Significance of TP53 Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children's Oncology Group

Abstract

Purpose To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumor (DAWT). 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 DAWT (48%) demonstrated TP53 mutations, 13(11%) copy loss without mutation, and 48(41%) lacked both (defined as TP53-wildtype (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. In-depth analysis of a subset of 39 DAWT showed 7(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 6/7 tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. Conclusion 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.

TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia

“…Thus, inactivation of both copies is frequent, but apparently not a prerequisite for oncogenic action. These numbers almost match the rates of 17p loss in 20/25 and 42/53 anaplastic TP53 mutant tumours reported previously . The difference may be due to reduced sensitivity in our testing of FFPE material, since the reference FISH probe used (CEN17) may lead to an underestimation of TP53 loss if the entire chromosome is lost.…”

“…Nevertheless, this correlation of histology and mutation does not include all anaplastic tumours. Rather, evidence for TP53 mutation has been found in only 48-55% of anaplastic cases, with another 11% having suspicious loss of chromosome 17p [11,12]. On the other hand, we have found TP53 mutations in tumours with sometimes inconclusive or even missing features of anaplasia [13], but this has not been studied systematically in non-anaplastic WT.…”

“…A high mutation rate was also found in tumours with only focal anaplasia (73%, 8/11). This is much higher than mutation rates of about 50% reported in prior studies [11,12]. There is likely no ascertainment bias due to our initial focus on tumours with lethal outcome, since we found similarly high mutation rates in fatal as well as longterm surviving anaplastic cases.…”

Recent advances in the management of Wilms' tumor

“…WT1 , CTNNB1 , and WTX genetic alterations are estimated to co-occur in approximately one-third of WTs 34 . Many other genes appear to be implicated, including TP53 and MYNC 34, 35 .…”

“…There is a clear relationship between TP53 mutations and anaplastic WT 35 . This indicates that these mutations are related to tumor progression and associated with a more aggressive type of disease.…”