Identification of cancer genes using a statistical framework for multiexperiment analysis of nondiscretized array CGH data

Tumor formation is in part driven by DNA copy number alterations (CNAs), which can be measured using microarray-based Comparative Genomic Hybridization (aCGH). Multiexperiment analysis of aCGH data from tumors allows discovery of recurrent CNAs that are potentially causal to cancer development. Until now, multiexperiment aCGH data analysis has been dependent on discretization of measurement data to a gain, loss or no-change state. Valuable biological information is lost when a heterogeneous system such as a solid tumor is reduced to these states. We have developed a new approach which inputs nondiscretized aCGH data to identify regions that are significantly aberrant across an entire tumor set. Our method is based on kernel regression and accounts for the strength of a probe's signal, its local genomic environment and the signal distribution across multiple tumors. In an analysis of 89 human breast tumors, our method showed enrichment for known cancer genes in the detected regions and identified aberrations that are strongly associated with breast cancer subtypes and clinical parameters. Furthermore, we identified 18 recurrent aberrant regions in a new dataset of 19 p53-deficient mouse mammary tumors. These regions, combined with gene expression microarray data, point to known cancer genes and novel candidate cancer genes.

[1]  P. Nederlof,et al.  Array-CGH and breast cancer , 2006, Breast Cancer Research.

[2]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[3]  T. Rebbeck,et al.  CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q. , 2002, Human molecular genetics.

[4]  N. L. Thangue,et al.  Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor , 1991, Nature.

[5]  Christian J Stoeckert,et al.  STAC: A method for testing the significance of DNA copy number aberrations across multiple array-CGH experiments. , 2006, Genome research.

[6]  Ajay N. Jain,et al.  Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. , 2006, Cancer cell.

[7]  W. Kuo,et al.  High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays , 1998, Nature Genetics.

[8]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Peter J. Park,et al.  Comparative analysis of algorithms for identifying amplifications and deletions in array CGH data , 2005, Bioinform..

[10]  Wessel N. van Wieringen,et al.  CGHcall: Calling aberrations for array CGH tumor profiles. , 2008 .

[11]  Céline Rouveirol,et al.  Bioinformatics Original Paper Computation of Recurrent Minimal Genomic Alterations from Array-cgh Data , 2022 .

[12]  R. Gallo,et al.  onc gene amplification in promyelocytic leukaemia cell line HL-60 and primary leukaemic cells of the same patient , 1982, Nature.

[13]  Jane Fridlyand,et al.  Bioinformatics Original Paper a Comparison Study: Applying Segmentation to Array Cgh Data for Downstream Analyses , 2022 .

[14]  J. Sebat,et al.  Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. , 2003, Genome research.

[15]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[16]  Ash A. Alizadeh,et al.  Genome-wide analysis of DNA copy number variation in breast cancer using DNA microarrays , 1999, Nature Genetics.

[17]  Marcel J T Reinders,et al.  Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. , 2002, Cancer research.

[18]  Andrew W. Moore,et al.  Locally Weighted Learning , 1997, Artificial Intelligence Review.

[19]  David I. Smith,et al.  A role for common fragile site induction in amplification of human oncogenes. , 2002, Cancer cell.

[20]  Zhiyuan Shen,et al.  The BRCA2-Interacting Protein BCCIP Functions in RAD51 and BRCA2 Focus Formation and Homologous Recombinational Repair , 2005, Molecular and Cellular Biology.

[21]  Eric S. Lander,et al.  Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays , 2000, Nature Biotechnology.

[22]  L. Chin,et al.  High-Resolution Global Profiling of Genomic Alterations with Long Oligonucleotide Microarray , 2004, Cancer Research.

[23]  W. Zundel,et al.  The Emerging Role of the COP9 Signalosome in Cancer , 2005, Molecular Cancer Research.

[24]  A. Berns,et al.  Cross-Species Oncogenomics in Cancer Gene Identification , 2006, Cell.

[25]  N. Carter,et al.  A whole-genome mouse BAC microarray with 1-Mb resolution for analysis of DNA copy number changes by array comparative genomic hybridization. , 2003, Genome research.

[26]  R. Kapur,et al.  Cul4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis. , 2005, Blood.

[27]  W. Kuo,et al.  Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene , 2000, Nature Genetics.

[28]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[29]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[30]  M. Groudine,et al.  Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line , 1982, Nature.

[31]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[32]  D. Pinkel,et al.  Array comparative genomic hybridization and its applications in cancer , 2005, Nature Genetics.

[33]  Christian A. Rees,et al.  Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. Parzen.  On Estimation of a Probability Density Function and Mode , 1962 .

[35]  Joe W. Gray,et al.  PIK3CA is implicated as an oncogene in ovarian cancer , 1999, Nature Genetics.

[36]  A. Gown,et al.  Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma , 2004, Clinical Cancer Research.

[37]  A. Ashworth,et al.  Haploinsufficiency for tumour suppressor genes: when you don't need to go all the way. , 2004, Biochimica et biophysica acta.

[38]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[39]  C. Maley,et al.  Cancer is a disease of clonal evolution within the body1–3. This has profound clinical implications for neoplastic progression, cancer prevention and cancer therapy. Although the idea of cancer as an evolutionary problem , 2006 .

[40]  W. Zundel,et al.  The Emerging Role of the COP 9 Signalosome in Cancer , 2005 .

[41]  A. Berns,et al.  Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer , 2001, Nature Genetics.

[42]  P. Kloetzel,et al.  The Zinc Finger of the CSN-Associated Deubiquitinating Enzyme USP15 Is Essential to Rescue the E3 Ligase Rbx1 , 2005, Current Biology.

[43]  Marcel J. T. Reinders,et al.  Detecting Statistically Significant Common Insertion Sites in Retroviral Insertional Mutagenesis Screens , 2006, PLoS Comput. Biol..

[44]  T. Lorca,et al.  Alterations of anaphase-promoting complex genes in human colon cancer cells , 2003, Oncogene.

[45]  Robert Tibshirani,et al.  Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene‐expression subtypes of breast cancer , 2006, Genes, chromosomes & cancer.

[46]  J. Schimenti,et al.  Synapsis or silence , 2005, Nature Genetics.

[47]  M. Wigler,et al.  Identification and Validation of Oncogenes in Liver Cancer Using an Integrative Oncogenomic Approach , 2006, Cell.

[48]  S. Knuutila,et al.  Manifestation, mechanisms and mysteries of gene amplifications. , 2006, Cancer letters.

[49]  L. Chin,et al.  Frequent met oncogene amplification in a Brca1/Trp53 mouse model of mammary tumorigenesis. , 2006, Cancer research.

[50]  Sang-Gu Hwang,et al.  WD repeat‐containing mitotic checkpoint proteins act as transcriptional repressors during interphase , 2004, FEBS letters.

[51]  H. Ropers,et al.  Characterization of FBX25, encoding a novel brain-expressed F-box protein. , 2006, Biochimica et biophysica acta.

[52]  Michael R. Speicher,et al.  High resolution array-CGH analysis of single cells , 2006, Nucleic acids research.

[53]  Barbara J. Trask,et al.  Array Comparative Genomic Hybridization Analysis of Genomic Alterations in Breast Cancer Subtypes , 2004, Cancer Research.

[54]  Ash A. Alizadeh,et al.  Genome-wide analysis of DNA copy-number changes using cDNA microarrays , 1999, Nature Genetics.

[55]  D. Pinkel,et al.  Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors , 2022 .

[56]  S T Pals,et al.  The hepatocyte growth factor/Met pathway in development, tumorigenesis, and B-cell differentiation. , 2000, Advances in cancer research.

[57]  Joel Greshock,et al.  High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization , 2005, Breast Cancer Research.

[58]  Johan Staaf,et al.  BIOINFORMATICS ORIGINAL PAPER doi:10.1093/bioinformatics/btm359 Data and text mining , 2022 .

[59]  Yudi Pawitan,et al.  Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients , 2006, Breast Cancer Research.

[60]  J Piper,et al.  Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[61]  Masakazu Ueda,et al.  TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas , 2002, Hepatology.

[62]  Jane Fridlyand,et al.  High-resolution analysis of DNA copy number alterations in colorectal cancer by array-based comparative genomic hybridization. , 2004, Carcinogenesis.