DNA repair-gene variants linked to subsequent neoplasm risk in pediatric cancer survivors
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Pediatric cancer survivors who harbor pathogenic variants in DNA repair genes have an increased risk for subsequent neoplasms, according to study results published in Journal of Clinical Oncology.
Researchers reported especially higher risk among those treated with high-dose radiotherapy or chemotherapy.
“We initially examined pathogenic variants in a set of 60 cancer predisposition genes and found that carriers of pathogenic variants in these genes, which are likely linked to their childhood cancer development, had increased risk for developing second cancers irrespective of prior cancer treatment exposures,” Zhaoming Wang, PhD, researcher in the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, told Healio. “Shortly after publishing this initial research, we started to further expand our investigation by examining the pathogenic variants in a set of 127 DNA damage repair genes. We knew that therapeutic agents and modalities used to treat childhood cancers do not spare healthy tissues and may cause DNA damage. We therefore hypothesized that carriers of pathogenic variants in DNA repair genes would have increased risk for developing subsequent neoplasms.”
The U.S. childhood cancer survivor population is expected to surpass 500,000 this year. Survivors often experience a significant burden of long-term chronic health conditions, including subsequent neoplasms, which often are considered to be therapy-related. However, pathogenic germline mutations can contribute to increased risk for these neoplasms, researchers noted.
Wang and colleagues sought to characterize germline pathogenic mutations in DNA repair genes and explore the risk for subsequent neoplasms based on mutation status among 4,402 childhood cancer survivors (52.5% male; 81.4% white) included in the St. Jude Lifetime Cohort. They used whole-genome sequencing to evaluate 127 genes from six key DNA repair pathways.
Nearly half (49.3%) of survivors had been treated with radiation therapy, 55.8% received anthracyclines, 56.3% received alkylating agents and 34% received epipodophyllotoxins.
Median follow-up was 22.3 years (interquartile range [IQR], 14.2-32.1).
Among the survivors, 495 (11.2%) developed a total of 1,269 subsequent neoplasms. Median time to first subsequent neoplasm was 26.5 years (IQR, 19.1-33.9) and median age at first subsequent neoplasm was 35.9 years (IQR, 29-43.2).
Overall, 11.5% of the survivors had a total of 538 pathogenic germline mutations in 98 DNA repair genes, including POLG (n = 30), MUTHY (n = 27), ERCC2 (n = 25) and BRCA2 (n = 20). Mutations in homologous recombination genes appeared associated with a significantly higher rate of subsequent female breast cancer (relative rate [RR] = 3.7; 95% CI, 1.8-7.7), particularly among survivors who received chest radiotherapy of 20 Gy or greater (RR = 4.4; 95% CI, 1.6-12.4) or a cumulative dose of anthracyclines in the second or third tertile (RR = 4.4; 95% CI, 1.7-11.4).
Researchers also observed associations between mutations in homologous recombination genes and an increased rate of subsequent sarcoma among those treated with alkylating agent doses in the third tertile (RR = 14.9; 95% CI, 4-38). Among survivors who received neck radiotherapy of 30 Gy or greater, mutations in nucleotide excision repair appeared associated with subsequent thyroid cancer (RR = 12.9; 95% CI, 1.6-46.6).
“Our findings have the potential to facilitate identification of high-risk survivors who may benefit from genetic counseling and/or testing of DNA repair genes, which may further inform personalized cancer surveillance and prevention strategies,” Wang said. “I have started to apply a similar research strategy investigating the link between inherited pathogenic variants in DNA repair genes and risk for developing cardiovascular outcomes among survivors of childhood cancer, and hope to identify the synergistic effects between genotoxic treatment exposures and carrying pathogenic variants in genes that are responsible for repair DNA damage.”
For more information:
Zhaoming Wang, PhD, can be reached at St. Jude’s Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN 38105; email: zhaoming.wang@stjude.org.
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