Clinical and genetic risk prediction of subsequent CNS tumors in survivors of childhood cancer: A report fromthe COG ALTE03N1 study

Xuexia Wang, Can Lan Sun, Leo Mascarenhas, Doojduen Villaluna, Lindsey Hageman, Kandice Smith, Purnima Singh, Wendy Landier, Smita Bhatia, Joseph P Neglia, Douglas S. Hawkins, Melissa M. Hudson, Leslie L. Robison, Kevin C. Oeffinger, A. Kim Ritchey

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [BRCA2], rs1805389 [LIG4], rs8079544 [TP53], rs25489 [XRCC1], rs1673041 [POLD1], and rs11615 [ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior (P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.

Original languageEnglish (US)
Pages (from-to)3688-3696
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number32
DOIs
StatePublished - Nov 10 2017

Bibliographical note

Funding Information:
Adamson), U10CA098413 (COG Statistics and Data Center Grant, PI: Anderson), and U10CA180899 (NCTN Statistics and Data Center Grant, PI: Devidas); Leukemia and Lymphoma Society Award No. 6093-08 (S.B.); Mathew Larson Foundation Award No. MIL110389 (X.W. and S.B.); and St Baldrick’s Foundation through an unrestricted grant to the COG.

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