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Nat Biotechnol DOI:10.1038/nbt.2203

Absolute quantification of somatic DNA alterations in human cancer.

Publication TypeJournal Article
Year of Publication2012
AuthorsCarter, SL, Cibulskis, K, Helman, E, McKenna, A, Shen, H, Zack, T, Laird, PW, Onofrio, RC, Winckler, W, Weir, BA, Beroukhim, R, Pellman, D, Levine, DA, Lander, ES, Meyerson, M, Getz, G
JournalNat Biotechnol
Volume30
Issue5
Pages413-21
Date Published2012 May
ISSN1546-1696
KeywordsAlleles, Aneuploidy, Biotechnology, Cell Line, Tumor, Cell Separation, Cyclin-Dependent Kinases, Disease Progression, DNA, DNA Mutational Analysis, Female, Flow Cytometry, Gene Dosage, Genetic Techniques, Genome, Human, Homozygote, Humans, Male, Neoplasms, Neurofibromin 1, Ovarian Neoplasms, Ploidies, Point Mutation, Tumor Suppressor Protein p53
Abstract

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.

URLhttp://dx.doi.org/10.1038/nbt.2203
DOI10.1038/nbt.2203
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22544022?dopt=Abstract

Alternate JournalNat. Biotechnol.
PubMed ID22544022
PubMed Central IDPMC4383288
Grant ListK08CA122833 / CA / NCI NIH HHS / United States
U24 CA143882 / CA / NCI NIH HHS / United States
U54 CA143798 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
5R01 GM083299-14 / GM / NIGMS NIH HHS / United States
K08 CA122833 / CA / NCI NIH HHS / United States
U24CA143867 / CA / NCI NIH HHS / United States
F32 CA113126 / CA / NCI NIH HHS / United States
5 T32 GM008313 / GM / NIGMS NIH HHS / United States
U24CA126546 / CA / NCI NIH HHS / United States
T32 GM008313 / GM / NIGMS NIH HHS / United States
F32CA113126 / CA / NCI NIH HHS / United States
R01 GM083299 / GM / NIGMS NIH HHS / United States
U24CA143845 / CA / NCI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States
U54CA143798 / CA / NCI NIH HHS / United States
U24 CA126546 / CA / NCI NIH HHS / United States