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

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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

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Neoplasms
Area Under Curve
Radiotherapy
Genetic Predisposition to Disease
Single Nucleotide Polymorphism
Sensitivity and Specificity

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Clinical and genetic risk prediction of subsequent CNS tumors in survivors of childhood cancer : A report fromthe COG ALTE03N1 study. / Wang, Xuexia; Sun, Can Lan; Mascarenhas, Leo; Villaluna, Doojduen; Hageman, Lindsey; Smith, Kandice; Singh, Purnima; Landier, Wendy; Bhatia, Smita; Neglia, Joseph P ; Hawkins, Douglas S.; Hudson, Melissa M.; Robison, Leslie L.; Oeffinger, Kevin C.; Kim Ritchey, A.

In: Journal of Clinical Oncology, Vol. 35, No. 32, 10.11.2017, p. 3688-3696.

Research output: Contribution to journalArticle

Wang, X, Sun, CL, Mascarenhas, L, Villaluna, D, Hageman, L, Smith, K, Singh, P, Landier, W, Bhatia, S, Neglia, JP, Hawkins, DS, Hudson, MM, Robison, LL, Oeffinger, KC & Kim Ritchey, A 2017, 'Clinical and genetic risk prediction of subsequent CNS tumors in survivors of childhood cancer: A report fromthe COG ALTE03N1 study', Journal of Clinical Oncology, vol. 35, no. 32, pp. 3688-3696. https://doi.org/10.1200/JCO.2017.74.7444
Wang, Xuexia ; Sun, Can Lan ; Mascarenhas, Leo ; Villaluna, Doojduen ; Hageman, Lindsey ; Smith, Kandice ; Singh, Purnima ; Landier, Wendy ; Bhatia, Smita ; Neglia, Joseph P ; Hawkins, Douglas S. ; Hudson, Melissa M. ; Robison, Leslie L. ; Oeffinger, Kevin C. ; Kim Ritchey, A. / Clinical and genetic risk prediction of subsequent CNS tumors in survivors of childhood cancer : A report fromthe COG ALTE03N1 study. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 32. pp. 3688-3696.
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title = "Clinical and genetic risk prediction of subsequent CNS tumors in survivors of childhood cancer: A report fromthe COG ALTE03N1 study",
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.",
author = "Xuexia Wang and Sun, {Can Lan} and Leo Mascarenhas and Doojduen Villaluna and Lindsey Hageman and Kandice Smith and Purnima Singh and Wendy Landier and Smita Bhatia and Neglia, {Joseph P} and Hawkins, {Douglas S.} and Hudson, {Melissa M.} and Robison, {Leslie L.} and Oeffinger, {Kevin C.} and {Kim Ritchey}, A.",
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TY - JOUR

T1 - Clinical and genetic risk prediction of subsequent CNS tumors in survivors of childhood cancer

T2 - A report fromthe COG ALTE03N1 study

AU - Wang, Xuexia

AU - Sun, Can Lan

AU - Mascarenhas, Leo

AU - Villaluna, Doojduen

AU - Hageman, Lindsey

AU - Smith, Kandice

AU - Singh, Purnima

AU - Landier, Wendy

AU - Bhatia, Smita

AU - Neglia, Joseph P

AU - Hawkins, Douglas S.

AU - Hudson, Melissa M.

AU - Robison, Leslie L.

AU - Oeffinger, Kevin C.

AU - Kim Ritchey, A.

PY - 2017/11/10

Y1 - 2017/11/10

N2 - 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.

AB - 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.

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JO - Journal of Clinical Oncology

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