SARCOMAS and RHABDOID TUMORS Professor Hélène Antoine-Poirel, MD, PhD Center for Human Genetics INTERUNIVERSITY CERTIFICATE IN HUMAN GENETICS Université catholique de Louvain Brussels,19/02/2016 de DUVE INSTITUTE
SARCOMAS and
RHABDOID TUMORS
Professor Hélène Antoine-Poirel, MD, PhD
Center for Human Genetics
INTERUNIVERSITY CERTIFICATE IN HUMAN GENETICS
Université catholique de LouvainBrussels,19/02/2016
de DUVEINSTITUTE
Sarcomas
• I - Introduction
• II – Specific translocation
• III- Simple genomic amplification
• IV- Complex & specific genetic anomalies
• V – Activating mutations
Rhabdoid tumors
• VI – Inactivating mutations
SARCOMAS I. Introduction
Malignant tumour of the connective tissue
• 1-2% cancers
• Incidence : 6/100 000 hab / yr
• Localisation : • Soft Tissue (60%)
– Limb, trunk, abdomen, head & neck (Liposarcomas, rhabdomyosarcomas, poorly
differentiated sarcomas,…)
• Viscera (30%)
– Digestive tract (GIST)
– Uterus (leiomyosarcoma)
– Other viscera
• Bone (10%)
– Limb bones (osteosarcomas, Ewing)
– Spine, pelvis (chondrosarcoma)
SARCOMAS I. Introduction
Characteristics
SARCOMAS I. Introduction
2012 WHO Classification
• Phenotypic characteristics :
– Morphology
– Immunohistochemistry
• Genetic anomalies :
– Specific translocations : 10-15%
– Simple genomic amplification : 10-15%
– Complex & non specific genetic anomalies : 50-60%
– Activating mutations : 20%
• 15-20% of soft tissue sarcomas
• Young patient
• Frequently aggressive tumors
• Small monomorphic cells
SARCOMAS II.
Sarcomas with specific translocation
SARCOMAS II.
Sarcomas with specific translocation
• Child/young adult
• Bone tumors (> Soft tissue in adult)
• Small round blue cell sarcoma, with varying degrees of
neurectodermal differentiation, CD99+
CD99
SARCOMAS II. Sarcoma with specific translocation
Ex : Ewing Sarcoma
48,XY,+8,t(11;22)(q24;q12),+12[5]
EWSR1(22q12)
Ewing sarcoma/PNET FLI-1 (11q24)
SARCOMAS II. Sarcoma with specific translocation
Ex : Ewing Sarcoma
Chimeric protein � neo-oncogene with transforming properties
EWSR1(22q12)
Ewing sarcoma/PNET FLI-1 (11q24) 85% bone (soft tissue)
ERG (21q22) 10%
FEV (2q33)ETV1 (7p22) soft tissue
E1AF/ETV4 (17q12) soft tissue
Other partner genes of EWSR1 in the Ewing sarcoma :
ETS family of transcription factors
~ similar functional consequences
SARCOMAS II. Sarcoma with specific translocation
Ex : Ewing Sarcoma
• Spectre of lesions initially reported separatly � EWSR1 fusion gene– Ewing sarcoma
– Askin tumor (chest wall)
– Extra-skeletic Ewing sarcoma
– Peripheral neuroepithelioma
� Peripheral primitive NeuroEctodermal Tumor / Ewing Sarcoma Family(PNET/ESFT)
variation in the level of neurectodermal differentiation
undifferentiated form : differentiated form :
Ewing sarcoma peripheral neuroepithelioma
• Cell of origin : neural crest cells ?
SARCOMAS II. Sarcoma with specific translocation
Ex : Ewing Sarcoma
• No prognostic impact of the different fusion transcripts (RT-PCR)
Le Deley M et al. JCO 2010
EF1 : EWSR1-FLI1 type 1
EF2 : EWSR1-FLI1 type 2
EE : EWSR1-ERG
EFX : EWSR1-Other
SARCOMAS II. Sarcoma with specific translocation
Ex : Ewing Sarcoma : prognosis
• Prognostic significance of bone marrow (BM) micrometastasis and circulating tumor cells (PB), especially in clinically localized tumors
Schleiermacher G et al. JCO 2003
All patients Localized tumors
SARCOMAS II. Sarcoma with specific translocation
Ex : Ewing Sarcoma : Minimal Disseminated Disease
EWSR1(22q12)
NFATC2 (20q13)
Ewing sarcoma/PNET
CIZ/NMP4 (17p13)
Small round cell sarcoma
Desmoplastic small round cell tumour
WT1 (11p13)
Clear cell soft tissue sarcoma
ATF1 (12q13)
Extraskeletal myxoid chondrosarcoma
NR4A3 (9q22)
Angiomatoid fibrous histiocytoma
Embryonal rhabdomyosarcoma
DUX4 (4q35)
Myxoid liposarcoma
DDIT3 (12q13)
Myoepithelioma / Soft tissue myoepithelial carcinoma PBX1(1q23)
ZNF444 (19q13)
Mucoepidermoid carcinoma of the salivary glands
Hydradenoma of the skin
Acute lymphoblastic leukemia
ZNF384 (12p12)
Small cell osteosarcoma
Low-grade fibromyxoid sarcomaSclerosing epithelioid sarcoma
Hemangioma of the bone
CREB3L1 (11p11)
NFATC1 (18q23)
Ewing-like sarcoma/ undifferentiated small round cells sarcoma
FLI-1 (11q24) 85%ERG (21q22) 10%FEV (2q33)ETV1 (7p22)ETV4 (17q12)SP3 (2q31)
VQCRH (1p34)
PATZ1 (22q12)
POU5F1 (6p21)
CREB1 (2q33)
SMARCA5 (4q31)
Mesothelioma
YY1 (14q23)
Primary pulmonary myxoid sarcoma
Angiosarcoma
Hyalinising clear cell carcinoma of salivary gland
CREB3L2 (7q32-34)
PBX3 (9q33)KLF17(1p34)
SARCOMAS II. Sarcoma with specific translocation
Differential diagnosis of tumours with EWSR1 Rgt
HELP !
SARCOMAS III. Sarcoma with simple genomic amplification
Well differentiated / Dedifferentiated liposarcoma
Atypical lipomatous tumour/
Well differentiated liposarcoma Dedifferentiated liposarcoma
2 different morphological aspects
• 10 - 15 % sarcomas
• Location : deep limbs, retro-peritoneal (60% sarcomas)
Same genomic alteration
MDM2/CEN12
MDM2
TP53
S
M
G1
G2..
SARCOMAS III. Sarcoma with simple genomic amplification
Well differentiated / Dedifferentiated liposarcoma Giant chromosome with HSR / Rings
MDM2/12q14.3q15 amplification (+- CDK4 : 90%)
• Most common primary high-grade sarcoma of the skeleton
• Bimodal distribution : children, older adults
• Complex aneuploid karyotypes
• Multiple numerical & structural chromosomal aberrations
– Amplification 6p (40-50%), 8q /MYC (45-55%)
– RB / 13q14 inactivation (35%) *
– TP53 / 17p13 inactivation (40%) **
– Amplification 12q / MDM2 (10%) = low grade central osteosarcoma
– Deletion CDKN2A / 9p21 (15%)
• Transition low grade to high grade :
– polyploidy with structural alterations
• Inherited predisposition :
* Hereditary Retinoblastoma (RB/13q14)
** Li-Fraumeni syndrome (TP53/17p13)
SARCOMAS IV. Complex and non specific genetic alterations
Osteosarcomas
• Adult > 50 yr
• Frequently « pleomorphic »
• Aggressive tumors, metastasis (50%)
• Transition low grade to high grade :
– polyploidy with structural alterations
SARCOMAS IV. Complex and non specific genetic alterations
Poorly differentiated sarcomas
Exon 9 : 18%
Exon 11 : 67%Exon 13-14 : 2%
Exon 17-18 : 2%
Exon 12 : 1%
Exon 18 : 4%
KIT (89%) PDGFRA (5%)
• Constitutive activation of the tyrosine kinase receptors
• Targeted treatment (Tyrosin kinase inhibitor Imatinib / Glivec) :
adjuvant to surgery
SARCOMAS V. Activating mutations
Gastro-intestinal tumour (GIST)
• Most common mesenchymal tumor in the gastrointestinal tract
• Mutually exclusive mutations in KIT or PDGFRA genes
MALIGNANT RHABDOID TUMORS VI. Inactivation mutations
Recent & expanding entity• 1978 : malignant rhabdoid tumors
= separate morphological entity of renal tumours (≠ Wilms tumor)
close histological resemblance to rhabdomyoblasts (later not confirmed)
• 1994 : extrarenal locations : central nervous system (CNS), soft tissue Difficult classification :
– high variation in the histologic and immunologic characteristics
– variable rhabdoid cell component (hallmark cells) : few isolated to ~100%
– tumor spectrum extended to choroid plexus carcinoma, schwannomatosis, cribriform
neuroepithelial tumor of the ventricle
Xiaofeng Wang et al. Clin Cancer Res 2014
MALIGNANT RHABDOID TUMORS VI. Inactivation mutations
SWI/SNF complex• 1998 : bi-allelic inactivation of SMARCB1/22q11
∈ chromatin remodeling complex (SWI/SNF)
• 5% rhabdoid tumours : no SMARCB1 mutations
• 2010 : bi-allelic inactivation of SMARCA4/19p13
• Remarkably stable genome :
– Paucity of other additional / recurrent genetic aberrations
– lowest rate of base variations reported in all sequenced cancer types
• Early age of onset (< 3 yr-old), but also adult patients
• Highly aggressive
– High metastatic potential, poor survival rates : ~30% at 1 yr
– Prognostic factors : tumor stage, age at presentation
– No correlation genotype - phenotype
• Inherited predisposition
– Germline mutations in SMARCB1 ~35 – 50% of children with rhabdoid tumours
• higher frequency (up to 60%) in younger children (< 6months at diagnosis)
• more extensive disease, multi-site disease
– Germline mutations in SMARCA4 :~50% ?
– worse prognosis ?
– The majority of germline mutations appear de novo
– Gonadal mosaicism may account for familial cases with incomplete penetrance
MALIGNANT RHABDOID TUMORS VI. Inactivation mutations
Underestimated entity crucial to diagnose
� In practice :1. Screening by IHC on tumor : SMARCB1/INI1 or SMARCA4/BRG1 � loss of expression?
2. Genetic analysis on tumoral DNA : sequencing + MLPA � bi-allelic aberration?
3. Genetic analysis on blood DNA �germline mutation?
MALIGNANT RHABDOID TUMORS VI. Inactivation mutations
• Inactivation mutation in adult tumors (mainly somatic) :
– SMARCB1 : epithelioid sarcomas, epithelioid malignant peripheral nerve sheath
tumours, extraskeletal myxoid carcinoma, renal medullary carcinoma, myoepithelial
carcinoma, chordoma, meningioma,…
– SMARCA4 :
• small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) (2014)
(somatic & germline mutations)
• new category of 'SMARCA4-deficient thoracic sarcomas' (2015)
• Cell of origin ?
2 possible scenarii of pathogenesis of SMARCB1-deficient neoplasia :
1/ primary genetic event in (yet unidentified) progenitor cells existing only during fetal
development
� Children, few genomic mutations, highly reproducible diagnosis = « rhabdoid tumor »
2/ secondary genetic event in epithelial organs : shift from a differentiated carcinoma to a
predominantly undifferentiated « rhabdoid » phenotype = « rhabdoid carcinomas »:
� Adults, complex pattern of genomic mutations = « SMARCB1-deficient tumor »
Enigmatic tumour
GENETICS OF ACQUIRED CANCERS : CONCLUSION
• Better understanding of oncogenesis
• Useful for the clinical management of patients :
� Diagnosis
� Prognosis
� MDD, MRD
� Treatment
• NGS :
� Intra-tumoral heterogeneity
� New prognostic biomarkers
� New therapeutic targets