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Role of Genetic Mutations and Treatment Exposures in Increased Subsequent Malignancy Risk for Childhood Cancer Survivors


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In a study reported in the Journal of Clinical Oncology, Qin et al identified combinations of pathogenic germline mutations in DNA repair genes and cancer treatment exposures that increased risk of subsequent neoplasms in long-term survivors of childhood cancer.

“These 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."
— Qin et al

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Study Details

The study involved whole-genome sequencing of blood-derived DNA from 4,402 survivors in the St. Jude Lifetime Cohort. Median ages of patients were 6.3 years at diagnosis and 30.6 years at follow-up, with a median follow-up of 22.3 years. Pathogenic germline mutations in DNA repair genes were evaluated in 127 genes from six major DNA repair pathways.

Key Findings

Of 4,402 survivors, 495 (11.2%) developed 1,269 subsequent neoplasms. A total of 538 pathogenic germline mutations were identified in 98 DNA repair genes (most common = POLG, MUTYH, ERCC2, and BRCA2) in 508 (11.5%) survivors.

A total of 192 mutations in homologous recombination genes were identified in 185 survivors (cohort prevalence = 4.2%). Homologous recombination gene mutations were associated with increased rate of subsequent female breast cancer (relative rate [RR] = 3.7, 95% confidence interval [CI] =1.8–7.7), with risk augmented among those patients who had received chest radiotherapy ≥ 20 Gy (RR = 4.4, 95% CI = 1.6–12.4) and in those with a cumulative anthracycline dose in the second or third tertile (≥ 98 mg/m2; RR = 4.4, 95% CI = 1.7–11.4). Homologous recombination gene mutations were also associated with increased rate of subsequent sarcoma among patients who received alkylating agent doses in the third tertile (≥ 10,451 mg/m2; RR = 14.9, 95% CI = 4.0­–38.0).

A total of 143 Fanconi anemia gene mutations were identified in 140 survivors (prevalence = 3.2%). Fanconi anemia gene mutations were associated with increased rate of subsequent female breast cancer (RR = 3.7, 95% CI =1.3­–10.6), with risk augmented among those patients who had received chest radiotherapy ≥ 20 Gy (RR = 5.5, 95% CI = 1.5­–14.2) and in those with a cumulative anthracycline dose in the second or third tertile (RR = 4.2, 95% CI = 1.4–12.3).

A total of 98 mutations in nucleotide excision repair genes were identified in 97 survivors (prevalence = 2.2%). Nucleotide excision repair gene mutations were associated with subsequent thyroid cancer among patients treated with neck radiotherapy ≥ 30 Gy (RR = 12.9, 95% CI = 1.6–46.6).

The investigators concluded, “Our study provides novel insights regarding the contribution of genetics, in combination with known treatment-related risks, for the development of subsequent neoplasms. These 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."

Zhaoming Wang, PhD, of the Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Institutes of Health and by the American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit ascopubs.org.

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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