Molecular Subtypes of Uterine Leiomyosarcoma and Correlation with Clinical Outcome

Abstract

The molecular etiology of uterine leiomyosarcoma (ULMS) is poorly understood, which accounts for the wide disparity in outcomes among women with this disease. We examined and compared the molecular profiles of ULMS and normal myometrium (NL) to identify clinically relevant molecular subtypes. Discovery cases included 29 NL and 23 ULMS specimens. RNA was hybridized to Affymetrix U133A 2.0 transcription microarrays. Differentially expressed genes and pathways were identified using standard methods. Fourteen NL and 44 ULMS independent archival samples were used for external validation. Molecular subgroups were correlated with clinical outcome. Pathway analyses of differentially expressed genes between ULMS and NL samples identified overrepresentation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes (P < 4.4 × 10− 4, Bonferroni corrected), with 84% of the overexpressed genes, including CDC7, CDC20, GTSE1, CCNA2, CCNB1, and CCNB2, participating in cell cycle regulation. Unsupervised clustering of ULMS identified two clades that were reproducibly associated with progression-free (median, 4.0 vs 26.0 months; P = .02; HR, 0.33) and overall (median, 18.2 vs 77.2 months; P = .04; HR, 0.33) survival. Cell cycle genes play a key role in ULMS sarcomagenesis, providing opportunities for therapeutic targeting. Reproducible molecular subtypes associated with clinical outcome may permit individualized adjuvant treatment after clinical trial validation.

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).…”

The role of adjuvant therapy in uterine leiomyosarcoma

“…If identified, these pathways could be exploited with targeted therapies that may offer improved survival advantage to our current regimens. A recent publication identified 19 significantly overexpressed genes in uLMS samples compared with normal leiomyoma controls [69]. Sixteen (84%) of the overexpressed genes included cell cycle associated genes ( CDC7 , CDC20 , GTSE1 , CCNA2 , CCNB1 , and CCNB2 ).…”

“…Sixteen (84%) of the overexpressed genes included cell cycle associated genes ( CDC7 , CDC20 , GTSE1 , CCNA2 , CCNB1 , and CCNB2 ). These data suggest that cell cycle control may play a key role in the pathogenesis of uLMS, and these agents may be used in the treatment of patients with this disease [69]. …”

Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways

“…However, these regions are very broad and contain many potential cancer driver genes. Recently, a few studies managed to perform transcriptome analyses in up to 50 uLMS patients, identifying expression‐based molecular subtypes of LMS that correlated with survival . Some genetic and transcriptome‐based studies also included extrauterine LMS (euLMS), which arise from smooth muscle cells located throughout the body with exclusion of the uterus .…”