Comprehensive Homozygous Deletion Mapping of Myeloma Defines a Poor Prognosis Cell Death Gene Expression Signature

Myeloma is a clonal malignancy of plasma cells. Poor prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor prognosis patients and this can be improved by combination with information about DNA level changes. Using SNP-based gene mapping in combination with global gene expression analysis we have identified homozygous deletions in genes and networks that are relevant to myeloma. From these, we have generated an expression-based signature associated with shorter survival in 247 patients and confirmed this signature in data from 2 independent groups totalling 800 patients. We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the “Cell Death” network was over-represented and cases with these deletions have impaired overall survival. We defined a gene expression signature of 97 cell death genes that reflects prognosis confirmed this in two independent data sets. We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor prognosis myeloma in the clinical environment. The signature can form the basis of future trials aimed at improving the outcome of poor prognosis myeloma. 247 expression samples from CD138+ cell selection, 168 SNP-based gene mapping data from CD138+ cell selection and peripheral white blood cell