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. 2014 Apr 15;30(8):1056-1063.
doi: 10.1093/bioinformatics/btt759. Epub 2014 Jan 2.

AbsCN-seq: a statistical method to estimate tumor purity, ploidy and absolute copy numbers from next-generation sequencing data

Lei Bao  1 , Minya Pu  1 , Karen Messer  1
Affiliations

AbsCN-seq: a statistical method to estimate tumor purity, ploidy and absolute copy numbers from next-generation sequencing data

Lei Bao et al. Bioinformatics. .

Abstract

Motivation: Detection and quantification of the absolute DNA copy number alterations in tumor cells is challenging because the DNA specimen is extracted from a mixture of tumor and normal stromal cells. Estimates of tumor purity and ploidy are necessary to correctly infer copy number, and ploidy may itself be a prognostic factor in cancer progression. As deep sequencing of the exome or genome has become routine for characterization of tumor samples, in this work, we aim to develop a simple and robust algorithm to infer purity, ploidy and absolute copy numbers in whole numbers for tumor cells from sequencing data.

Results: A simulation study shows that estimates have reasonable accuracy, and that the algorithm is robust against the presence of segmentation errors and subclonal populations. We validated our algorithm against a panel of cell lines with experimentally determined ploidy. We also compared our algorithm with the well-established single-nucleotide polymorphism array-based method called ABSOLUTE on three sets of tumors of different types. Our method had good performance on these four benchmark datasets for both purity and ploidy estimates, and may offer a simple solution to copy number alteration quantification for cancer sequencing projects.

Availability and implementation: The R package absCNseq is available from http://biostats.mcc.ucsd.edu/files/absCNseq_1.0.tar.gz CONTACT: kmesser@ucsd.edu Supplementary information: Supplementary data are available at Bioinformatics online.

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Figures

Fig. 1.
Fig. 1.
Simulation showing effects of subclonal fraction on estimated purity, at three purity levels (30, 50 and 70%; horizontal lines). Data modeled after tumor sample BR-M-028. X-axis: proportion of segments set to be subclonal, for which the copy number was perturbed by a uniform random shift away from its integer value. Y-axis: estimated purity for n = 50 simulations. Solutions which would normally be ‘no call’ are included for completeness. A subclonal fraction >30% is seen to introduce some bias, but estimated purity remains reasonable
Fig. 2.
Fig. 2.
Ploidy estimates of Abs-CNseq versus SKY for 31 NCI cell lines. Spearman rank correlation coefficient = 0.80, P < 0.001; RMSE = 0.34
Fig. 3.
Fig. 3.
Comparison of purity (a) and ploidy (b) estimates from AbsCN-seq (exome data) versus ABSOLUTE (SNP array data). The alternate estimate for BR-M-038 mentioned in the main text is shown as an open triangle
Fig. 4.
Fig. 4.
Assignment of integer copy numbers to the segments on chromosome 16 for subject BR-M-030. Raw copy ratios and segmented copy ratios between the tumor DNA mixture and the match germ line DNA are in green and blue, respectively. The estimated absolute copy numbers in pure tumor cells are in red. As a copy ratio of 1.0 corresponds to a normal diploid segment, we multiply the copy ratios by two to bring the copy ratio and the absolute copy number to the same scale
Fig. 5.
Fig. 5.
Comparison of purity (a) and ploidy (b) estimates from AbsCN-seq versus ABSOLUTE for 17 GBM samples and 16 prostate samples
See this image and copyright information in PMC

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