Bilateral Wilms Tumor withTP53-Related Anaplasia

Abstract

Wilms tumor (WT) with diffuse anaplasia has an unfavorable prognosis and is often (>70%) associated with mutations in the TP53 gene. Although most WTs are unilateral, 5-10% are bilateral, and they are almost always present with nephrogenic rests. The latter are considered a precursor of WT. Two cases of bilateral WTs with nephroblastomatosis, in which anaplastic changes were detected over a period of time, were analyzed using clinical, radiological, histopathological, and molecular-genetic data. TP53 was analyzed by direct sequencing of its full coding sequence and intron-exon boundaries in 11 fragments. DNA was extracted from paraffin-embedded or frozen specimens. High-resolution genomic copy number profiling was carried out by UCL Genomics on the Affymetrix Human Mapping 250K Nsp or Genome-Wide Human SNP Array 6.0 platform. Both cases demonstrated a strong association between the appearance of anaplastic clones and TP53 mutations. Synchronous ganglioneuroma was diagnosed in one case. Our cases are unique as they represent a long disease history and demonstrate the difficulties in managing rare cases of bilateral WT with anaplasia. These cases also emphasize the practical importance of modern molecular-genetic techniques and their clinical application. Moreover, they highlight the issue of the adequate sampling needed in order to gather comprehensive, efficient, and sufficient information about genetic events in a single tumor.

Multiple mechanisms of MYCN dysregulation in Wilms tumour

“…Two spatially separated samples from the initial right partial nephrectomy carried the P44L mutation, and a SNP array of one of these indicated normal MYCN copy number. There were no MYCN mutations in any other material from the right kidney (Table 2), but as previously reported [36], this tumour carried a p.I195T mutation in TP53 at relapse, consistent with its anaplastic histology; high quality DNA suitable for copy number analysis was not available for the sample at this time point.…”

“…As we reported previously [36], this case also has independent contralateral TP53 mutations, albeit with apparently dissimilar timing of the mutational events. In the left kidney, MYCN gain was detected in all specimens examined (Table 2), including the initial pre-chemotherapy biopsy, while the V173L TP53 mutation was absent at initial biopsy and in a precursor lesion (nephrogenic rest).…”

“…In the left kidney, P44 was wild type in all material, including 3 tumour samples that carried the previously reported contralateral p.V173L mutation in TP53 [36]. SNP arrays were available for two of these samples and from an initial biopsy (Figure 2); all showed clear evidence of MYCN gain.…”

“…One of the samples in which a P44L mutation was detected by exome sequencing was taken from the right side of a second bilateral case we have previously described [36]. This case is notable for its significant intra-tumour heterogeneity on the left side (Figure 2, Supplementary Figure 2, Table 2), and for the evolution of different anaplasia-associated TP53 mutations in each contralateral tumour.…”

Review of prognostic and predictive aspects of mutated TP53 in Wilms’ tumor biology with morphological report and molecular analysis of 37-year-old man’s nephroblastoma

“…TP53genemutationsareahallmarkofpoorprog-nosis of Wilms' tumor as they coexist with diffuse anaplasia,pointingatcloselinkageofanaplasiaand TP53mutationsincaseofbilateralnephroblastomas withanaplasia [23].Moreover,itseemsthatreportingonTP53inactivatingmutationunderliesmulti-drug resistance (MDR) mediated by P-glycoprotein (Pgp/MDR1)andmultidrug-resistantrelatedprotein (MRP1) [23].Namely,24%oftumorsampleswere Pgp/MDR1-positive,48%wereimmunoreactivefor MRP1,andonly8%werepositivelystainedforwild-typeTP53,withthefindingofverylowcoexpression ofMDRandwild-typeTP53inastudyof25pediat-ricnephroblastomas [24](Chart1).Thus,evaluation of genetic abnormalities is so pivotal in prognostic andpredictiveperspectiveinsuchasingletumoras describedinourcase.…”