Inferring copy number and genotype in tumour exome data

Abstract

BackgroundUsing whole exome sequencing to predict aberrations in tumours is a cost effective alternative to whole genome sequencing, however is predominantly used for variant detection and infrequently utilised for detection of somatic copy number variation.ResultsWe propose a new method to infer copy number and genotypes using whole exome data from paired tumour/normal samples. Our algorithm uses two Hidden Markov Models to predict copy number and genotypes and computationally resolves polyploidy/aneuploidy, normal cell contamination and signal baseline shift. Our method makes explicit detection on chromosome arm level events, which are commonly found in tumour samples. The methods are combined into a package named ADTEx (Aberration Detection in Tumour Exome). We applied our algorithm to a cohort of 17 in-house generated and 18 TCGA paired ovarian cancer/normal exomes and evaluated the performance by comparing against the copy number variations and genotypes predicted using Affymetrix SNP 6.0 data of the same samples. Further, we carried out a comparison study to show that ADTEx outperformed its competitors in terms of precision and F-measure.ConclusionsOur proposed method, ADTEx, uses both depth of coverage ratios and B allele frequencies calculated from whole exome sequencing data, to predict copy number variations along with their genotypes. ADTEx is implemented as a user friendly software package using Python and R statistical language. Source code and sample data are freely available under GNU license (GPLv3) at http://adtex.sourceforge.net/.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-732) contains supplementary material, which is available to authorized users.

Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia

“…These variants had been identified as high-confidence variants in at least one other tumour or plasma sample from the same individual. To adjust for purity and ploidy, we used the average of purity estimates from ADTEx36 and Sequenza37, the copy number estimates generated by Sequenza and adjusted MAF using the formula described by Nik-Zainal et. al 38…”

Detection of structural mosaicism from targeted and whole-genome sequencing data

“…These tools are relatively insensitive to mosaic abnormalities (post-zygotic abnormalities, i.e., "mutations"), however, because they typically rely on single metrics, such as copy-number change (rather than copy-number and allele-fraction), or on genotype, which is not well assessed in mosaic state. Specialized methods have been developed for the analysis of cancer exomes where tumor and normal tissue can be isolated (Lonigro et al 2011;Amarasinghe et al 2014) or, in the context of a parent-fetus trio, for fetal DNA in maternal plasma (Rampášek et al 2014). However, a method to detect copy-number and copy-neutral mosaicism from an individual's exome (or genome) is lacking, but if available, could further extend the capacity of sequence-based analyses.…”

A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data

“…Many tools have been developed for estimating CNAs from WES data based on paired normal-tumor samples such as CNV-seq [53], SegSeq [54], ADTEx [55], CONTRA [56], EXCAVATOR [57], ExomeCNV [58], Control-FREEC (control-FREE Copy number caller) [59], and CNVseeqer [60]. For example, VarScan2 [61] is a computational tool that can estimate somatic mutations and CNAs from paired normal-tumor samples.…”