Array CGH profiling of favourable histology Wilms tumours reveals novel gains and losses associated with relapse

Abstract

Despite the excellent survival of Wilms tumour patients treated with multimodality therapy, approximately 15% will suffer from tumour relapse, where response rates are markedly reduced. We have carried out microarray-based comparative genomic hybridisation on a series of 76 Wilms tumour samples, enriched for cases which recurred, to identify changes in DNA copy number associated with clinical outcome. Using 1Mb-spaced genome-wide BAC arrays, the most significantly different genomic changes between favourable histology tumours that did (n = 37), and did not (n = 39), subsequently relapse were gains on 1q, and novel deletions at 12q24 and 18q21. Further relapse-associated loci included losses at 1q32.1, 2q36.3-2q37.1, and gain at 13q31. 1q gains correlated strongly with loss of 1p and/or 16q. In 3 of 11 cases with concurrent 1p(-)/1q(+), a breakpoint was identified at 1p13. Multiple low-level sub-megabase gains along the length of 1q were identified using chromosome 1 tiling-path arrays. One such recurrent region at 1q22-q23.1 included candidate genes RAB25, NES, CRABP2, HDGF and NTRK1, which were screened for mRNA expression using quantitative RT-PCR. These data provide a high-resolution catalogue of genomic copy number changes in relapsing favourable histology Wilms tumours.

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

“…In Wilms tumors, 1q gain was described to be a predominant alteration in comparative genomic hybridization analyses (Hing et al, 2001). Interestingly, LOH at loci 1q21-22 and 1q32 has been also associated with tumor adverse outcome (Law et al, 1997;Natrajan et al, 2006). Our LOH findings are consistent with these previous reports and indicate that the HRPT2 locus HRPT2 loss and mutation in renal tumors J Zhao et al might be one of critical targets contributing to the development of these renal tumors.…”

“…No specific gene mutation has yet been identified as a direct contributor to their pathogenesis. Wilms tumor is known to have allelic loss at numerous loci (Grundy et al, , 1998Law et al, 1997;Klamt et al, 1998;Natrajan et al, 2006). One Wilms tumor gene (WT1) has been identified and mapped to 11p13 (Call et al, 1990;Gessler et al, 1990).…”

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

“…Bacterial artificial chromosome clones were spotted in triplicate onto Corning GAPSII-coated glass slides (Corning, NY, USA). Labelling of 250 ng of non-amplified DNA obtained from microdissected frozen sections or 1000 ng of DNA retrieved from microdissected formalin-fixed paraffin-embedded tissue sections, hybridisation and washes were carried out essentially as described previously (Reis-Filho et al, 2005b, 2006aNatrajan et al, 2006).…”

Late recurrence of Wilms’ tumour with exclusive skeletal muscle phenotype 23 years after primary diagnosis

“…Approximately 15-20% of cases of Wilms tumour relapse, more frequently within the first 2-5 years following the primary diagnosis; in these cases, the risk of recurrence is mainly related to the morphological and molecular features of the previous tumour [12,8,18,7,14].…”

“…The association of chemotherapy and radiotherapy to radical nephrectomy has increased the overall survival rate up to 85-90% [3,6];however, in spite of these therapeutic improvements, tumour relapses in a subset of patients (15-20%) [12].Numerous studies have demonstrated that the risk of recurrence can be associated to different features such as histological tumour pattern and loss of heterozygosis (LOH) at 1p and/or 16q, as well as gain of chromosome 1 and other recently described alterations [8,18,7,14]. The recurrence risk is greater within the first 2 years after primary diagnosis (in these patients the percentage of survival approximaly ranges from 24% to 43%) but late relapses have occasionally been reported [1,10].…”