A high proportion of germline variants in pediatric chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) typically occurs in late adulthood. Pediatric CML is a rare form of leukemia. In all age groups, the characteristic genetic driver of the disease is the BCR::ABL1 fusion gene. However, additional genomic events contribute to leukemic transformation, which is not yet well-characterized in pediatric CML. We investigated the mutational landscape of pediatric CML to determine whether predisposing germline variants may play a role in early-age disease development. Whole exome sequencing and targeted sequencing were performed in pediatric and adult CML samples to identify age-related germline and somatic variants in addition to the BCR::ABL1 translocation. Germline variants were detected in about 60% of pediatric patients with CML, with predominantly hematopoietic genes affected, most frequently ASXL1, NOTCH1, KDM6B, and TET2. The number of germline variants was significantly lower in adult patients with CML. If only confirmed pathogenic variants were regarded as cancer-predisposing variants, the occurrence was ~ 10% of pediatric CML, which is comparable to other hematological malignancies and most childhood cancer entities in general. We hypothesize that the interaction with the strong oncogene BCR::ABL1 may also favor the development of leukemia by weaker variants in the same genes. In pediatric patients, the germline variants of genes associated with clonal hematopoiesis may increase the likelihood that an incidental BCR::ABL1 translocation triggers the early manifestation of CML.

Keywords: Cancer predisposition; Chronic myeloid leukemia; Germline variants; Pediatric CML.

Fig. 1

Whole exome sequencing in pediatric CML reveals a high proportion of individuals with germline variants but few somatic variants. (A) Age distribution of CML in children based on data from the German CMLpaed II study (2004–2015), and adults based on cancer registry data from the Robert Koch Institute over 11 years (2004–2014). The median age at diagnosis in the respective cohort is indicated by dashed lines. (B) Oncoplot showing germline (dark colors) and somatic (light colors) variants in 12 pediatric (green) and 11 adult (blue) patients with CML. Each column represents one patient. Every patient has a detectable BCR::ABL1 fusion gene (red). (C) Quantification of germline and somatic variants in parallel to the BCR::ABL1 fusion gene and BCR::ABL1 fusion transcript at initial diagnosis and under tyrosine kinase inhibitor treatment in three pediatric patients with CML. Corresponding pedigree charts (D) show the inheritance of germline variants. An asterisk indicates SNP with > 1% allele frequency

Fig. 2

Targeted exome sequencing in pediatric CML exhibits both similarities and differences to adult CML. (A) Germline (dark colors) and somatic variants (light colors) in 61 pediatric patients with CML are displayed, with variant allele frequency (VAF). Variants with unknown mutation status are presented using gradient colors. Each column represents one patient, and genes are functionally grouped. (B, C) The bar plots demonstrate the proportion of pediatric and adult patients with CML affected by any variation (somatic and/or germline) (B), and in germline variations only (C). Differences were tested for significance using Fisher´s exact test (*, p < 0.05). The scatter plots show the age at diagnosis plotted for both age cohorts according to the group with all variants (top) and according to the group with germline variants (bottom). The Kolmogorov-Smirnov test was used to test for significant differences (*, p < 0.05). The vertical black lines indicate the median in the respective group, and the dashed green line the median age of the analyzed cohort. (D) Pie charts showing the distribution of mutation types for pediatric and adult patients with CML. (E) Proportion of individuals with CML with germline variants, subdivided according to the variant prediction score. (F) Presentation of the number of patients with the sum score for all individual germline variants. (G, H) Visualization of the modeled structural change by the IDH2 V75M (G) and the JAK1 M1128T (H) variant in the study patient #255. (I) Pie charts illustrating the distribution of functionally grouped genes with germline variants in pediatric CML, adult CML, pediatric MDS, adult MDS, and pediatric AML. For pediatric AML, functional groups rather than individual genes are presented, as over half of the patients (52%) display multiple germline variants (3–8 germline variants). (J) Graphic illustration of the hypothesis regarding the contribution of predisposing germline variants or acquired somatic mutations with the crucial BCR::ABL1 fusion in the progression of CML in children and adults