Blastemal Expression of Type I Insulin-Like Growth Factor Receptor in Wilms' Tumors Is Driven by Increased Copy Number and Correlates with Relapse

Abstract

Most Wilms' tumors are of low stage, favorable histology, and have a high likelihood of cure with current multimodal therapy. Despite this, there remains a group of patients whose tumors recur for whom intensive salvage regimens result in survival of only 50%. Fitting a Cox proportional hazards model to microarray-based comparative genomic hybridization (aCGH) data on 68 Wilms' tumor samples, we identified a significant correlation between increased copy number at chromosome 15q26.3 insulin-like growth factor I receptor (IGFIR) and tumor relapse (adjusted P = 0.014). Wilms' tumors (13%) exhibited a low-level gain corresponding to three to four copies of the gene by aCGH analysis, 9 of 10 of which exhibited high IGFIR mRNA levels. Although IGFIR protein expression was restricted to the epithelial cells of fetal kidney and Wilms' tumors in most cases, 12% of tumors were also found to express IGFIR in the blastemal compartment. Blastemal IGFIR protein expression was associated with an increased copy number and a shorter relapse-free survival time (P = 0.027, log-rank test). In addition to the membrane localization, IGFIR was localized to the perinuclear region of the blastemal cells in 6% of Wilms' tumors. These data provide evidence that an increase in IGFIR gene copy number results in aberrant expression in the blastemal compartment of some Wilms' tumors and is associated with an adverse outcome in these patients. These findings suggest the possibility of use of targeted agents in the therapy of these children. (Cancer Res 2006; 66(23): 11148-55)

IGF2 and cancer

“…Signalling through this receptor has been reviewed in detail elsewhere (Kim et al 2009, Djiogue et al 2013 and is mentioned only briefly here. IGF1R has an established role in tumour progression, its copy number negatively associated with survival time (Natarajan et al 2006). Its increased expression by cancer cells is associated with over-expression of IGF2 and tendency to metastasize (Guerra et al 1996).…”

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

“…Linked to their proliferative, differentiation and apoptotic properties, both GH and insulin-like growth factor 1 (IGF1) have been identified as risk factors for certain malignancies (1)(2)(3)(4)(5), even in the pediatric age group and young adults (6)(7)(8). There is also evidence that most tumors and transformed cells display increased IGF1 receptor (IGF-1R) concentration and high IGF1R mRNA, causing enhanced IGF1 binding (9,10), leading to the axiom that overexpression of IGF1R is a pre-requirement for acquisition or progress of malignant tumors (11).…”

Getting it right: designing microarray (and not ‘microawry') comparative genomic hybridization studies for cancer research

“…7,[51][52][53][54][55] Another way of using aCGH is in the molecular genetic characterization of tumours, leading to the identification of putative genetically important aberrations in carcinogenesis and tumour progression, thus providing a basis for hypothesis testing to determine the clinical relevance of genes within aberrant regions. This approach has led to the identification of novel oncogenes, prognostic markers and putative therapeutic targets in various tumours such as E2F3 in bladder cancer, 56 RAB25 in breast and ovarian cancer, 57 IGF1R in Wilm's tumours, 58 and FGFR1 in breast cancer. 9 Here, the emphasis in on discovering individual genetic aberrations that have a significant impact on tumour biology.…”

“…These include quantitative real-time PCR (QPCR) techniques 93 and FISH, CISH, or SISH. 9,58,[66][67][68]91 Additionally, in studies where matched normal DNA samples are not available, all regions of copy number change should be cross-referenced with available CNV databases.…”

“…The fact is that aCGH currently remains a crude, albeit powerful, screening tool, and should be used as an adjunct to other molecular techniques. Although aCGH has definitely expedited the identification of novel amplicons and tumour suppressor genes, 57,58,91,97 this is only a step forward towards our understanding of the complexity of cancer. Indeed, the vogue is an integrative, systems biology approach 43,96 where results from aCGH, gene-expression analysis and functional assays are combined to develop models that facilitate the understanding of complex biological systems such as cancer, and can serve as a basis for hypothesis generation, testing, and validation.…”