Format

Send to

Choose Destination
See comment in PubMed Commons below
Clin Cancer Res. 2016 Sep 28. doi: 10.1158/1078-0432.CCR-16-0610. [Epub ahead of print]

Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

Author information

  • 1Department of Radiation Oncology, University of California, San Francisco, California.
  • 2Department of Finance and Statistical Analysis, University of Alberta, Edmonton, Alberta, Canada.
  • 3Department of Neurological Surgery, University of California, San Francisco, California.
  • 4Department of Pathology, University of California, San Francisco, California.
  • 5Department of Pediatrics, University of California, San Francisco, California.
  • 6Department of Pediatrics, Dana Farber/Boston Children's Cancer and Blood Disorders Program and Harvard Medical School, Boston, Massachusetts.
  • 7Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
  • 8Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
  • 9Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 10Department of Surgery, University of California, San Francisco, California.
  • 11Department of Pediatrics, University of Alabama, Birmingham, Alabama.
  • 12Department of Radiation Oncology, University of California, San Francisco, California. Jean.Nakamura@ucsf.edu.

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 p53's DNA-binding 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. Clin Cancer Res; 1-10. ©2016 AACR.

PMID:
27683180
DOI:
10.1158/1078-0432.CCR-16-0610
[PubMed - as supplied by publisher]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center