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Today, most children treated for acute lymphoblastic leukemia (ALL) can be cured by the application of intensive combination chemotherapy regimens 1,2.However, within 20 years, up to 10% develop a second malignant neoplasm (SMN) with cure rates often being dismal 3,4.Therefore, strategies are needed for an early identification of patients at risk for SMN development, an improved understanding of the underlying pathobiology and, ideally, the development of preventive actions.In this study, we analyzed genetic variation in 159 selected cancer predisposition genes (CPG) to determine their potential association with SMN.Patients included were 1-22 years of age at diagnosis of ALL and enrolled in the German part of the European AIEOP-BFM ALL 2000 multicenter clinical trial for frontline treatment of pediatric ALL 5.Median follow-up for the entire patient group was 14.8 (4.6-19.2) years as of November, 2020.Treatment details were described previously 6.We identified 75 SMN patients with sufficient DNA available, representing 94% of all 80 SMN cases observed in the entire AIEOP-BFM ALL 2000 study population up to this follow-up date.In a matched case-control approach, we analyzed germline DNA obtained from remission bone marrow samples of 223 individuals (75 cases, 148 controls); see Supplementary Methods section for sequencing details and Supplementary Table 1 for clinical background information.Matching criteria were sex, age at diagnosis of ALL, immunophenotype, and treatment.Candidate genes included genes based on own work and/or genes recommended by Byrjalsen et al. 2021; 7 variant pathogenicity was assessed according to standard interpretation guidelines (see Supplementary Table 2 for details).Statistical analyses and plotting were conducted with SAS (SAS-PC, Version 9.1, Cary, NC: SAS Institute Inc.), SPSS (IBM Deutschland GmbH, Ehningen, Germany) or R (4.0.5), and Rstudio (1.0.153); see Supplementary Methods section.Overall we observed 31 conspicuous findings in 22 genes: 17 (6 likely pathogenic and 11 pathogenic) in 16 (21%) cases with ALL
Junk et al. (Tue,) studied this question.