Short telomeres are associated with inferior outcome, genomic complexity, and clonal evolution in chronic lymphocytic leukemia

Abstract

Telomere length in chronic lymphocytic leukemia (CLL) has been shown to be of prognostic importance, but the analyses have largely been executed on heterogeneous patient cohorts outside of clinical trials. In the present study, we performed a comprehensive analysis of telomere length associations in the well characterized CLL8 trial (n = 620) of the German CLL study group, with validation in a representative cohort of the CLL4 trial (n = 293). Absolute telomere length was analyzed using quantitative-PCR. Apart from identifying associations of short telomere length with adverse prognostic factors and survival, the study identified cases with 17p- and 11q- associated with TP53 and ATM loss, respectively, to have the shortest telomeres, even when these aberrations were present in small subclones. Thus, telomere shortening may precede acquisition of the high-risk aberrations, contributing to disease evolution. In line with this, telomere shortening was associated with an increase in genomic complexity as well as clonal evolution, highlighting its importance as a biomarker especially in monitoring disease progression in non-high-risk CLL.

Conflict of interest statement

Conflict of interest M.K.W. and G.F.-R.: employment at F. Hoffmann-La Roche; C.W.: consultancy, membership in board of directors or advisory committees, research funding from Hoffmann-La Roche; K.F.: travel grants from Roche; M.K., U.J., M.H., and S.S.: consultancy, honoraria, and research funding from Roche. The remaining authors declare no conflict of interests.

Figures

Fig. 1

a Comparison of telomere length between CD19 +, CD19−, and unsorted CLL samples (n = 48) and with age-matched healthy donors n = 20 (CD19 + ) and n = 8 (CD19−). b telomere length in cases with mutated and unmutated IGHV; mutated and wildtype TP53, NOTCH1, SF3B1.c Telomere length in the hierarchically classified genomic aberration subgroups namely, 17p-, 11q-, + 12q, normal karyotype and 13q- in CLL8 (red bars indicate the median telomere length). All P values from Mann–Whitney test

Fig. 2

Comparison of a, b PFS (FC: median 27.1 vs. 44.0 months, P < 0.001; FCR: median 44.8 vs. 69.9 months, P <0.001) and c, d OS (FC: median 70.9 vs. 89.5 months, P < 0.001; FCR: median 90.2 months vs. median not reached, P = 0.017) between cases with short ( ≤ median) and long ( > median) telomere length, treated with FC (n = 153 vs. 159) and FCR (n = 157 vs. 151) in CLL8

Fig. 3

a Telomere length association with genomic complexity (copy number alterations (CNA) and loss of heterozygosity (LOH)) and high-risk aberrations (17p-, 11q-, and mutated TP53). The red lines indicate the median telomere length (left Y axis), the green symbols indicate the percentage of high-risk aberrations (right Y axis) and the black dots show the distribution of telomere length corresponding to the number of genomic alterations b. Telomere length distribution in relation to the number of clonal and subclonal driver events including and c excluding genomic aberrations. rs in Figs. a–c is derived from spearman rank correlation and R2 in a from linear regression

Fig. 4

Telomere length association with percentage of cells with a 17p- and b 11q- as analyzed using FISH and with mutant allele frequency of cSF3B1 and dTP53 mutations as analyzed using whole-exome sequencing (WES). e Distribution of telomere length in IGHV, genomic aberration (with their respective cancer cell fractions—CCF, as analyzed by FISH) and gene mutation subgroups as well as association with copy number variation (analyzed by SNP array). f Telomere length at baseline and follow-up in cases with (n = 24) and without clonal evolution (n = 41). Cases with hierarchical 17p- and 11q- are represented as green and brown symbols, respectively. P values and R2 in a–d from linear regression and P values in f from Mann–Whitney test