Abstract
A bivariate mixture model utilizing information across two species was proposed to solve the fundamental problem of identifying differentially expressed genes in microarray experiments. The model utility was illustrated using a dog and human lymphoma data set prepared by a group of scientists in the College of Veterinary Medicine at North Carolina State University. A small number of genes were identified as being differentially expressed in both species and the human genes in this cluster serve as a good predictor for classifying diffuse large-B-cell lymphoma (DLBCL) patients into two subgroups, the germinal center B-cell-like diffuse large B-cell lymphoma and the activated B-cell-like diffuse large B-cell lymphoma. The number of human genes that were observed to be significantly differentially expressed (21) from the two-species analysis was very small compared to the number of human genes (190) identified with only one-species analysis (human data). The genes may be clinically relevant/important, as this small set achieved low misclassification rates of DLBCL subtypes. Additionally, the two subgroups defined by this cluster of human genes had significantly different survival functions, indicating that the stratification based on gene-expression profiling using the proposed mixture model provided improved insight into the clinical differences between the two cancer subtypes.
Highlights
Diffuse large-B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma in adults, accounts for 30% to 40% of newly diagnosed lymphomas and has an annual incidence in America of more than 25,000 cases
It appeared that the magnitude of the estimated difference of expression in genes related to lymphoma in both species tended to be larger than in genes where differential expression was exhibited in only one species
Gene selection and cancer type classification For the 156 LOOCV instances, the proposed mixture model determined 21 (14 genes appearing in the intersection of all hold-outs) human genes in categories (1, 2, 3, and 4) and 279 (185 genes appearing in the intersection of all hold-outs) human genes in categories (1, 2, 3, 4, 5, and 6)
Summary
Diffuse large-B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma in adults, accounts for 30% to 40% of newly diagnosed lymphomas and has an annual incidence in America of more than 25,000 cases. Combination chemotherapy has transformed DLBCL from a fatal disease into one that is often curable, but only approximately 50% of all patients are cured [1,2]. This suggests that DLBCL comprises several subgroups that differ in responsiveness to chemotherapy. In other words, studying gene expression profiles in lymphomas may provide the opportunity to identify pathways on which the tumor depends and to target the pathways for the development of new drugs. Gene-expression profiling studies have distinguished three molecular subtypes of DLBCL: germinal-center B-cell-like (GCB) DLBCL, activated Bcell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL) [2,5,6,7,8]
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