Clinically Relevant Molecular Subtypes in Leiomyosarcoma

Abstract

Purpose Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 LMS, we identified three molecular subtypes in LMS. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts. Experimental Design 99 cases of LMS were expression profiled with 3′end RNA-Sequencing (3SEQ). Consensus Clustering was conducted to determine the optimal number of subtypes. Results We identified 3 LMS molecular subtypes and confirmed this finding by analyzing publically available data on 82 LMS from The Cancer Genome Atlas (TCGA). We identified two new FFPE tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I LMS and ARL4C for subtype II LMS. An LMS tissue microarray with known clinical outcome was used to show that subtype I LMS is associated with good outcome in extrauterine LMS while subtype II LMS is associated with poor prognosis in both uterine and extrauterine LMS. The LMS subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that LMS subtypes may respond differentially to these targeted therapies. Conclusion We confirm the existence of 3 molecular subtypes in LMS using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating LMS in a subtype-specific targeted approach.

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

“…Thus, our findings are consistent with prior reports of LMS having 3 mRNA expression subtypes, i.e. a mostly uterine type and two mostly soft tissue types with very different prognoses (Beck et al, 2010; Guo et al, 2015). …”

Molecular biomarkers for uterine leiomyosarcoma and endometrial stromal sarcoma

“…The other, which accounts for two‐thirds of STS, has a complicated karyotype, with instability of many genes and mutation of the TP53 gene that encodes p53 in many cases; u‐LMS is considered to belong to the latter group. Moreover, u‐LMS demonstrates complicated tumor development and pathology that differs from LMS originating from other sites due to the involvement of estrogen …”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…These transcriptomic classifications were later confirmed, refined (Ando, Suguro, Kobayashi, Seto, & Honda, 2003;Guedj et al, 2012;Hu et al, 2006;Loi et al, 2007;Mackay et al, 2011;Rosenwald et al, 2002;Sørlie et al, 2001), used in preclinical models to stratify clinical trials (Barton, Hawkes, Wotherspoon, & Cunningham, 2012), and inspired the discovery of clinically and biologically heterogeneous subgroups in many other malignancies, including colorectal cancer (Budinska et al, 2013;De Sousa E Melo et al, 2013;Marisa et al, 2013;Roepman et al, 2014;Sadanandam et al, 2013;Schlicker et al, 2012), renal cell carcinoma (Brannon et al, 2012(Brannon et al, , 2010, glioma (Nutt et al, 2003;Shai et al, 2003), liver (Boyault et al, 2007;Chiang et al, 2008;Hoshida et al, 2009;Lee et al, 2004), bladder (Biton et al, 2014), prostate (Tomlins et al, 2015), acute myeloid leukemia (de Jonge, Huls, & de Bont, 2011;Mrózek, Radmacher, Bloomfield, & Marcucci, 2009;Silva et al, 2009;Verhaak et al, 2009), and other cancers (Barlin et al, 2015;de Reyni es et al, 2014;Guo et al, 2015).…”