Inferring parameters of cancer evolution in chronic lymphocytic leukemia

Abstract

As a cancer develops, its cells accrue new mutations, resulting in a heterogeneous, complex genomic profile. We make use of this heterogeneity to derive simple, analytic estimates of parameters driving carcinogenesis and reconstruct the timeline of selective events following initiation of an individual cancer, where two longitudinal samples are available for sequencing. Using stochastic computer simulations of cancer growth, we show that we can accurately estimate mutation rate, time before and after a driver event occurred, and growth rates of both initiated cancer cells and subsequently appearing subclones. We demonstrate that in order to obtain accurate estimates of mutation rate and timing of events, observed mutation counts should be corrected to account for clonal mutations that occurred after the founding of the tumor, as well as sequencing coverage. Chronic lymphocytic leukemia (CLL), which often does not require treatment for years after diagnosis, presents an optimal system to study the untreated, natural evolution of cancer cell populations. When we apply our methodology to reconstruct the individual evolutionary histories of CLL patients, we find that the parental leukemic clone typically appears within the first fifteen years of life.

Evolving copy number gains promote tumor expansion and bolster mutational diversification

“…Building on the results of 43 , we derived the expected number of dominant post-GD gains in a tumor with size N as which is only slightly larger than the clonal ones. Assuming that u 0 and λ 0 are comparable (based on experimentally measured u 0 for SCNA around 0.2 and the cancer cell death rate not significantly approaching the birth rate 44 , 45 ), would be no more than just a few. Moreover, numerical simulations show that the number of dominant post-GD gains continues to follow a geometrical-like distribution with the mode at zero (Supplementary Fig.…”