Somatic and GermlineTP53Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.
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 germlineTP53variants in SMNs, Sanger sequencing was performed to analyze germlineTP53in 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 revealedTP53mutations involving p53's DNA-binding domain in both index cases, one of which was also present in the germline. The germline and somaticTP53-mutant variants were enriched in the transcriptomes for both sarcomas. Analysis ofTP53-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 germlineTP53variant.Conclusions:Currently, germlineTP53is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germlineTP53variants 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.Clin Cancer Res; 23(7); 1852-61. ©2016 AACR.
Department of Radiation Oncology, University of California, San Francisco, California.
Amy L
AL
Sherborne
Department of Radiation Oncology, University of California, San Francisco, California.
Vincent
V
Lavergne
Department of Radiation Oncology, University of California, San Francisco, California.
Katharine
K
Yu
Department of Radiation Oncology, University of California, San Francisco, California.
Leah
L
Lee
Department of Finance and Statistical Analysis, University of Alberta, Edmonton, Alberta, Canada.
Philip R
PR
Davidson
Department of Neurological Surgery, University of California, San Francisco, California.
Tali
T
Mazor
Department of Neurological Surgery, University of California, San Francisco, California.
Ivan V
IV
Smirnoff
Department of Pathology, University of California, San Francisco, California.
Andrew E
AE
Horvai
Department of Pediatrics, University of California, San Francisco, California.
Mignon
M
Loh
Department of Pediatrics, Dana Farber/Boston Children's Cancer and Blood Disorders Program and Harvard Medical School, Boston, Massachusetts.
Steven G
SG
DuBois
Department of Pediatrics, University of California, San Francisco, California.
Robert E
RE
Goldsby
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
Joseph P
JP
Neglia
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
Sue
S
Hammond
Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.
Leslie L
LL
Robison
Department of Surgery, University of California, San Francisco, California.
Rosanna
R
Wustrack
Department of Neurological Surgery, University of California, San Francisco, California.
Joseph F
JF
Costello
Department of Finance and Statistical Analysis, University of Alberta, Edmonton, Alberta, Canada.
Alice O
AO
Nakamura
Department of Neurological Surgery, University of California, San Francisco, California.
Kevin M
KM
Shannon
Department of Pediatrics, University of Alabama, Birmingham, Alabama.
Smita
S
Bhatia
Department of Radiation Oncology, University of California, San Francisco, California. Jean.Nakamura@ucsf.edu.
Jean L
JL
Nakamura
D000293:Adolescent; D000073116:Cancer Survivors; D002648:Child; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000473:pathology; D010372:Pediatrics; D020641:Polymorphism, Single Nucleotide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000073359:Exome Sequencing
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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