Neutral Tumor Evolution in Myeloma is Associated With Poor Response to Therapy
Section snippets
Background
Understanding the evolutionary history of a tumor is an important determinant of patient outcome. To gain insight into clonal dynamics of newly diagnosed multiple myeloma (MM), we studied whole exome sequencing data of 436 patients from the Myeloma XI trial.
Methods
Tumor mutant allele frequency distributions were analysed using a novel approach (Williams, MJ, Nat Gen 2016) that discriminates whether clonal competition with changing dominance or neutral evolution with a stable sub-clonal structure characterised the clonal development up to diagnosis.
Results
We demonstrate that a high proportion (19%) of MM tumors at diagnosis is under neutral evolutionary dynamics. We further characterised these tumors and their patient characteristics. Neutral evolution tumors were more likely to carry IGH translocations and gain of 1q21. Overall, 26.7% of t(4;14) and 29.4% of t(14;16) versus 16.7% of HRD cases were characterised by neutral evolution. Gain of 1q21 occurred in 34.2% of HRD cases and 24.6% of this group showed neutral evolution, compared to 12.9%
Conclusion
We demonstrate a high frequency of MM tumors with neutral clonal evolution dynamics. Neutral evolution is associated with reduced responsiveness to micro-environment-modulating IMiD therapy, which might indicate superior tumor cell 'fitness' with relative independence from microenvironment survival factors. Assaying for neutral evolution might improve our understanding of therapy resistance and help with improving therapy outcomes.