Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation

Abstract

Purpose: Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL.

Experimental design: We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity.

Results: We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number.

Conclusions: We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735-45. ©2016 AACR.

Figure 1. Overall survival and heatmap characteristics of patients

A) OS by total number of mutations and treatment status at sampling; (B) OS by total number of mutations and del(17p) status. (C) OS by total CNA events and treatment status at sampling. (D) OS by total CNA events and del(17p) status. Mutations low: mutations < 21; mutations high: mutations >=21. CNAs low: CNA < 4; CNA high: CNA >=4. The optimal cutoff values for total number of mutations and CNAs were identified using the method of recursive partitioning for survival trees. (E) Heatmap characteristics of the 99 patients with both SNP and WES profiles. The first 9 rows are indicated by presence (red) or absence (blue) of TP53 mutation, IGHV mutation or abnormal cytogenetics by FISH. CNA events, weights and nonsynonymous mutations represent percentiles of ranks across 99 observations. i.e., the highest value in each row is denoted as 1 (100^th percentile) and the lowest value is denoted as 0.01 (1^th percentile).

Figure 2. Analysis of TP53 disruptions

A. Cancer cell fractions of the TP53 mutations in each patient. B. Kaplan-Meier curves of OS by clonality status of TP53 mutations. C. Relationship of CNAs and TP53 disruptions. wt: no TP53 mutation or deletion; single null: monoallelic TP53 mutation or del(17p) deletion; double null: biallelic disruption. D. Relationship of somatic mutations and TP53 disruptions. E-F. Dose-dependent impact of TP53 disruption on overall survival in all patients (E) or previously untreated patients (F).

Figure 3. Driver genes in del(17p) CLL

A. Comut plot of del(17p) CLL. B. Comut plot of wild type CLL. C. Mutation frequencies of known CLL driver genes in del(17p) and wt 17p CLL. * indicates p < 0.05.

Figure 4. Overall survival (OS) and failure free survival (FFS)

A. OS by CKT vs no CKT (n=94). B. OS by del(17p) and CKT status. C. OS by CKT vs CNA numbers. Cutoff for high vs low CNAs is 4. D-F: FFS for previously untreated patients (n = 122). D. FFS by number of CNA events. The cutoff for high vs low is 4 CNA events. E. FFS by CKT status. F. FFS by number of total mutations, with cutoff for low vs high mutations 21.