Diagnostic yield of cancer predisposition in a nationwide prospective childhood acute leukemia cohort

Abstract

The utility of whole-genome sequencing (WGS) for detecting childhood leukemia predisposition remains unclear. We perform a nationwide, prospective, population-based study of 181 children with acute leukemia to assess diagnostic yield and clinical utility of a uniformly applied three-pronged strategy, including systematic phenotyping, germline WGS-based 189-gene panel and tumor sequencing of positive cases. Trio-WGS is performed in 11 high-suspicion families. Nine patients have pathogenic germline alterations: six (3.3%) with leukemia predisposition syndromes (TP53, CEBPA, DNMT3A, trisomy 21) and three (1.6%) with solid tumor predisposition syndromes (MSH6, PALB2, SDHA). Trio-WGS identifies one likely-pathogenic de novo DNMT3A variant. Six of nine diagnoses are previously unrecognized. Findings lead to tailored surveillance in 8/9 patients and treatment modifications in 4/9. Here, we show that this strategy gives a modest diagnostic yield. Nevertheless, the actionability of the findings supports its feasibility and validity in practice. Whether to restrict analysis to leukemia-relevant genes or broaden the panel should reflect local resources and counseling capacity. The potential of germline whole-genome sequencing (WGS) in detecting childhood leukemia predisposition remains to be elucidated. Here the authors show that a three-pronged diagnostic strategy including systematic phenotyping, germline WGS based 189-gene panel and tumor sequencing of positive cases may be feasible and clinically useful for cancer predisposition screening in childhood acute leukemia.