Rare Germline Variants' Role in Pediatric Tumors

Largescale changes in the genome inherited from parents are significant risk factors for pediatric solid tumors, such as Ewing sarcoma, neuroblastoma, and osteosarcoma, according to a new study. The findings, which highlight the role of germline structural variants (SVs) in early genome instability, provide new insights into the genetic underpinnings of pediatric cancers and open doors for improved diagnostic and treatment strategies. Unlike adult cancers, which often result from environmental factors or DNA damage built up over time, childhood cancers develop too quickly for these mechanisms to play a major role. Such an early age of onset suggests that germline genetic factors are involved. Although studies suggest a 4.5-fold increased familial risk for pediatric solid tumors, only 10–15% of cases can be attributed to known pathogenic germline variants. Here, Riaz Gillani and colleagues conducted a comprehensive analysis of rare germline SVs in pediatric extracranial solid tumors using whole-genome sequencing from 1,765 affected children and 943 unaffected relatives. They sought to determine inheritance patterns. They evaluated 6,665 unrelated adult controls for comparison. The germline genome sequencing analysis identified 84 rare, large (larger than 1megabase) unbalanced chromosomal abnormalities – alterations involving the gain or loss of genetic material – associated with an increased risk of pediatric solid tumors, particularly in males. According to the findings, these abnormalities were predominantly inherited from unaffected parents (82%), with a smaller proportion (18%) arising de novo. In addition to large chromosomal abnormalities, smaller gene-disruptive germline SVs were identified as risk factors for pediatric tumors, absent in controls but present in cancers like neuroblastoma and Ewing sarcoma. These SVs included disruptions of DNA repair genes such as BARD1 and genes involved in tumorigenesis. Overall, Gillani et al. estimate that rare germline SVs explain up to 5.6% of an individual's total liability for childhood cancer. In a Perspective, Jayne Hehir-Kwa and Geoff Macintyre discuss the study and its findings in greater detail.