5/07/2018 1 MDM2 IN SOFT TISSUE AND BONE SARCOMAS Raf Sciot, M.D., PhD. Department of Pathology, University Hospitals Katholieke Universiteit Leuven, LEUVEN, Belgium NO CONFLICT OF INTERESTS WHAT IS MDM2? (MDMTWOMICS) MDM2 IN SARCOMAS? (MDMTWOMAS) MDM2MICS? n Murine Double Minute clone 2: oncogene in double minutes of spontaneously transformed mouse fibroblasts n 12q15 n Controls/blocks p53 activity: °p53: nucleus → cytoplasm, ubiquitination °inhibits p53 transactivation domain
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MDM2 IN SOFT TISSUE AND BONE SARCOMAS
Raf Sciot, M.D., PhD.Department of Pathology, University HospitalsKatholieke Universiteit Leuven, LEUVEN, Belgium
NO CONFLICT OF INTERESTS
WHAT IS MDM2? (MDMTWOMICS)
MDM2 IN SARCOMAS?(MDMTWOMAS)
MDM2MICS?
n Murine Double Minute clone 2: oncogene in double minutes of spontaneously transformedmouse fibroblasts
n Recurrence ≥ 40%n Metastasis: 15-30%n Correlation between grade and outcome?*
*Dantey K et al. Human Pathol 2017;66:86-92.
DEDIFFERENTIATED LIPOSARCOMA
n Giant markers/supernumerary ring chromosomes: 12q13-15 (MDM2, CDK4, HMGA2…)
n MDM2 immuno usually strongly +n 6p23, 1p32 (JUN!) co-amplification
*Barretina et al. Nat Genetics 2010;42:715-721.
Well differentiatedliposarcoma/atypical lipoma
12q amplification (MDM2, CDK4,…): low → high level
Dedifferentiated liposarcoma
12q amplification (MDM2, CDK4,…): high level
+JUN, YEATS4*
*
*
Male, 66 yrs, retroperitoneal tumor (35 cm)…
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Ring chromosome
Ring
FISHMDM2/12q15-BIOCDK4/12q14.1-DIG
…dod 3 yrs after resection: recurrences and inoperability
Male, 83 yrs, retroperitoneal tumor (26 cm)…
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MDM2
MDM2…dod 5 yrs after resection (inoperable recurrence)
Female, 58 yrs, retroperitoneal tumor…
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MDM2
MDM2…awd, inoperable recurrence after 3 yrs, chemotherapy
MDM2
Male, 52 yrs, tumor lower pole kidney: punction biopsy
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MDM2
FISH probes: MDM2-SO (red) + CEP12-SG (green) as a reference probe (coveringcentromeric region of chromosome 12)
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INTIMAL SARCOMA
n Very rare, adults with broad age rangen Wall of large blood vessels, proximal pulmonary
arteries most frequentn Most frequent primary cardiac sarcoma*n Very poor prognosis (embolic dissemination)n Histology very heterogeneous: spindly/anaplastic/
myxoid/sclerotic/osteoid…→ any weird looking intraluminal sarcoma: thinkintimal sarcoma!
*Neuville et al. Am J Surg Path 2014;38:461-469.
INTIMAL SARCOMA
n Amplification of 12q12-15: MDM2/CDK4n Amplification/activation of PDGFRα/KIT (4q12)