Absolute quantification of somatic DNA alterations in human cancer

By Scott L. Carter, Kristian Cibulskis, E. Helman, A. McKenna, Hui Shen, Travis Zack, Peter W. Laird, R. Onofrio, W. Winckler, B. Weir and 6 more. Nature Biotechnology, 2012

1,929 citations recorded by the source corpus.

We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.

Subfields: Cancer Research, Genetics, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/82c2119400cb4fe329074afaacb2d00465ebc9ab

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Genetics

In Pathology and Forensic Medicine

Citations in the corpus

Co-occurring genomic alterations define major subsets of KRAS - mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities (2015, positive): “The ABSOLUTE algorithm was employed for clonality analyses (22).”
Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma (2013, positive): “To discriminate early from late genetic events, we integrated variant allele frequencies (VAFs) generated from our high-depth sequencing data with SNP array copy number profiles on 29 cases (26 FL-tFL pairs and 3 diagnostic FLs), using the ABSOLUTE algorithm 35 .”
An Extensive Evaluation of Read Trimming Effects on Illumina NGS Data Analysis (2013, background): “However, the read correction approach cannot be applied wherever sequence abundance is intrinsically not uniform, such as in transcriptomics (RNA-Seq) [20], metagenomics [21] or heterogeneous cancer DNA samples [22].”
Mining TCGA database for genes of prognostic value in glioblastoma microenvironment (2018, neutral): “Algorithms [14, 19] have been developed to predict tumor purity using gene expression data from the TCGA database.”
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution (2014, methodology): “To determine the intra-tumor heterogeneity of copy number aberrations, we estimated integer DNA copy numbers for each tumor region (7, 16, 21, 22).”
Evolution of the cancer genome (2012, background): “Some of cluster A Some of cluster A Del13 Del t(1;22)”
The molecular taxonomy of primary prostate cancer (2015, methodology): “…primary prostate cancer specimens of high tumor cellularity, we also performed a multi-platform analysis of tumor content, estimating tumor purity with analytical approaches utilizing both DNA (Carter et al., 2012, Prandi et al., 2014) and RNA (Quon et al., 2013, Ahn et al., 2013) sequencing data.”
Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, neutral): “0.3 https://github.com/hammerlab/pyensembl OptiType Snyder et al., 2017 (PMID 28552987); Szolek et al., 2014 (PMID 25143287) https://github.com/FRED-2/Optitype Topiary Nathanson et al., 2017 (PMID 27956380) https://github.com/hammerlab/topiary/ ABSOLUTE Carter et al., 2012 (PMID 22544022) http://arc”
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia (2013, positive): “We applied ABSOLUTE to estimate sample purity, ploidy, and absolute somatic copy numbers.”