High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma

Abstract

K E Y P O I N T S l Association of del17p CCF threshold and poor prognosis in NDMM is established via fluorescence in situ hybridization and sequencing methods. l TP53 mutations are enriched in a high-risk patient segment characterized by high del17p CCF.Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta-analysis conducted across 3 data sets confirmed the robustness of the CCF threshold for PFS and OS. Our analyses demonstrate the feasibility of fluorescence in situ hybridization-and sequencingbased methods to identify TP53 deletions, estimate CCF, and establish that both CCF threshold of 0.55 and presence of TP53 deletion are necessary to identify del17p-carrying NDMM patients with poor prognosis. (Blood. 2019; 133(11):1217-1221

Molecular basis of clonal evolution in multiple myeloma

“…TP53 mutations are mostly detected in subclones, consistent with the idea that the abnormalities appear relatively late during the clonal evolution of MM [51]. Mutant p53 usually possesses oncogenic functions, including the ability to up-regulate c-Myc and genes encoding proteasome subunits [53], which induce further anti-cancer drug resistance [54][55][56].…”

Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma

“…The MGP data also showed a significant association between the presence of CCF >0.55 and of mutation on the second allele of TP53, where 27 of 28 patients with a TP53 mutation had CCF >0.55 [6]. Patients with biallelic inactivation had significantly shorter PFS than patients with one wild-type copy of TP53 [6]. In an updated analysis of this dataset with longer clinical follow-up, patients with HR del17p + TP53 mutation have the shortest OS ( Figure 2, orange line, median 28.8 mo, p = 0.008).…”

“…Using the >0.55 CCF cutoff defined by genomics-based methods, analysis from MGP identified high-risk del17p patients as discussed in Section 3.1. The MGP data also showed a significant association between the presence of CCF >0.55 and of mutation on the second allele of TP53, where 27 of 28 patients with a TP53 mutation had CCF >0.55 [6]. Patients with biallelic inactivation had significantly shorter PFS than patients with one wild-type copy of TP53 [6].…”

“…The MGP systematically evaluated large FISH and genomic datasets for the association of CCF to OS in NDMM patients [6]. This analysis indicated that patients with greater than 55% del17p-positive cells (CCF > 0.55), had poor clinical outcomes, where patients had median PFS and median OS of only 14 and 36 months as compared to the low CCF group (≤0.55) who had median PFS of 24 months and median OS of 84 months (FISH dataset, n = 605) [6].…”

“…The MGP systematically evaluated large FISH and genomic datasets for the association of CCF to OS in NDMM patients [6]. This analysis indicated that patients with greater than 55% del17p-positive cells (CCF > 0.55), had poor clinical outcomes, where patients had median PFS and median OS of only 14 and 36 months as compared to the low CCF group (≤0.55) who had median PFS of 24 months and median OS of 84 months (FISH dataset, n = 605) [6]. The CCF > 0.55 threshold to identify high-risk del17p patients (high-risk [HR] del17p,~7% of NDMM) was validated in a meta-analysis across three datasets, the original test dataset from the IFM, as well as an independent FISH replication dataset (n = 235) and a genomic dataset (n = 108) [6].…”