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Multicenter Study
. 2021 Aug;43(4):683-692.
doi: 10.1111/ijlh.13435. Epub 2020 Dec 16.

A reduced panel of eight genes (ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53) as an estimator of the tumor mutational burden in chronic lymphocytic leukemia

Jasmine Chauzeix  1 , Cédric Pastoret  2 , Lucie Donaty  1 , Nathalie Gachard  1 , Thierry Fest  2 , Jean Feuillard  1 , David Rizzo  1
Affiliations
Multicenter Study

A reduced panel of eight genes (ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53) as an estimator of the tumor mutational burden in chronic lymphocytic leukemia

Jasmine Chauzeix et al. Int J Lab Hematol. 2021 Aug.

Abstract

Introduction: Mutational complexity or tumor mutational burden (TMB) influences the course of chronic lymphocytic leukemia (CLL). However, this information is not routinely used because TMB is usually obtained from whole genome or exome, or from large gene panel high-throughput sequencing.

Methods: Here, we used the C-Harrel concordance index to determine the minimum panel of genes for which mutations predict treatment-free survival (TFS) as well as large resequencing panels.

Results: An eight gene estimator was defined encompassing ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53. TMB estimated from either a large panel of genes or the eight gene estimator was increased in treated patients or in those with a short TFS (<2 years), unmutated IGHV gene or with an unfavorable karyotype. Being an independent prognostic parameter, any mutation in the eight gene estimator predicted a shorter TFS better than Binet stage and IGHV mutational status among patients with an apparently non-progressive disease (TFS >6 months). Strikingly, the eight gene estimator was also highly informative for patients with Binet stage A CLL or with a good prognosis karyotype.

Conclusion: These results suggest that the eight gene estimator, that is easily achievable by high-throughput resequencing, brings robust and valuable information that predicts evolution of untreated patients at diagnosis better than any other parameter.

Keywords: chronic lymphocytic leukemia; high-throughput sequencing; prognosis; tumor mutational burden.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

FIGURE 1
FIGURE 1
Relationship between TFS and TMB (A) or mutations among the eight gene estimator (B). Number of cases with a TMB < or ≥2 (A) or with mutations < or ≥1 among the eight gene estimator (B) are indicated. The chi‐square test P‐values are given
FIGURE 2
FIGURE 2
Relationship between the main cytogenetic categories and TMB from the entire gene panel (A) or from the eight gene estimator (B). Number of cases with a TMB < or ≥2 (A) or with mutations < or ≥1 among the eight gene estimator (B) are indicated. The Fisher's exact test P‐values are given
FIGURE 3
FIGURE 3
Relationship between IGHV mutational status and TMB from the entire gene panel (A) or from the eight genes estimator (B). Number of cases with a TMB < or ≥2 (A) or with mutations < or ≥1 among the eight gene estimator (B) are indicated. The chi‐square test P‐values are given
FIGURE 4
FIGURE 4
Treatment‐free survival (TFS) according to TMB from the eight gene estimator for Binet stage A patients (A) or patients with a normal karyotype or isolated del(13q) (B). Kaplan‐Meier survival curves for the eight gene estimator or for the whole gene panel minus the eight gene estimator are presented on the left and right panels, respectively. The mutation threshold was 1. Number of patients and P‐value of the logrank test are given
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