Differential and limited expression of mutant alleles in multiple myeloma.
Rashid NU., Sperling AS., Bolli N., Wedge DC., Van Loo P., Tai YT., Shammas MA., Fulciniti M., Samur MK., Richardson PG., Magrangeas F., Minvielle S., Futreal PA., Anderson KC., Avet-Loiseau H., Campbell PJ., Parmigiani G., Munshi NC.
Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications.