancer studies. They represent a new type of mutation and are larger-scaled than the single nucleotide polymorphisms. Using genotyping microarray for copy number variation detection has become standard, and there is a need for improving analysis methods. Results: We apply the cumulative plot to the detection of regions with copy number variation/alteration, on samples taken from a chronic lymphocytic leukemia patient. Two sets…
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 …
BACOM is a statistically principled and unsupervised method that detects copy number deletion types (homozygous versus heterozygous), estimates normal cell fraction, and recovers cancer specific copy number profiles, using allele specific copy number signals. In a subsequent analysis of TCGA ovarian cancer dataset, the average normal cell fraction estimated by BACOM was found higher than expected. In this letter, we first discuss the advantages of the BACOM in relation to alternative approaches. Then, we show that this elevated estimate of normal cell fraction is the combined result of inaccur…
We call change-point problem (CPP) the identification of changes in the probabilistic behavior of a sequence of observations. Solving the CPP involves detecting the number and position of such changes. In genetics the study of how and what characteristics of a individual's genetic content might contribute to the occurrence and evolution of cancer has fundamental importance in the diagnosis and treatment of such diseases and can be formulated in the framework of chage-point analysis. In this article we propose a modification to a existing method of segmentation with the objective of producing a…
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…
We develop a cross-platform open-source Java application (BACOM2) with graphic user interface (GUI), and users also can use a XML file to set the parameters of algorithm model, file paths and the dataset of paired samples. BACOM2 implements the new entire pipeline of copy number change analysis for heterogeneous cancer tissues, including extraction of raw copy number signals from CEL files of paired samples, attenuation correction, identification of balanced AB-genotype loci, copy number detection and segmentation, global baseline calculation and absolute normalization, differentiation of dele…
University of Science and Technology of China（中国科学技术大学）；The Fourth Affiliated Hospital of Anhui Medical University（安徽医科大学第四附属医院）；Genmab Inc.（Genmab公司）
Deep-learning models based on whole-slide digital pathology images (WSIs) become increasingly popular for predicting molecular biomarkers. Instance-based models has been the mainstream strategy for predicting genetic alterations using WSIs although bag-based models along with self-attention mechanism-based algorithms have been proposed for other digital pathology applications. In this paper, we proposed a novel Attention-based Multiple Instance Mutation Learning (AMIML) model for predicting gene mutations. AMIML was comprised of successive 1-D convolutional layers, a decoder, and a residual we…
Background: The delineation of genomic copy number abnormalities (CNAs) from cancer samples has been instrumental for identification of tumor suppressor genes and oncogenes and proven useful for clinical marker detection. An increasing number of projects have mapped CNAs using high-resolution microarray based techniques. So far, no single resource does provide a global collection of readily accessible oncoge- nomic array data. Methodology/Principal Findings: We here present arrayMap, a curated reference database and bioinformatics resource targeting copy number profiling data in human cancer. …
The reconstruction of phylogenetic trees from mixed populations has become important in the study of cancer evolution, as sequencing is often performed on bulk tumor tissue containing mixed populations of cells. Recent work has shown how to reconstruct a perfect phylogeny tree from samples that contain mixtures of two-state characters, where each character/locus is either mutated or not. However, most cancers contain more complex mutations, such as copy-number aberrations, that exhibit more than two states. We formulate the Multi-State Perfect Phylogeny Mixture Deconvolution Problem of reconst…
Barcelona Supercomputing Center（巴塞罗那超级计算中心）；Universitat Politècnica de Catalunya - BarcelonaTech（加泰罗尼亚理工大学-巴塞罗那理工）
Finding tumour genetic markers is essential to biomedicine due to their relevance for cancer detection and therapy development. In this paper, we explore a recently released dataset of chromosome rearrangements in 2,586 cancer patients, where different sorts of alterations have been detected. Using a Random Forest classifier, we evaluate the relevance of several features (some directly available in the original data, some engineered by us) related to chromosome rearrangements. This evaluation results in a set of potential tumour genetic markers, some of which are validated in the bibliography,…
Comparative studies of cancer-related genes allow us to gain novel information about the evolution and function of these genes, but also to understand cancer as a driving force in biological systems and species life histories. So far, comparative studies of cancer genes have focused on mammals. Here, we provide the first comparative study of cancer-related gene copy number variation in fish. As fish are evolutionarily older and genetically more diverse than mammals, their tumour suppression mechanisms should not only include most of the mammalian mechanisms, but also reveal novel (but potentia…
During cancer progression, malignant cells accumulate somatic mutations that can lead to genetic aberrations. In particular, evolutionary events akin to segmental duplications or deletions can alter the copy-number profile (CNP) of a set of genes in a genome. Our aim is to compute the evolutionary distance between two cells for which only CNPs are known. This asks for the minimum number of segmental amplifications and deletions to turn one CNP into another. This was recently formalized into a model where each event is assumed to alter a copy-number by $1$ or $-1$, even though these events can …
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…
Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, which provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant assoc…
Epigenetic aberrations have profound effects on phenotypic output. Genome wide methylation alterations are inheritable to pass down the aberrations through multiple generations. We developed a statistical method, Genome-wide Identification of Significant Methylation Alteration, GISAIM, to study the significant transgenerational methylation changes. GISAIM finds the significant methylation aberrations that are inherited through multiple generations. In a concrete biological study, we investigated whether exposing pregnant rats (F0) to a high fat (HF) diet throughout pregnancy or ethinyl estradi…
Explicit accounting for copy number alterations can dramatically improve mutation frequency estimates, leading to more accurate phylogeny reconstructions and subclone characterizations.
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 …
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…
The medical research facilitates to acquire a diverse type of data from the same individual for particular cancer. Recent studies show that utilizing such diverse data results in more accurate predictions. The major challenge faced is how to utilize such diverse data sets in an effective way. In this paper, we introduce a multiple kernel based pipeline for integrative analysis of high-throughput molecular data (somatic mutation, copy number alteration, DNA methylation and mRNA) and clinical data. We apply the pipeline on Ovarian cancer data from TCGA. After multiple kernels have been generated…
Washington University School of Medicine, Washington University in St. Louis（圣路易斯华盛顿大学医学院）；Dalian University of Technology（大连理工大学）
Drug resistance is still a major challenge in cancer therapy. Drug combination is expected to overcome drug resistance. However, the number of possible drug combinations is enormous, and thus it is infeasible to experimentally screen all effective drug combinations considering the limited resources. Therefore, computational models to predict and prioritize effective drug combinations is important for combinatory therapy discovery in cancer. In this study, we proposed a novel deep learning model, AuDNNsynergy, to prediction drug combinations by integrating multi-omics data and chemical structur…
DNA copy number aberrations (CNAs) can be found in the majority of cancer genomes, and are crucial for understanding the potential mechanisms underlying tumor initiation and progression. Since the first release in 2001, the Progenetix project (http://www.progenetix.org) has provided a reference resource dedicated to provide the most comprehensive collection of genome-wide CNA profiles. Reflecting the application of comparative genomic hybridization (CGH) techniques to tens of thousands of cancer genomes, over the past 12 years our data curation efforts have resulted in a more than 60-fold incr…
DNA methylation is a well-studied genetic modification crucial to regulate the functioning of the genome. Its alterations play an important role in tumorigenesis and tumor-suppression. Thus, studying DNA methylation data may help biomarker discovery in cancer. Since public data on DNA methylation become abundant, and considering the high number of methylated sites (features) present in the genome, it is important to have a method for efficiently processing such large datasets. Relying on big data technologies, we propose BIGBIOCL an algorithm that can apply supervised classification methods to…
The development of cancer is largely driven by the gain or loss of subsets of the genome, promoting uncontrolled growth or disabling defenses against it. Identifying genomic regions whose DNA copy number deviates from the normal is therefore central to understanding cancer evolution. Array-based comparative genomic hybridization (aCGH) is a high-throughput technique for identifying DNA gain or loss by quantifying total amounts of DNA matching defined probes relative to healthy diploid control samples. Due to the high level of noise in microarray data, however, interpretation of aCGH output is …
Recent breakthroughs in cancer research have come via the up-and-coming field of pathway analysis. By applying statistical methods to prior known gene and protein regulatory information, pathway analysis provides a meaningful way to interpret genomic data. While many gene/protein regulatory relationships have been studied, never before has such a significant amount data been made available in organized forms of gene/protein regulatory networks and pathways. However, pathway analysis research is still in its infancy, especially when applying it to solve practical problems. In this paper we prop…
For a genomically unstable cancer, a single tumour biopsy will often contain a mixture of competing tumour clones. These tumour clones frequently differ with respect to their genomic content (copy number of each gene) and structure (order of genes on each chromosome). Modern bulk genome sequencing mixes the signals of tumour clones and contaminating normal cells, complicating inference of genomic content and structure. We propose a method to unmix tumour and contaminating normal signals and jointly predict genomic structure and content of each tumour clone. We use genome graphs to represent tu…
Motivation: Array-based comparative genomic hybridization (arrayCGH) has recently become a popular tool to identify DNA copy number variations along the genome. These profiles are starting to be used as markers to improve prognosis or diagnosis of cancer, which implies that methods for automated supervised classification of arrayCGH data are needed. Like gene expression profiles, arrayCGH profiles are characterized by a large number of variables usually measured on a limited number of samples. However, arrayCGH profiles have a particular structure of correlations between variables, due to the …
We present a nonparametric Bayesian method for disease subtype discovery in multi-dimensional cancer data. Our method can simultaneously analyse a wide range of data types, allowing for both agreement and disagreement between their underlying clustering structure. It includes feature selection and infers the most likely number of disease subtypes, given the data. We apply the method to 277 glioblastoma samples from The Cancer Genome Atlas, for which there are gene expression, copy number variation, methylation and microRNA data. We identify 8 distinct consensus subtypes and study their prognos…
