Prioritization of candidate cancer genes—an aid to oncogenomic studies

The development of techniques for oncogenomic analyses such as array comparative genomic hybridization, messenger RNA expression arrays and mutational screens have come to the fore in modern cancer research. Studies utilizing these techniques are able to highlight panels of genes that are altered in cancer. However, these candidate cancer genes must then be scrutinized to reveal whether they contribute to oncogenesis or are coincidental and non-causative. We present a computational method for the prioritization of candidate (i) proto-oncogenes and (ii) tumour suppressor genes from oncogenomic experiments. We constructed computational classifiers using different combinations of sequence and functional data including sequence conservation, protein domains and interactions, and regulatory data. We found that these classifiers are able to distinguish between known cancer genes and other human genes. Furthermore, the classifiers also discriminate candidate cancer genes from a recent mutational screen from other human genes. We provide a web-based facility through which cancer biologists may access our results and we propose computational cancer gene classification as a useful method of prioritizing candidate cancer genes identified in oncogenomic studies.

[1]  V. McKusick Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders , 1997 .

[2]  Vladimir A Kuznetsov,et al.  In the pursuit of complexity: systems medicine in cancer biology. , 2006, Cancer cell.

[3]  Alfonso Valencia,et al.  CARGO: a web portal to integrate customized biological information , 2007, Nucleic Acids Res..

[4]  Chris Sander,et al.  CancerGenes: a gene selection resource for cancer genome projects , 2006, Nucleic Acids Res..

[5]  K. Lindblad-Toh,et al.  Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals , 2005, Nature.

[6]  Paul A. Bates,et al.  Global topological features of cancer proteins in the human interactome , 2006, Bioinform..

[7]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[8]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[9]  Pedro Larrañaga,et al.  Learning Bayesian classifiers from positive and unlabeled examples , 2007, Pattern Recognit. Lett..

[10]  Núria López-Bigas,et al.  Differences in the evolutionary history of disease genes affected by dominant or recessive mutations , 2006, BMC Genomics.

[11]  A. Bardelli,et al.  Identification of cancer genes by mutational profiling of tumor genomes , 2005, FEBS letters.

[12]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[13]  B Marshall,et al.  Gene Ontology Consortium: The Gene Ontology (GO) database and informatics resource , 2004, Nucleic Acids Res..

[14]  Christos A. Ouzounis,et al.  Highly consistent patterns for inherited human diseases at the molecular level , 2006, Bioinform..

[15]  Rémi Gilleron,et al.  Text Classification from Positive and Unlabeled Examples , 2002 .

[16]  Yan Zhang,et al.  CanPredict: a computational tool for predicting cancer-associated missense mutations , 2007, Nucleic Acids Res..

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

[18]  Desmond G. Higgins,et al.  Distinct Patterns in the Regulation and Evolution of Human Cancer Genes , 2008, Silico Biol..

[19]  P. Brown,et al.  Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Andrew D. Yates,et al.  Athletics: Momentous sprint at the 2156 Olympics? , 2004, Nature.

[21]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[22]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[23]  L. Staudt,et al.  Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. , 2004, The New England journal of medicine.

[24]  Z. Szallasi,et al.  A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers , 2006, Nature Genetics.

[25]  Pingzhao Hu,et al.  Computational prediction of cancer-gene function , 2007, Nature Reviews Cancer.

[26]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[27]  D. Pinkel,et al.  Regional copy number–independent deregulation of transcription in cancer , 2006, Nature Genetics.

[28]  Yuriy Gusev,et al.  Computational analysis of biological functions and pathways collectively targeted by co-expressed microRNAs in cancer , 2007, BMC Bioinformatics.

[29]  T. Golub,et al.  DNA microarrays in clinical oncology. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  L. Chin,et al.  Comparative Oncogenomics Identifies NEDD9 as a Melanoma Metastasis Gene , 2006, Cell.

[31]  C. Ouzounis,et al.  Genome-wide identification of genes likely to be involved in human genetic disease. , 2004, Nucleic acids research.

[32]  J. Baak,et al.  Genomics and proteomics--the way forward. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[33]  Giovanni Parmigiani,et al.  Mutational Analysis of the Tyrosine Kinome in Colorectal Cancers , 2003, Nature Reviews Cancer.

[34]  D. Haber,et al.  Cancer: Drivers and passengers , 2007, Nature.

[35]  Zhihua Li,et al.  Regulatory Circuit of Human MicroRNA Biogenesis , 2007, PLoS Comput. Biol..

[36]  Erich E. Wanker,et al.  Comparison of Human Protein-Protein Interaction Maps , 2007, German Conference on Bioinformatics.

[37]  R. Stahel,et al.  ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of small-cell lung cancer (SCLC). , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[38]  Richard Wooster,et al.  Sequence-based cancer genomics: progress, lessons and opportunities , 2003, Nature Reviews Genetics.

[39]  Marvin Minsky,et al.  Steps toward Artificial Intelligence , 1995, Proceedings of the IRE.

[40]  T. Golub,et al.  Impaired microRNA processing enhances cellular transformation and tumorigenesis , 2007, Nature Genetics.

[41]  John T. Wei,et al.  Integrative molecular concept modeling of prostate cancer progression , 2007, Nature Genetics.

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

[43]  K. Kinzler,et al.  The multistep nature of cancer. , 1993, Trends in genetics : TIG.

[44]  B. Peters,et al.  Distinguishing cancer-associated missense mutations from common polymorphisms. , 2007, Cancer research.

[45]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[46]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[47]  V. McKusick Mendelian inheritance in man , 1971 .

[48]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[49]  Robert D. Finn,et al.  New developments in the InterPro database , 2007, Nucleic Acids Res..

[50]  Donna R. Maglott,et al.  RefSeq and LocusLink: NCBI gene-centered resources , 2001, Nucleic Acids Res..

[51]  Christos A Ouzounis,et al.  Structural and functional properties of genes involved in human cancer , 2006, BMC Genomics.

[52]  Philip Lijnzaad,et al.  The Ensembl genome database project , 2002, Nucleic Acids Res..