Disruption of Imprinted Genes at Chromosome Region 11p15.5 in Paediatric Rhabdomyosarcoma

Abstract

Rhabdomyosarcomas are characterized by loss of heterozygosity (LOH) at chromosome region 11p15.5, a region known to contain several imprinted genes including insulin-like growth factor 2 (IGF2), H19, and p57(KIP2). We analyzed 48 primary tumour samples and found distinct genetic changes at 11p15.5 in alveolar and embryonal histological subtypes. LOH was a feature of embryonal tumours, but at a lower frequency than previous studies. Loss of imprinting (LOI) of the IGF2 gene was detected in 6 of 13 informative cases, all harbouring PAX3-FKHR or PAX7-FKHR fusion genes characteristic of alveolar histology. In contrast, H19 imprinting was maintained in 14 of 15 informative cases and the case with H19 LOI had maintenance of the IGF2 imprint indicating separate mechanisms controlling imprinting of IGF2 and H19. The adult promoter of IGF2, P1, was used in 5 of 14 tumours and its expression was unrelated to IGF2 imprinting status implying a further mechanism of altered IGF2 regulation. The putative tumour suppressor gene p57(KIP2) was expressed in 15 of 29 tumours and expression was unrelated to allele status. Moreover, in tumours with p57(KIP2) expression, there was no evidence for inactivating mutations, suggesting that p57(KIP2) is not a tumour suppressor in rhabdomyosarcoma.

Uncovering metabolism in rhabdomyosarcoma

“…To date, turning off the expression and/or activity of Pax3-Foxo1 represents one of the major milestones for researchers, and considerable results have been already obtained using targeted inhibitors which, destabilizing Pax3-Foxo1 oncoprotein, elicit tumor regression in xenograft and transgenic mouse models. [41][42][43] In fusion-negative RMS the genomic landscape is wider, and includes IGF-2 overexpression due to loss of heterozygosity (LOH) at 11p15.5, 40,44 mutations in genes that deliberately activate the RTK/RAS/PI3K signaling axis, 33,[45][46][47] such as plateletderived growth factor receptor A (PDGFRA), erb-b2 receptor tyrosine kinase 2 (ERBB2), FGFR4, and transducers like NRAS, KRAS and HRAS, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit a (PIK3CA); in addition, somatic mutations in cell cycle genes such as CTNNB1, FBXW7, BCOR 33 and p53, 48 and gain of chromosomes 2, 8 and 13 33,36 are frequently observed (Fig. 2).…”

“…34,35 Pax3-Foxo1 is found in 70% ARMS cases and is considered a strong predictor of poor prognosis, while fusion-negative ARMS have better resolution and are clinically and molecularly indistinguishable from the larger group of ERMS in the majority of patients. 36 Because of the ability of Pax3-Foxo1 to drive the transcription of genes like fibroblast growth factor receptor 4 (FGFR4) and insulin-like growth factor 2 (IGF-2), fusionpositive RMS are characterized by sustained activation of the RTK/RAS/phosphatidylinositol-3-kinase (PI3K) axis; 33 in addition, these tumors often carry high copy number of N-Myc gene [37][38][39] and exhibit IGF-2 overexpression due to loss of imprinting (LOI) at 11p15.5 locus 40 (Fig. 2).…”

Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas

“…In fact, imprinting is thought to play a role in the etiology of Hirschsprung's disease caused by mutations in the RET proto-oncogene (10q11.2). 34 Up to now, genomic imprinting in sarcomas has been reported in insulin-like growth factor 2 (IGF2; 11p15.5) in rhabdomyosarcomas 35 and Ewing tumors. 36 In the 10q region, genomic imprinting of FGFR2 has been reported in Apert syndrome.…”

PAX3-FKHR Induces Morphological Change and Enhances Cellular Proliferation and Invasion in Rhabdomyosarcoma

“…9 There are also molecular changes in common between the different histological subtypes, including disruption of the p53 pathway through mutation or mdm2 amplification, 10,11 and deregulation of imprinted genes at chromosome region 11p15.5. 12,13 Hence it is an attractive hypothesis that ERMS and ARMS represent distinct pathologies, rather than being part of a spectrum, and that the essential difference resides in the presence of the FKHR disrupting translocations. The implication is that both ERMS and ARMS are derived from cells committed to myogenic differentiation, but that PAX3-FKHR expression in ARMS results in the activation of an array of downstream transcriptional target genes that confer a distinct and more aggressive phenotype to ARMS tumors.…”