Absolute Quantification of Somatic DNA Alterations in Human Cancer

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2012 May 1

PMID 22544022

Citations 1199

Authors

Scott L Carter

Kristian Cibulskis

Elena Helman

Aaron McKenna

Hui Shen

Travis Zack

Peter W Laird

Robert C Onofrio

Wendy Winckler

Barbara A Weir

Rameen Beroukhim

David Pellman

Douglas A Levine

Eric S Lander

Matthew Meyerson

Gad Getz

Affiliations

Soon will be listed here.

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.

Citing Articles

Genomic alterations in the WNT/β-catenin pathway and resistance of colorectal cancer cells to pathway-targeting therapies.

Voutsadakis I Explor Target Antitumor Ther. 2025; 6:1002295.

PMID: 40061138 PMC: 11886378. DOI: 10.37349/etat.2025.1002295.

TCGEx: a powerful visual interface for exploring and analyzing cancer gene expression data.

Kus M, Sahin C, Kilic E, Askin A, Ozgur M, Karahanogullari G EMBO Rep. 2025; .

PMID: 40033050 DOI: 10.1038/s44319-025-00407-7.

Tracking the Evolution of Cutaneous Melanoma by Multiparameter Flow Sorting and Genomic Profiling.

Roma L, Lorber T, Rau S, Barrett M, Ercan C, Panebianco F Int J Mol Sci. 2025; 26(4).

PMID: 40004220 PMC: 11855598. DOI: 10.3390/ijms26041758.

Homologous recombination deficiency (HRD) testing landscape: clinical applications and technical validation for routine diagnostics.

Witz A, Dardare J, Betz M, Michel C, Husson M, Gilson P Biomark Res. 2025; 13(1):31.

PMID: 39985088 PMC: 11846297. DOI: 10.1186/s40364-025-00740-y.

The Breast Cancer Classifier refines molecular breast cancer classification to delineate the HER2-low subtype.

Turova P, Kushnarev V, Baranov O, Butusova A, Menshikova S, Yong S NPJ Breast Cancer. 2025; 11(1):19.

PMID: 39979291 PMC: 11842814. DOI: 10.1038/s41523-025-00723-0.

References

Chiang D, Getz G, Jaffe D, OKelly M, Zhao X, Carter S . High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat Methods. 2008; 6(1):99-103. PMC: 2630795. DOI: 10.1038/nmeth.1276. View

Peltonen L, Altshuler D, de Bakker P, Deloukas P, Gabriel S, Gwilliam R . Integrating common and rare genetic variation in diverse human populations. Nature. 2010; 467(7311):52-8. PMC: 3173859. DOI: 10.1038/nature09298. View

Levanon K, Crum C, Drapkin R . New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol. 2008; 26(32):5284-93. PMC: 2652087. DOI: 10.1200/JCO.2008.18.1107. View

Mullighan C, Goorha S, Radtke I, Miller C, Coustan-Smith E, Dalton J . Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007; 446(7137):758-64. DOI: 10.1038/nature05690. View

Greenman C, Bignell G, Butler A, Edkins S, Hinton J, Beare D . PICNIC: an algorithm to predict absolute allelic copy number variation with microarray cancer data. Biostatistics. 2009; 11(1):164-75. PMC: 2800165. DOI: 10.1093/biostatistics/kxp045. View

Berger M, Lawrence M, Demichelis F, Drier Y, Cibulskis K, Sivachenko A . The genomic complexity of primary human prostate cancer. Nature. 2011; 470(7333):214-20. PMC: 3075885. DOI: 10.1038/nature09744. View

Li A, Liu Z, Lezon-Geyda K, Sarkar S, Lannin D, Schulz V . GPHMM: an integrated hidden Markov model for identification of copy number alteration and loss of heterozygosity in complex tumor samples using whole genome SNP arrays. Nucleic Acids Res. 2011; 39(12):4928-41. PMC: 3130254. DOI: 10.1093/nar/gkr014. View

Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J . Tumour evolution inferred by single-cell sequencing. Nature. 2011; 472(7341):90-4. PMC: 4504184. DOI: 10.1038/nature09807. View

Popova T, Manie E, Stoppa-Lyonnet D, Rigaill G, Barillot E, Stern M . Genome Alteration Print (GAP): a tool to visualize and mine complex cancer genomic profiles obtained by SNP arrays. Genome Biol. 2009; 10(11):R128. PMC: 2810663. DOI: 10.1186/gb-2009-10-11-r128. View

10.

Barrett M, Sanchez C, Prevo L, Wong D, Galipeau P, Paulson T . Evolution of neoplastic cell lineages in Barrett oesophagus. Nat Genet. 1999; 22(1):106-9. PMC: 1559997. DOI: 10.1038/8816. View

11.

Fujiwara T, Bandi M, Nitta M, Ivanova E, Bronson R, Pellman D . Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 2005; 437(7061):1043-7. DOI: 10.1038/nature04217. View

12.

Mei R, Galipeau P, Prass C, Berno A, Ghandour G, Patil N . Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res. 2000; 10(8):1126-37. PMC: 2235196. DOI: 10.1101/gr.10.8.1126. View

13.

Campbell P, Stephens P, Pleasance E, OMeara S, Li H, Santarius T . Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008; 40(6):722-9. PMC: 2705838. DOI: 10.1038/ng.128. View

14.

Lindblad-Toh K, Tanenbaum D, Daly M, Winchester E, Lui W, Villapakkam A . Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat Biotechnol. 2000; 18(9):1001-5. DOI: 10.1038/79269. View

15.

Bignell G, Huang J, Greshock J, Watt S, Butler A, West S . High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res. 2004; 14(2):287-95. PMC: 327104. DOI: 10.1101/gr.2012304. View

16.

Stransky N, Egloff A, Tward A, Kostic A, Cibulskis K, Sivachenko A . The mutational landscape of head and neck squamous cell carcinoma. Science. 2011; 333(6046):1157-60. PMC: 3415217. DOI: 10.1126/science.1208130. View

17.

Mermel C, Schumacher S, Hill B, Meyerson M, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41. PMC: 3218867. DOI: 10.1186/gb-2011-12-4-r41. View

18.

Van Loo P, Nordgard S, Lingjaerde O, Russnes H, Rye I, Sun W . Allele-specific copy number analysis of tumors. Proc Natl Acad Sci U S A. 2010; 107(39):16910-5. PMC: 2947907. DOI: 10.1073/pnas.1009843107. View

19.

Noushmehr H, Weisenberger D, Diefes K, Phillips H, Pujara K, Berman B . Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010; 17(5):510-22. PMC: 2872684. DOI: 10.1016/j.ccr.2010.03.017. View

20.

Bass A, Lawrence M, Brace L, Ramos A, Drier Y, Cibulskis K . Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet. 2011; 43(10):964-968. PMC: 3802528. DOI: 10.1038/ng.936. View