Virtual CGH: an integrative approach to predict genetic abnormalities from gene expression microarray data applied in lymphoma

摘要

Background Comparative Genomic Hybridization (CGH) is a molecular approach for detecting DNA Copy Number Alterations (CNAs) in tumor, which are among the key causes of tumorigenesis. However in the post-genomic era, most studies in cancer biology have been focusing on Gene Expression Profiling (GEP) but not CGH, and as a result, an enormous amount of GEP data had been accumulated in public databases for a wide variety of tumor types. We exploited this resource of GEP data to define possible recurrent CNAs in tumor. In addition, the CNAs identified by GEP would be more functionally relevant CNAs in the disease pathogenesis since the functional effects of CNAs can be reflected by altered gene expression. Methods We proposed a novel computational approach, coined virtual CGH (vCGH), which employs hidden Markov models (HMMs) to predict DNA CNAs from their corresponding GEP data. vCGH was first trained on the paired GEP and CGH data generated from a sufficient number of tumor samples, and then applied to the GEP data of a new tumor sample to predict its CNAs. Results Using cross-validation on 190 Diffuse Large B-Cell Lymphomas (DLBCL), vCGH achieved 80% sensitivity, 90% specificity and 90% accuracy for CNA prediction. The majority of the recurrent regions defined by vCGH are concordant with the experimental CGH, including gains of 1q, 2p16-p14, 3q27-q29, 6p25-p21, 7, 11q, 12 and 18q21, and losses of 6q, 8p23-p21, 9p24-p21 and 17p13 in DLBCL. In addition, vCGH predicted some recurrent functional abnormalities which were not observed in CGH, including gains of 1p, 2q and 6q and losses of 1q, 6p and 8q. Among those novel loci, 1q, 6q and 8q were significantly associated with the clinical outcomes in the DLBCL patients (p Conclusions We developed a novel computational approach, vCGH, to predict genome-wide genetic abnormalities from GEP data in lymphomas. vCGH can be generally applied to other types of tumors and may significantly enhance the detection of functionally important genetic abnormalities in cancer research.