Analysis by array CGH of genomic changes associated with the progression or relapse of Wilms' tumour

Abstract

Despite aggressive salvage regimens, approximately half of all children who suffer a Wilms' tumour recurrence will die of their disease. Although there are increasing data on molecular genetic prognostic factors present in the tumour at diagnosis, there is little information regarding the molecular events that occur with Wilms' tumour progression and relapse. In the present study, microarray-based comparative genomic hybridization (aCGH) analysis has been carried out on 58 Wilms' tumour samples, which included 38 untreated primary and 20 recurrent tumours. A higher degree of copy number changes was observed in the recurrent tumours (33.0% genomic clones) than in the primary tumour (21.2%). Paired analysis highlighted the acquisition of 15q gain with high levels of IGF1R expression in the tumour recurrence in two cases. The most statistically significant abnormality acquired between diagnosis and relapse was loss of 17p. One case that experienced 17p loss was classified as favourable histology at diagnosis, but exhibited diffuse anaplasia at recurrence and had a homozygous TP53 deletion. Another instructive case with a constitutional 11p13 deletion presented with bilateral tumours and suffered two subsequent recurrences in the left kidney. A somatic WT1 mutation was found only in the right kidney tumour, while the constitutional 11p13 deletion was the only abnormality detected in the initial left kidney tumour by aCGH. The two subsequent relapses in the left kidney contained an accumulation of additional genetic alterations, including an independent WT1 mutation.

Value and difficulties of a common European strategy for recurrent Wilms’ tumor

“…To date, expression profiling studies have provided inconsistent results, perhaps due to the cellular heterogeneity found in WT, whereas genomic copy number analyses look more promising to discriminate relapsing tumors [20][21][22]. This is consistent with the predictive value of allele loss at chromosomes 1p and 16q found in the large NWTS-5 trial, although the critical genes or pathways remain to be defined [23].…”

Loss of Heterozygosity at 2q37 in Sporadic Wilms' Tumor: Putative Role for miR-562

“…It encompasses five genes, including ING5, a putative tumor suppressor gene that may modulate p53 function (37). The translocation is unbalanced and duplicates a 28-Mb region of distal 15q, a rearrangement that has also been implicated in the pathogenesis of Wilms' tumor (15,38). Thus, although this is one of the three germ-line rearrangements that inspired the study, the partial trisomy 15q likely also contributed to the pathogenesis of Wilms' tumor in this patient and the 2q37 deletion alone may not have been causal.…”

“…Identification of other genes involved in the etiology of sporadic Wilms' tumor therefore remains an important priority. Studies of loss of heterozygosity (LOH), loss of imprinting, and constitutional chromosomal defects have implicated several recurrent changes in Wilms' tumor at chromosomes 11p15, 1p, 1q, 7p, 9q, 14q, 16q, and 22 (13)(14)(15)(16).…”

Comparative genomic hybridization and the importance of oncological research

“…Natrajan ve ark. 'nın (14) Wilms tümöründe KGH yöntemi ile genomik değişiklikleri inceledikleri bir çalışmada, Wilms tümöründe kromozomal sapmanın sayısındaki artış ile tümör progresyonu ve relaps arasında ilişki bulunmuştur. Ek olarak spesifik genetik değişiklik 17p kaybının, tümör progresyonuyla bağ-lantılı ve bu anomalinin olasılıkla tümör gelişiminde son basamak olduğu saptanmıştır.…”