sarcomas and rhabdoid tumors - beshg · sarcomas and rhabdoid tumors ... sarcoma with specific...

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)


Characteristics


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)


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


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 ?


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


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


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)


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


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


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?


• 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

[email protected]

Merci !de DUVE

INSTITUTE

sarcomas and rhabdoid tumors - beshg · sarcomas and rhabdoid tumors ... sarcoma with specific...

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