Clin Cancer Res. Volume 22, Issue 22: p.5582–5591, 4 October 2016, 10.1158/1078-0432.CCR-16-0985
PURPOSE: To investigate the role and significance of TP53 mutation in diffuse anaplastic Wilms tumors (DAWTs). EXPERIMENTAL DESIGN: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were sequenced (either WGS or WXS, when possible mRNA-seq). The data was analyzed for TP53 mutations and copy loss and in 39 cases the genomic data was integrated.
This study characterized TARGET cases as described below:
44 Discovery Cases | 74 validation cases |
---|---|
43 cases had chip-based GE | - |
42 cases had mRNA-Seq | - |
43 had miRNA-Seq | - |
42 cases had CN array | - |
42 cases had methylation array | - |
21 cases had WGS | - |
20 cases had WXS | - |
44 cases had TCS | 74 cases had TCS |
E=gene expression; CN=copy number, TCS=targeted capture sequencing
RESULTS: 57 DAWTs (48%) had mutations in the TP53 gene, 13 had (11%) gene copy loss without mutation, and 48 (41%) lacked either [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 alterations. In-depth analysis of a subset of 39 DAWTs with CAN and expression data showed seven (18%) to be TP53-wt: The TP53-wt tumors demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of these TP53-wt DAWT revealed no or very low volume of anaplasia in six tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry.
CONCLUSIONS: These data support the key role of TP53 loss in the development of anaplasia in WT and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582-91.
In order to access Controlled TARGET WT data using the links below, users must submit an application for Authorized Access via dbGaP as described on dbGaP’s TARGET Study Page. To begin the application process, please view the information and instructions provided on the dbGaP Authorized Access Login Page under “dbGaP Data Download”.
Supplemental Data
- GDC Manifests
- Controlled-Access Data Download Manifest (8 Files)
- Open-Access Data Download Manifest (25 Files)
- WGS CGI Files Download Manifest (82 Files)
- Copy Number Array
- TARGET WT Copy number array Level 1 Data (Controlled)
- TARGET WT Copy number array Level 2 Data (Controlled)
- TARGET WT Copy number array Level 3 Data
- TARGET WT Copy number array Metadata
- Gene Expression Array
- mRNA-Seq
- TARGET WT mRNA-Seq Level 3 data
- TARGET WT mRNA-Seq Level 3 data (Controlled)
- TARGET WT mRNA-Seq Metadata
- miRNA-Seq
- Whole Exome Sequencing
- TARGET WT WXS Level 3 Data
- TARGET WT WXS Level 3 Data (Controlled)
- TARGET WT WXS Design
- TARGET WT WXS Metadata
- Methylation Array
- TARGET WT Methylation array Level 1 Data (Controlled)
- TARGET WT Methylation array Level 2 Data
- TARGET WT Methylation array Level 3 Data
- TARGET WT Methylation array Level 4 Data
- TARGET WT Methylation array Metadata
- Whole Genome Sequencing
- TARGET WT WGS Level 3 Data
- TARGET WT WGS Level 3 Data (Controlled)
- TARGET WT WGS Level 4 Data
- TARGET WT WGS Metadata
- Targeted Capture Sequencing
- TARGET WT Targeted Capture Sequencing Level 3 Data (Controlled)
- TARGET WT Targeted Capture Sequencing Design
- TARGET WT Targeted Capture Sequencing Metadata
- Miscellaneous Files
- TARGET WT Sample Matrices
- TARGET WT CGI Requested Reports (Controlled)
Additional Resources
- OCG TARGET Data Matrix (link is external) Office of Cancer Genomics
- TARGET-WT at SRA (link is external) NCBI
Instructions for Data Download
Open Access Data
- Download the appropriate manifest file from the publication page
- Use the manifest file to download data using the GDC Data Transfer Tool (DTT) or the GDC API
- GDC DTT ( Download, User's Guide)
- GDC API ( User’s Guide)
Controlled Access Data
- Download the appropriate manifest file from the publication page
- Download a token from the GDC Data Portal
- GDC Data Portal ( Launch, User’s Guide)
- Use the manifest file and token to download data using the GDC DTT or the GDC API
- GDC DTT ( Download, User’s Guide)
- GDC API ( User’s Guide)
For assistance, please contact the GDC Help Desk: support@nci-gdc.datacommons.io.