Genetic Risk for Subsequent Neoplasms in Long-Term Survivors of Childhood Cancer

Key Points

  • Subsequent neoplasms were diagnosed in 14.6% of survivors and pathogenic/likely pathogenic mutations were identified in 5.8%.
  • Mutations were associated with an increased risk of breast cancer and sarcoma among irradiated survivors and increased risk of any subsequent neoplasm, breast cancer, nonmelanoma skin cancer, and ≥ 2 histologically distinct subsequent neoplasms among nonirradiated survivors.

In a study reported in the Journal of Clinical Oncology, Wang et al found that germline pathogenic/likely pathogenic mutations significantly contributed to the risk of subsequent neoplasms in long-term survivors of childhood cancers.

Study Details

The study involved whole-genome sequencing on samples from 3,006 childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis in the St. Jude Lifetime Cohort Study. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by pathogenicity according to the American College of Medical Genetics and Genomics guidelines.

Relative rates (RRs) of subsequent neoplasm occurrence according to mutation status were estimated by multivariable piecewise exponential regression stratified by radiation exposure. Survivors had a median age of 35.8 years (range = 7.1–69.8 years), 53% were male, and 56% had received radiotherapy.

Among all 3,006 patients, 1,120 subsequent neoplasms were diagnosed in 439 (14.6%) and 175 pathogenic/likely pathogenic mutations were identified in 5.8%. These mutations were associated with significantly increased risks of breast cancer (RR = 13.9, 95% confidence interval [CI] = 6.0–32.2) and sarcoma (RR = 10.6, 95% CI = 4.3–26.3) among irradiated survivors and increased risks of any subsequent neoplasm (RR = 4.7, 95% CI = 2.4–9.3), breast cancer (RR = 7.7, 95% CI = 2.4–24.4), nonmelanoma skin cancer (RR = 11.0, 95% CI = 2.9–41.4), and ≥ 2 histologically distinct subsequent neoplasms (RR = 18.6, 95% CI = 3.5–99.3) among nonirradiated survivors.

The investigators concluded, “The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any [subsequent neoplasm] and for those with breast cancer or sarcoma in the field of prior irradiation.”

The study was supported by the American Lebanese Syrian Associated Charities and National Cancer Institute grants.

Jinghui Zhang, PhD, of the Department of Computational Biology, St Jude Children’s Research Hospital, is the corresponding author for the Journal of Clinical Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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