RESOLVE
Cancer is a genetic disease caused by somatic mutations in genes controlling key biological functions such as cellular growth and division. Such mutations may arise both through cell-intrinsic and exogenous processes, generating characteristic mutational patterns over the genome named mutational signatures. The study of mutational signatures have become a standard component of modern genomics studies, since it can reveal which (environmental and endogenous) mutagenic processes are active in a tumor, and may highlight markers for therapeutic response. Mutational signatures computational analysis presents many pitfalls. First, the task of determining the number of signatures is very complex and depends on heuristics. Second, several signatures have no clear etiology, casting doubt on them being computational artifacts rather than due to mutagenic processes. Last, approaches for signatures assignment are greatly influenced by the set of signatures used for the analysis. To overcome these limitations, we developed RESOLVE (Robust EStimation Of mutationaL signatures Via rEgularization), a framework that allows the efficient extraction and assignment of mutational signatures. RESOLVE implements a novel algorithm that enables (i) the efficient extraction, (ii) exposure estimation, and (iii) confidence assessment during the computational inference of mutational signatures.
- Repository
- github.com/danro9685/resolve
Source attribution
- Bioconductor — RESOLVE
Related resources
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Uses quadratic programming for signature refitting, i.e., to decompose the mutation catalog from an individual tumor sample into a set of given mutational signatures (either Alexandrov-model signatures or Shiraishi-model signatures), computing weights that reflect the contributions of the signatures to the mutation load of the tumor.
Point mutations occurring in a genome can be divided into 96 categories based on the base being mutated, the base it is mutated into and its two flanking bases. Therefore, for any patient, it is possible to represent all the point mutations occurring in that patient's tumor as a vector of length 96, where each element represents the count of mutations for a given category in the patient. A mutational signature represents the pattern of mutations produced by a mutagen or mutagenic process inside the cell. Each signature can also be represented by a vector of length 96, where each element represents the probability that this particular mutagenic process generates a mutation of the 96 above mentioned categories. In this R package, we provide a set of functions to extract and visualize the mutational signatures that best explain the mutation counts of a large number of patients.
The ZygosityPredictor allows to predict how many copies of a gene are affected by small variants. In addition to the basic calculations of the affected copy number of a variant, the Zygosity-Predictor can integrate the influence of several variants on a gene and ultimately make a statement if and how many wild-type copies of the gene are left. This information proves to be of particular use in the context of translational medicine. For example, in cancer genomes, the Zygosity-Predictor can address whether unmutated copies of tumor-suppressor genes are present. Beyond this, it is possible to make this statement for all genes of an organism. The Zygosity-Predictor was primarily developed to handle SNVs and INDELs (later addressed as small-variants) of somatic and germline origin. In order not to overlook severe effects outside of the small-variant context, it has been extended with the assessment of large scale deletions, which cause losses of whole genes or parts of them.
The TRONCO (TRanslational ONCOlogy) R package collects algorithms to infer progression models via the approach of Suppes-Bayes Causal Network, both from an ensemble of tumors (cross-sectional samples) and within an individual patient (multi-region or single-cell samples). The package provides parallel implementation of algorithms that process binary matrices where each row represents a tumor sample and each column a single-nucleotide or a structural variant driving the progression; a 0/1 value models the absence/presence of that alteration in the sample. The tool can import data from plain, MAF or GISTIC format files, and can fetch it from the cBioPortal for cancer genomics. Functions for data manipulation and visualization are provided, as well as functions to import/export such data to other bioinformatics tools for, e.g, clustering or detection of mutually exclusive alterations. Inferred models can be visualized and tested for their confidence via bootstrap and cross-validation. TRONCO is used for the implementation of the Pipeline for Cancer Inference (PICNIC).