Genetic analysis of peripheral nerve sheath tumours in NF1 patients
description
Transcript of Genetic analysis of peripheral nerve sheath tumours in NF1 patients
Eline BeertCatholic University of Leuven
Belgium
To investigate the malignant transformation
of a pre-existing (plexiform) neurofibroma towards an MPNST
(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%
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
243 504 oligonucleotide probes 60-mer each spotted once
overall median probe spacing of 8,9 kb
average resolution of ± 10kb
neurofibroma atypical neurofibroma high grade MPNST
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)
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
8 (sub)cut. neurofibr.
7 plexif. neurofibr.
11 atyp. neurofibr.
MPNSTs
2 Low gr.
2 Int. gr.
22High gr.
CDKN2A
Deletion (homozyg.)
0/8 0/710/11 (1)
2/2 (1)
1/215/22 (10)
Mutation 0/8 0/7 0/11 1/2 0/2 1/22
TP53
Deletion (homozyg.)
0/8 0/7 0/11 0/2 1/211/22 (0)
Mutation 0/8 0/7 0/11 0/2 0/2 3/22
Chr.
Overlapping region
Atypical neurofibr.
MPNST Tumor-suppressorgenesLow gr. Int.
Gr.High gr.
1 1p33 0/11 0/2 1/2 12/22 CDKN2C
9 9pter-p24.1 4/11 1/2 1/2 14/22 ?
9p21.3 10/11 (1) 2/2 (1) 1/2 15/22 (10)
CDKN2A,CDKN2B
10 10p13-p11.1
2/11 0/2 2/2 14/22 (2) ?
10q23.31 0/11 0/2 1/2 9/22 PTEN
11 11q23.1-qter
1/11 0/2 1/2 16/22 (1)
?
13 13q14.2 1/11 0/2 2/2 8/22 RB1
17 17p13.3-p12
0/11 0/2 1/2 11/22 TP53
18 18p 0/11 0/2 0/2 13/22 ?
18q23 0/11 0/2 1/2 13/22 ?
20 20p12.2-p12.1
0/11 0/2 0/2 11/22 ?
22 22q11.22 0/11 0/2 0/2 11/22 ?
Chr. Overlapping region
Atypical neurofibr.
MPNST Oncogenes
Low gr. Int. Gr.
High gr.
3 3q26.32 0/11 0/2 0/2 5/22 PIK3CA
4 4q12 0/11 0/2 1/2 9/22 PDGFRA, KIT
7 7p11.2 0/11 0/2 0/2 15/22 EGFR
7q21.2 0/11 0/2 1/2 10/22 CDK6
7q31.2 0/11 0/2 1/2 14/22 MET
8 8q 1/11 0/2 0/2 18/22 MYC
12 12p13.32 0/11 0/2 0/2 10/22 CCND2
12q14.1 0/11 0/2 0/2 8/22 CDK4
12q15 1/11 0/2 0/2 10/22 MDM2
17 17q24.3-25.3
1/11 0/2 1/2 13/22 BIRC5
20 20q13.33 0/11 0/2 1/2 11/22 ?
Chr. Overlapping region
High grade MPNST
Oncogenes
4 4q12 5/22 PDGFRA, KIT
7 7p11.2 6/22 EGFR
8 8q24.21 9/22 MYC
12 12q15 6/22 MDM2
17 17q25.3 6/22 BIRC5
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)
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
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