Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors

Amy L. Sherborne, Vincent Lavergne, Katharine Yu, Leah Lee, Philip R. Davidson, Tali Mazor, Ivan V. Smirnoff, Andrew E. Horvai, Mignon Loh, Steven G. DuBois, Robert E. Goldsby, Joseph P. Neglia, Sue Hammond, Leslie L. Robison, Rosanna Wustrack, Joseph F. Costello, Alice O. Nakamura, Kevin M. Shannon, Smita Bhatia, Jean L. Nakamura

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Abstract

Purpose: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors. Experimental Design:We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline TP53 variants in SMNs, Sanger sequencing was performed to analyze germline TP53 in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs. Results: WES revealed TP53 mutations involving p530s DNAbinding domain in both index cases, one of which was also present in the germline. The germline and somatic TP53-mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of TP53-coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27%) harboring a germline TP53 variant. Conclusions: Currently, germline TP53 is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline TP53 variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring.

Original languageEnglish (US)
Pages (from-to)1852-1861
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number7
DOIs
StatePublished - Apr 1 2017

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Second Primary Neoplasms
Survivors
Pediatrics
Neoplasms
Sarcoma
Exome
RNA Sequence Analysis
Amino Acid Substitution
Transcriptome
Single Nucleotide Polymorphism
Exons
Cohort Studies
Research Design
Radiotherapy
Therapeutics
Radiation
Mutation

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Sherborne, A. L., Lavergne, V., Yu, K., Lee, L., Davidson, P. R., Mazor, T., ... Nakamura, J. L. (2017). Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors. Clinical Cancer Research, 23(7), 1852-1861. https://doi.org/10.1158/1078-0432.CCR-16-0610

Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors. / Sherborne, Amy L.; Lavergne, Vincent; Yu, Katharine; Lee, Leah; Davidson, Philip R.; Mazor, Tali; Smirnoff, Ivan V.; Horvai, Andrew E.; Loh, Mignon; DuBois, Steven G.; Goldsby, Robert E.; Neglia, Joseph P.; Hammond, Sue; Robison, Leslie L.; Wustrack, Rosanna; Costello, Joseph F.; Nakamura, Alice O.; Shannon, Kevin M.; Bhatia, Smita; Nakamura, Jean L.

In: Clinical Cancer Research, Vol. 23, No. 7, 01.04.2017, p. 1852-1861.

Research output: Contribution to journalArticle

Sherborne, AL, Lavergne, V, Yu, K, Lee, L, Davidson, PR, Mazor, T, Smirnoff, IV, Horvai, AE, Loh, M, DuBois, SG, Goldsby, RE, Neglia, JP, Hammond, S, Robison, LL, Wustrack, R, Costello, JF, Nakamura, AO, Shannon, KM, Bhatia, S & Nakamura, JL 2017, 'Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors', Clinical Cancer Research, vol. 23, no. 7, pp. 1852-1861. https://doi.org/10.1158/1078-0432.CCR-16-0610
Sherborne, Amy L. ; Lavergne, Vincent ; Yu, Katharine ; Lee, Leah ; Davidson, Philip R. ; Mazor, Tali ; Smirnoff, Ivan V. ; Horvai, Andrew E. ; Loh, Mignon ; DuBois, Steven G. ; Goldsby, Robert E. ; Neglia, Joseph P. ; Hammond, Sue ; Robison, Leslie L. ; Wustrack, Rosanna ; Costello, Joseph F. ; Nakamura, Alice O. ; Shannon, Kevin M. ; Bhatia, Smita ; Nakamura, Jean L. / Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 7. pp. 1852-1861.
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abstract = "Purpose: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors. Experimental Design:We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline TP53 variants in SMNs, Sanger sequencing was performed to analyze germline TP53 in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs. Results: WES revealed TP53 mutations involving p530s DNAbinding domain in both index cases, one of which was also present in the germline. The germline and somatic TP53-mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of TP53-coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27{\%}) harboring a germline TP53 variant. Conclusions: Currently, germline TP53 is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline TP53 variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring.",
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T1 - Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors

AU - Sherborne, Amy L.

AU - Lavergne, Vincent

AU - Yu, Katharine

AU - Lee, Leah

AU - Davidson, Philip R.

AU - Mazor, Tali

AU - Smirnoff, Ivan V.

AU - Horvai, Andrew E.

AU - Loh, Mignon

AU - DuBois, Steven G.

AU - Goldsby, Robert E.

AU - Neglia, Joseph P.

AU - Hammond, Sue

AU - Robison, Leslie L.

AU - Wustrack, Rosanna

AU - Costello, Joseph F.

AU - Nakamura, Alice O.

AU - Shannon, Kevin M.

AU - Bhatia, Smita

AU - Nakamura, Jean L.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Purpose: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors. Experimental Design:We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline TP53 variants in SMNs, Sanger sequencing was performed to analyze germline TP53 in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs. Results: WES revealed TP53 mutations involving p530s DNAbinding domain in both index cases, one of which was also present in the germline. The germline and somatic TP53-mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of TP53-coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27%) harboring a germline TP53 variant. Conclusions: Currently, germline TP53 is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline TP53 variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring.

AB - Purpose: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors. Experimental Design:We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline TP53 variants in SMNs, Sanger sequencing was performed to analyze germline TP53 in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs. Results: WES revealed TP53 mutations involving p530s DNAbinding domain in both index cases, one of which was also present in the germline. The germline and somatic TP53-mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of TP53-coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27%) harboring a germline TP53 variant. Conclusions: Currently, germline TP53 is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline TP53 variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring.

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