Blastemal expression of type I insulin-like growth factor receptor in Wilms' tumors is driven by increased copy number and correlates with relapse.
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.
Natrajan
Rachael
R
Paediatric Oncology, Institute of Cancer Research/Royal Marsden National Health Service Trust, Sutton, UK.
Reis-Filho
Jorge S
JS
Little
Suzanne E
SE
Messahel
Boo
B
Brundler
Marie-Anne
MA
Dome
Jeffrey S
JS
Grundy
Paul E
PE
Vujanic
Gordan M
GM
Pritchard-Jones
Kathy
K
Jones
Chris
C
D002467:Cell Nucleus / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D017404:In Situ Hybridization, Fluorescence / Q000379:methods / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009364:Neoplasm Recurrence, Local; D009693:Nucleic Acid Hybridization / Q000379:methods; D011379:Prognosis; D016016:Proportional Hazards Models; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D017526:Receptor, IGF Type 1