Genetic Profiling Identifies Two Classes of Soft-Tissue Leiomyosarcomas with Distinct Clinical Characteristics

Abstract

Purpose: Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited.Experimental Design: From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases.Results: Median age was 59 years (range, 21-98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59-67]. On multivariate analysis, age ! 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome.Conclusion: Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients.

Smooth muscle differentiation identifies two classes of poorly differentiated pleomorphic sarcomas with distinct outcome

“…In the Italiano et al 17 study, leiomyosarcomas were diagnosed according to histologic features that could explain this discrepancy. 17 According to our analysis, their group of leiomyosarcomas of the extremities could probably be in reality heterogeneous and could regroup both undifferentiated pleomorphic sarcomas and leiomyosarcomas. This heterogeneity could at least in part explain the two different biologies that the authors observed between their two leiomyosarcomas groups from different locations.…”

“…The authors also studied the genomic profiles of leiomyosarcomas and showed that 43% of leiomyosarcomas presented a 'complex/arm-type' profile and 57% a 'complex/rearranged-type' profile. 17 Moreover, a significant correlation was observed between the genomic profile and the tumor location, as 69% of tumors with an 'complex/arm-type' profile were internal trunk tumors, whereas 76% of 'complex/ rearranged-type' tumors were located in the extremities. Concerning the association between the genomic profile type and tumor location, our results are consistent with these findings (a majority of internal trunk tumors in the 'complex/arm-type' group: 61% for scoring leiomyosarcomas and 57% for equally classified leiomyosarcomas, and a majority of tumors of the extremities in the 'complex/ rearranged-type' group: 67% for scoring leiomyosarcomas and 90% for equally classified leiomyosarcomas).…”

“…17 The retroperitoneal leiomyosarcomas group was characterized by a higher risk of metastatic relapse and a distinct genomic and expression profile compared with other leiomyosarcomas.…”

“…It was not possible to perform expression profiles or genomic profiles comparisons in the present series as the scoring leiomyosarcomas group was too small to obtain statistically relevant results. However, Italiano et al 17 also show that the retroperitoneal leiomyosarcomas group was characterized by a higher risk of metastatic relapse so we have compared metastastic outcome of tumors classified by histological classification or by smooth muscle differentiation according to tumor location. In our study, whatever the classification used, no significant association between location and outcome was observed (data not shown).…”

“…These results are also in line with those previously published, which have shown that muscle differentiation pathways are over-represented in metastatic leiomyosarcomas versus non-metastatic leiomyosarcomas, reflecting the implication of smooth muscle differentiation in the metastasis process. 17 However, the role of smooth muscle proteins in tumor oncogenesis and invasion is still controversial. h-CD and calponin were described as tumor suppressor genes and migration inhibitors, 19,20 while transgelin seemed to be a potent inducer of tumor invasion 21 such as the LPP protein, [22][23][24] which is overexpressed in leiomyosarcomas and whose expression was induced by MYOCD overexpression.…”