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      Absolute quantification of somatic DNA alterations in human cancer

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          Abstract

          We developed a computational method (ABSOLUTE) that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. ABSOLUTE can detect subclonal heterogeneity, somatic homozygosity, and calculate statistical sensitivity to detect specific aberrations. We used ABSOLUTE to analyze ovarian cancer data and identified pervasive subclonal somatic point mutations. In contrast, mutations occurring in key tumor suppressor genes, TP53 and NF1 were predominantly clonal and homozygous, as were mutations in a candidate tumor suppressor gene, CDK12. Analysis of absolute allelic copy-number profiles from 3,155 cancer specimens revealed that genome-doubling events are common in human cancer, and likely occur in already aneuploid cells. By correlating genome-doubling status with mutation data, we found that homozygous mutations in NF1 occurred predominantly in non-doubled samples. This finding suggests that genome doubling influences the pathways of tumor progression, with recessive inactivation being less common after genome doubling.

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          Variance stabilization applied to microarray data calibration and to the quantification of differential expression.

          Wolfgang Huber, Anja von Heydebreck, Holger Sültmann … (2002)
          We introduce a statistical model for microarray gene expression data that comprises data calibration, the quantification of differential expression, and the quantification of measurement error. In particular, we derive a transformation h for intensity measurements, and a difference statistic Deltah whose variance is approximately constant along the whole intensity range. This forms a basis for statistical inference from microarray data, and provides a rational data pre-processing strategy for multivariate analyses. For the transformation h, the parametric form h(x)=arsinh(a+bx) is derived from a model of the variance-versus-mean dependence for microarray intensity data, using the method of variance stabilizing transformations. For large intensities, h coincides with the logarithmic transformation, and Deltah with the log-ratio. The parameters of h together with those of the calibration between experiments are estimated with a robust variant of maximum-likelihood estimation. We demonstrate our approach on data sets from different experimental platforms, including two-colour cDNA arrays and a series of Affymetrix oligonucleotide arrays.
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            High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.

            D. Pinkel, R. Segraves, D. Sudar … (1998)
            Gene dosage variations occur in many diseases. In cancer, deletions and copy number increases contribute to alterations in the expression of tumour-suppressor genes and oncogenes, respectively. Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes. Comparative genomic hybridization (CGH) was developed for genome-wide analysis of DNA sequence copy number in a single experiment. In CGH, differentially labelled total genomic DNA from a 'test' and a 'reference' cell population are cohybridized to normal metaphase chromosomes, using blocking DNA to suppress signals from repetitive sequences. The resulting ratio of the fluorescence intensities at a location on the 'cytogenetic map', provided by the chromosomes, is approximately proportional to the ratio of the copy numbers of the corresponding DNA sequences in the test and reference genomes. CGH has been broadly applied to human and mouse malignancies. The use of metaphase chromosomes, however, limits detection of events involving small regions (of less than 20 Mb) of the genome, resolution of closely spaced aberrations and linking ratio changes to genomic/genetic markers. Therefore, more laborious locus-by-locus techniques have been required for higher resolution studies. Hybridization to an array of mapped sequences instead of metaphase chromosomes could overcome the limitations of conventional CGH (ref. 6) if adequate performance could be achieved. Copy number would be related to the test/reference fluorescence ratio on the array targets, and genomic resolution could be determined by the map distance between the targets, or by the length of the cloned DNA segments. We describe here our implementation of array CGH. We demonstrate its ability to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.
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              Characterizing the cancer genome in lung adenocarcinoma.

              Barbara Weir, Michele S. Woo, Gad Getz … (2007)
              Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9604648
                Journal ID (pubmed-jr-id): 20305
                Journal ID (nlm-ta): Nat Biotechnol
                Journal ID (iso-abbrev): Nat. Biotechnol.
                Title: Nature biotechnology
                ISSN (Print): 1087-0156
                ISSN (Electronic): 1546-1696
                Publication date Nihms-submitted: 19 March 2015
                Publication date (Print): May 2012
                Publication date PMC-release: 02 April 2015
                Volume: 30
                Issue: 5
                Pages: 413-421
                Affiliations
                [1 ]The Broad Institute of Harvard and MIT, Cambridge, MA 02142
                [2 ]Division of Health Sciences and Technology, MIT, Cambridge, MA 02139
                [3 ]USC Epigenome Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033
                [4 ]Biophysics Program, Harvard University, Cambridge, 12 Oxford St., MA 02138
                [5 ]Divisions of Medical Oncology and Cancer Biology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, 02115
                [6 ]Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115
                [7 ]Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital, Department of Cell Biology, Harvard Medical School, Boston, MA 02115
                [8 ]Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
                [9 ]Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142
                [10 ]Department of Systems Biology, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115
                [11 ]MIT Department of Biology, 31 Ames Street, Cambridge MA 02139
                Author notes
                [#]

                These authors contributed equally to this work

                Article
                Manuscript ID: NIHMS368579
                DOI: 10.1038/nbt.2203
                PMC ID: 4383288
                PubMed ID: 22544022
                SO-VID: ad9ac1cc-f2dc-47e4-ae9a-4ba013032109
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                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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