Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome

Abstract

High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B-cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biologic events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep-sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution. We found somatic non-synonymous mutations in 25 MBLs(52%) at the initial time-point analyzed, including 13(27%) with >1 mutated gene. In cases that subsequently progressed to CLL, mutations were detected 41 months (median) prior to progression. Excepting NOTCH1, TP53 and XPO1, which showed a lower incidence in MBL, genes were mutated with a similar prevalence to CLL, indicating the early origin of most driver mutations in the MBL/CLL continuum. MBLs with mutations at the initial time-point analyzed were associated with shorter time-to-treatment (TTT). Furthermore, MBLs showing subclonal expansion of driver mutations on sequential evaluation had shorter progression time to CLL and shorter TTT. These findings support that clonal evolution have prognostic implications already at the pre-malignant MBL stage, anticipating which individuals will progress earlier to CLL.

Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy

“…45 Overall, if confirmed in other cohorts, our results have direct clinical implications considering that rapid subclonal expansion and high tumor plasticity are key determinants of rapid cALL evolution and predictive factors of early therapeutic escapes. This is in line with previous findings associating shorter remissions with the early presence of subclonal driver mutations in leukemia samples 7,46 or with MRD levels on day 19 of remission induction. 47 In this context, appropriate clinical use of novel genomic technologies could be an asset and, as previously suggested, 13 would allow a systematic postdiagnosis driver mutation-oriented survey of MRD to detect early re-emergence of cancer cells.…”

Leveraging premalignant biology for immune-based cancer prevention

“…New technologies, including human organoids with CRISPR/Cas9-based gene editing, are being applied to this model (15). NGS studies of minute tissue specimens with isolated reports of small numbers of premalignant lesion types, such as Barrett's esophagus (16), ductal and lobular carcinoma in situ (DCIS, LCIS) (4,17), serous tubal intraepithelial carcinoma (18), pancreatic intraepithelial neoplasia (PanIN) (19), monoclonal gammopathy of unknown significance (MGUS) (20), and highcount monoclonal B-cell lymphocytosis (MBL) (21), with colorectal adenomas being the most salient example.…”

Combined somatic mutation and copy number analysis in the survival of familial CLL

“…The mutation frequencies observed in our familial CLL sample are similar to those in the literature, with the exception of SF3B1 which is lower (2%) than other samples. This may reflect more favourable prognostic features in our sample, a less prominent role for the mutation in familial CLL, or chance (Gunnarsson et al, 2013;Landau et al, 2013;Barrio et al, 2017).…”