Allele-specific copy number profiling by next-generation DNA sequencing.

Hao Chen,Hanlee P Ji,John M Bell,Nancy R Zhang,Nicolas A Zavala

doi:10.1093/nar/gku1252

Abstract

The progression and clonal development of tumors often involve amplifications and deletions of genomic DNA. Estimation of allele-specific copy number, which quantifies the number of copies of each allele at each variant loci rather than the total number of chromosome copies, is an important step in the characterization of tumor genomes and the inference of their clonal history. We describe a new method, falcon, for finding somatic allele-specific copy number changes by next generation sequencing of tumors with matched normals. falcon is based on a change-point model on a bivariate mixed Binomial process, which explicitly models the copy numbers of the two chromosome haplotypes and corrects for local allele-specific coverage biases. By using the Binomial distribution rather than a normal approximation, falcon more effectively pools evidence from sites with low coverage. A modified Bayesian information criterion is used to guide model selection for determining the number of copy number events. Falcon is evaluated on in silico spike-in data and applied to the analysis of a pre-malignant colon tumor sample and late-stage colorectal adenocarcinoma from the same individual. The allele-specific copy number estimates obtained by falcon allows us to draw detailed conclusions regarding the clonal history of the individual's colon cancer.

Highlights

Each person inherits two copies of the genome
We describe a new method, falcon, for finding somatic allele-specific copy number changes by generation sequencing of tumors with matched normals. falcon is based on a change-point model on a bivariate mixed Binomial process, which explicitly models the copy numbers of the two chromosome haplotypes and corrects for local allele-specific coverage biases
By applying FALCON to a trio of normal, pre-malignant tumor and late-stage colorectal adenocarcinoma samples from the same individual, we show that accurately estimated allele-specific copy number (ASCN) allow one to draw conclusions about clonal history that would have been impossible using total copy number alone

Summary

Introduction

Each person inherits two copies of the genome. Tumor cells often undergo somatic structural mutations that delete or amplify certain chromosomal segments in one or both copies. Detecting and characterizing these mutations, called somatic copy number aberrations, are an important step in the study of the tumor. Copy number aberrations were traditionally studied by spectral karyotyping and more recently by comparative genome hybridization (CGH) and high-density single nucleotide polymorphism genotyping arrays. CGH allows the relative quantification, with respect to a control sample, of the total copy number of the two inherited homologous chromosome copies (see [1] and [2] for a review). By measuring the quantity of both alleles at heterozygous loci, genotyping arrays allow the estimation of the copy numbers of each allele, sometimes called allele-specific copy number (ASCN) [3,4,5,6,7,8,9,10,11]

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