Study provides new insights into the genetic basis of childhood cancer

Study provides new insights into the genetic basis of childhood cancer

Large-scale changes in the genome inherited from parents are significant risk factors for solid tumors in children such as Ewing's sarcoma, neuroblastoma and osteosarcoma, according to a new study. The findings, highlighting the role of germline structural variants (SVs) in early genome instability, provide new insights into the genetic basis of childhood 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 significant role. Such an early age of onset suggests that germline genetic factors are involved. Although studies indicate a 4.5-fold increased familial risk of solid tumors in children, 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 of 1,765 affected children and 943 unaffected relatives. They tried to determine patterns of inheritance. For comparison, they evaluated 6,665 unrelated adult controls. Germline genome sequencing analysis identified 84 rare, large (larger than 1 megabase) imbalanced chromosomal abnormalities - changes that involve the gain or loss of genetic material - that are associated with an increased risk of solid tumors in children, particularly men. According to the results, these anomalies were predominantly inherited from unaffected parents (82%), with a smaller proportion (18%) arising de novo. In addition to large chromosomal abnormalities, smaller gene-disrupting germline SVs have been identified as risk factors for pediatric tumors that were absent in controls but were present in cancers such as neuroblastoma and Ewing sarcoma. These SVs included disruptions of DNA repair genes such asBARD1and genes involved in tumor development.

Total Gillaniet al.estimate that rare germline SVs explain up to 5.6% of an individual's total burden of childhood cancer. In a Perspective, Jayne Hehir-Kwa and Geoff Macintyre discuss the study and its findings in more detail.

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