New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics.
Adult soft tissue sarcomas (STS) are rare tumours of mesenchymal lineage. Based on cytogenetic and comparative genomic hybridization (CGH) data, they can be divided into 'STS with simple genomics', displaying a characteristic genetic alteration, and 'STS with complex genomics' (SCG), where multiple genomic alterations occur. This latter group is mostly composed of leiomyosarcomas (LMS) and pleiomorphic undifferentiated tumours previously labelled as 'malignant fibrous histiocytomas' (MFH), corresponding in fact to myxofibrosarcomas (MFS), pleiomorphic liposarcomas/rhabdomyosarcomas (P-LPS, P-RMS), and undifferentiated pleiomorphic sarcomas (UPS). Their pathobiology is still not well understood, leading to challenges in diagnosis and therapeutic management. We report here a comprehensive study encompassing array-CGH and transcriptome analysis data of a large series of 160 SCG. Non-supervised clustering of transcriptome data led to the identification of five groups of tumours, one of them (group A) corresponding to well-differentiated LMS and the other four (B-E) to 'MFH' and poorly differentiated LMS. Welch analysis of transcriptome data in these groups allowed us to retrieve several genes of potential interest. Among them, RB1 alteration is a constant thread in SCG, often associated with RBL2 loss. PTEN tumour suppressor deletion would also stand out as a major recurrent event, especially in groups A, C, and D. The WNT canonical pathway could be potentially involved, as demonstrated by up-regulation of one of its inhibitors, DKK1, in groups D and E, whereas DKK1 is significantly down-regulated in groups A, B, and C. These data suggest a very complex interplay between pathways downstream of PTEN and the WNT canonical pathway, providing new hints about SCG pathobiology and their potential therapeutic targets.
Genetics and Biology of Cancers, Institut Curie, Paris, France.
Laure
L
Gibault
Gaëlle
G
Pérot
Frédéric
F
Chibon
Sarah
S
Bonnin
Pauline
P
Lagarde
Philippe
P
Terrier
Jean-Michel
JM
Coindre
Alain
A
Aurias
D000328:Adult; D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization / Q000379:methods; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling / Q000379:methods; D023281:Genomics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007890:Leiomyosarcoma / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D016160:Retinoblastoma Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human