TY - JOUR
T1 - Significance of TP53 mutation in Wilms tumors with diffuse anaplasia
T2 - A report from the Children's Oncology Group
AU - Ooms, Ariadne H.A.G.
AU - Gadd, Samantha
AU - Gerhard, Daniela S.
AU - Smith, Malcolm A.
AU - Guidry Auvil, Jaime M.
AU - Meerzaman, Daoud
AU - Chen, Qing Rong
AU - Hsu, Chih Hao
AU - Yan, Chunhua
AU - Nguyen, Cu
AU - Hu, Ying
AU - Ma, Yussanne
AU - Zong, Zusheng
AU - Mungall, Andrew J.
AU - Moore, Richard A.
AU - Marra, Marco A.
AU - Huff, Vicki
AU - Dome, Jeffrey S.
AU - Chi, Yueh Yun
AU - Tian, Jing
AU - Geller, James I.
AU - Mullighan, Charles G.
AU - Ma, Jing
AU - Wheeler, David A.
AU - Hampton, Oliver A.
AU - Walz, Amy L.
AU - Van Den Heuvel-Eibrink, Marry M.
AU - De Krijger, Ronald R.
AU - Ross, Nicole
AU - Gastier-Foster, Julie M.
AU - Perlman, Elizabeth J.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [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 abnormalities. Indepth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven 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.
AB - Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [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 abnormalities. Indepth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven 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.
UR - http://www.scopus.com/inward/record.url?scp=84995874862&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-0985
DO - 10.1158/1078-0432.CCR-16-0985
M3 - Article
C2 - 27702824
AN - SCOPUS:84995874862
SN - 1078-0432
VL - 22
SP - 5582
EP - 5591
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -