New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics

Abstract

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.

From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas

“…13 This study allowed us to evidence frequent chromosome 10q deletions in sarcomas with complex genomics; we could also demonstrate that the tumor suppressor gene PTEN is significantly underexpressed in 10q-deleted tumors. This gene encodes a dual phosphatase protein that can inhibit AKT signaling, implicated in cell proliferation and resistance to apoptosis.…”

“…Non-supervised clustering analysis of transcriptomic data among these tumors mostly sorted out smooth muscle differentiation genes in well-differentiated leiomyosarcomas without any conspicuous difference between other histological subtypes. [9][10][11][12][13] These results would suggest common complex biological pathways in the oncogenesis of these tumors.…”

“…This series included the 167 tumor samples (T1 to T167) of our previous series, 13 plus 12 additional tumor samples (tumors A01 to A12), for which we had performed an array comparative genomic hybridization analysis, but did not have transcriptomic data. Frozen samples and paraffin blocks were obtained from Pathology Departments throughout France, Switzerland and Canada.…”

“…Histological typing, tumor grade and smooth muscle differentiation were assessed as previously described. 13 Two cell lines were also analyzed, derived from sarcomas with complex genomics samples as previously described. 19 LMS148L is derived from T165, a poorly differentiated leiomyosarcoma with myocardin amplification; S19L is derived from an undifferentiated pleomorphic sarcoma (tumor A05).…”

“…13 Total RNAs from tumor samples were analyzed on GeneCHIP Human Genome U133 Plus 2.0 Array (Affymetrix) and normalized as previously described. 13 Hierarchical clustering of tumors T1 to T167 was performed using dChip software (centroid linkage method, rank correlation distance metric, IQR ¼ 2).…”