Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data

TY - JOUR

T1 - Sequenza

T2 - allele-specific copy number and mutation profiles from tumor sequencing data

AU - Favero, F

AU - Joshi, T

AU - Marquard, A M

AU - Birkbak, N J

AU - Krzystanek, M

AU - Li, Q

AU - Szallasi, Z

AU - Eklund, A C

N1 - © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - BACKGROUND: Exome or whole-genome deep sequencing of tumor DNA along with paired normal DNA can potentially provide a detailed picture of the somatic mutations that characterize the tumor. However, analysis of such sequence data can be complicated by the presence of normal cells in the tumor specimen, by intratumor heterogeneity, and by the sheer size of the raw data. In particular, determination of copy number variations from exome sequencing data alone has proven difficult; thus, single nucleotide polymorphism (SNP) arrays have often been used for this task. Recently, algorithms to estimate absolute, but not allele-specific, copy number profiles from tumor sequencing data have been described.MATERIALS AND METHODS: We developed Sequenza, a software package that uses paired tumor-normal DNA sequencing data to estimate tumor cellularity and ploidy, and to calculate allele-specific copy number profiles and mutation profiles. We applied Sequenza, as well as two previously published algorithms, to exome sequence data from 30 tumors from The Cancer Genome Atlas. We assessed the performance of these algorithms by comparing their results with those generated using matched SNP arrays and processed by the allele-specific copy number analysis of tumors (ASCAT) algorithm.RESULTS: Comparison between Sequenza/exome and SNP/ASCAT revealed strong correlation in cellularity (Pearson's r = 0.90) and ploidy estimates (r = 0.42, or r = 0.94 after manual inspecting alternative solutions). This performance was noticeably superior to previously published algorithms. In addition, in artificial data simulating normal-tumor admixtures, Sequenza detected the correct ploidy in samples with tumor content as low as 30%.CONCLUSIONS: The agreement between Sequenza and SNP array-based copy number profiles suggests that exome sequencing alone is sufficient not only for identifying small scale mutations but also for estimating cellularity and inferring DNA copy number aberrations.

AB - BACKGROUND: Exome or whole-genome deep sequencing of tumor DNA along with paired normal DNA can potentially provide a detailed picture of the somatic mutations that characterize the tumor. However, analysis of such sequence data can be complicated by the presence of normal cells in the tumor specimen, by intratumor heterogeneity, and by the sheer size of the raw data. In particular, determination of copy number variations from exome sequencing data alone has proven difficult; thus, single nucleotide polymorphism (SNP) arrays have often been used for this task. Recently, algorithms to estimate absolute, but not allele-specific, copy number profiles from tumor sequencing data have been described.MATERIALS AND METHODS: We developed Sequenza, a software package that uses paired tumor-normal DNA sequencing data to estimate tumor cellularity and ploidy, and to calculate allele-specific copy number profiles and mutation profiles. We applied Sequenza, as well as two previously published algorithms, to exome sequence data from 30 tumors from The Cancer Genome Atlas. We assessed the performance of these algorithms by comparing their results with those generated using matched SNP arrays and processed by the allele-specific copy number analysis of tumors (ASCAT) algorithm.RESULTS: Comparison between Sequenza/exome and SNP/ASCAT revealed strong correlation in cellularity (Pearson's r = 0.90) and ploidy estimates (r = 0.42, or r = 0.94 after manual inspecting alternative solutions). This performance was noticeably superior to previously published algorithms. In addition, in artificial data simulating normal-tumor admixtures, Sequenza detected the correct ploidy in samples with tumor content as low as 30%.CONCLUSIONS: The agreement between Sequenza and SNP array-based copy number profiles suggests that exome sequencing alone is sufficient not only for identifying small scale mutations but also for estimating cellularity and inferring DNA copy number aberrations.

KW - Algorithms

KW - Alleles

KW - Base Sequence

KW - DNA Copy Number Variations/genetics

KW - Exome/genetics

KW - Gene Dosage/genetics

KW - High-Throughput Nucleotide Sequencing/methods

KW - Humans

KW - Mutation

KW - Neoplasms/genetics

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, DNA

KW - Software

U2 - 10.1093/annonc/mdu479

DO - 10.1093/annonc/mdu479

M3 - Journal article

C2 - 25319062

SN - 0923-7534

VL - 26

SP - 64

EP - 70

JO - Annals of Oncology

JF - Annals of Oncology

IS - 1

ER -