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Genetic analysis of peripheral nerve sheath tumours in NF1 patients. Eline Beert Catholic University of Leuven Belgium. Aim of the study. To investigate the malignant transformation of a pre-existing (plexiform) neurofibroma towards an MPNST. Tumour samples in the study.
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Geneticanalysis of peripheralnervesheathtumoursin NF1 patients Eline Beert Catholic University of Leuven Belgium
Aim of the study To investigate the malignant transformation of a pre-existing (plexiform) neurofibroma towards an MPNST
Tumour samples in the study • (sub)cutaneous neurofibroma • isolated tumour in or under the skin • mostly asymptomatic • plexiform neurofibroma • spreads along a peripheral nerve • disfiguring, difficult to remove • atypical neurofibroma • symptomatic • painful, actively growing • increased glucose uptake (FDG-PET scan) • pathology • no mitoses ~ benign neurofibroma • BUT! hypercellular regions and atypical cells • MPNST • 8-13% life time risk • difficult to detect in early phase (→ bad prognosis if detected late) • metastasize often • five year survival of only 25%
Experimentalapproach • 33 NF1 patients → 52 PNSTs • 8 (sub)cutaneous neurofibromas • 7 plexiform neurofibromas • 11 atypical neurofibromas • 2 low grade MPNSTs • 2 intermediate grade MPNSTs • 22 high grade MPNSTs • genetic analysis • high resolution 244K oligonucleotide aCGH (Agilent Technologies) • CDKN2A (9p21.3) and TP53 (17p13.1) mutation analysis
244K oligonucleotideaCGH • 243 504 oligonucleotide probes • 60-mer • each spotted once • overall median probe spacing of 8,9 kb • average resolution of ± 10kb
ResultsaCGH: Chromosome 9 • 9p21.3 → CDKN2A • neurofibromas • → no deletion • atypical neurofibromas • → 10/11 deletion • (1 homozygous) • MPNSTs: • low grade • → 2/2 deletion • (1 homozygous) • intermediate grade • → 1/2 deletion • high grade • → 15/22 deletion • (10 homozygous) neurofibroma atypical neurofibroma high grade MPNST
ResultsaCGH: Chromosome 17 • 17p13.1 → TP53 • neurofibromas • → no deletion • atypical neurofibromas • → no deletion • MPNSTs: • low grade • → no deletion • intermediate grade • → 1/2 deletion • high grade • → 11/22 deletion neurofibroma atypical neurofibroma high grade MPNST
Conclusion • Signaling pathways possibly involved in malignant transformation • RB pathway • CDKN2A (p16INK4A), CDKN2B (p15), CDKN2C (p18) • CDK4/6 • RB1 • p53 pathway • CDKN2A (p14ARF) • MDM2 • TP53 • RTK/RAS and effector pathways • RTKs: EGFR, PDGFRA, MET • RAS/MAPK pathway • RAS/PI3K pathway (PIK3CA)
Conclusion • atypical neurofibromas → already multiple chromosomal aberrations • compared to high grade MPNST • smaller and less frequent deletions and duplications • in lower percentage of cells • role for inactivation of CDKN2A • no difference between atypical neurofibromas and low grade MPNSTs (! small sample size) • aCGH = a good tool to investigate genomic imbalances in tumours • if possible: detection and resection of atypical neurofibromas before further evolution
Acknowledgements • Prof. Dr. Eric Legius • Prof. Dr. Raf Sciot • Bruno Daniëls • Hilde Brems • Prof. Dr. Ivo De Wever • Prof. Dr. Frank Van Calenbergh • Prof. Dr. Maria Debiec-Rychter