Significance of Primary Immunodeficiency Disorder (PID)–associated Germline Mutations in Korean patients with ALL

Background In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is an emerging research issue. In this study, we investigated genetic alterations (both somatic and germline) in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. Method We selected ALL patients diagnosed at Samsung Medical Center. Eighty-two well known genes associated with 23 predisposition syndromes were included in the gene panel. In addition to sequence variants, gene-level copy number variants (CNVs) were investigated. Results Ninety-three ALL patients (65 children, 28 adults) were enrolled in this study. We identified 197 somatic sequence variants (excluding synonymous variants) and 223 somatic CNVs. Overall survival (OS) and relapse-free survival (RFS) differed significantly by cytogenetic group in childhood B-ALL. The IKZF1 alteration had an adverse effect on OS and RFS in childhood ALL. Among the 82 genes associated with 23 predisposition syndromes, known mutations (TP53, LIG4) and novel mutations (TINF2, CTC1) were identified. Nine patients (9.7%) had pathogenic or likely pathogenic variants associated with primary immunodeficiency disorder (PID) in a heterozygous state. Conclusions We found recurrent mutations and clinical effects similar to those reported in previous studies. We also found an unexpectedly high prevalence of PID-associated germline mutations. Our results suggest several important points: 1) paired leukemic and normal control samples are recommended to discriminate somatic and germline mutations; 2) gene panels must include genes associated with predisposition; 3) gene panels must include genes associated with PID.