Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.
Bibliographical noteFunding Information:
Funding for this project was provided by the Children’s Discovery Institute of Washington University and St Louis Children’s Hospital (TED), NIH grants R01 CA79940 (JAR), National Cancer Institute K08 CA140720-01A1 (TED), T32 CA099967, K05 CA157439, U10 CA98413, U10 CA98543, Alex’s Lemonade Stand ‘A’ Award (TED), the Hyundai Hope Award (TED), the Eli Seth Matthews Leukemia Foundation (TED) and the Children’s Cancer Research Fund (JAR), Minneapolis, MN, USA. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for next-generation sequencing. The Center is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. We also thank the Protein and Nucleic Acid Chemistry Laboratory at Washington University for dideoxy sequencing.