title: Expression of subtype-specific group 1 leiomyosarcoma markers in a wide variety of sarcomas by gene expression analysis and immunohistochemistry.
abstract: Leiomyosarcomas (LMSs) constitute approximately one quarter of all sarcomas and are usually defined by morphologic criteria and/or immunoreactivity for actin or desmin. Among high-grade lesions, the distinction from undifferentiated pleomorphic sarcoma (UPS) can be problematic, and previous studies have shown that a significant number of LMS cases may be hiding under the diagnosis of UPS. We recently described 3 novel molecular LMS subtypes that are distributed similarly over LMSs of gyneocologic and non-gyneocologic origins. The group 1 subtype shows an improved disease-specific survival compared with the other 2 groups that is independent of histologic grade. Group 1 comprises approximately 25% of all LMSs, and is defined by a shared pattern of gene expression, a distinct pattern of genomic changes, and reactivity for at least 3 of 5 immunohistochemistry (IHC) markers (smooth muscle gamma actin, calsequestrin 2, human muscle cofilin2, myosin light chain kinase, and sarcolemmal membrane associated protein), as tested on 271 cases of LMS in tissue microarrays. These IHC markers have not been well characterized in non-LMS sarcomas. Here we provide a characterization of these 5 markers across normal tissues, an additional 59 cases of LMS, and a wide range of 565 non-LMS soft tissue tumors from 44 diagnostic categories, with a focus on UPS. When analyzed individually, the 5 markers were found to be expressed in many sarcomas other than LMSs. However, when analyzed by the same criteria used for the recognition of group 1 LMSs, in which a case is scored positive when at least 3 of 5 markers reacted, coordinate expression was seen in significant numbers of cases from only 3 diagnostic groups that included 22% of leiomyomas (n=22), 16% of gastrointestinal stromal tumors (n=43), and 18% of endometrial stromal sarcomas (n=11). In addition, 5% (n=57) of UPSs showed a staining pattern similar to that seen in group 1 LMSs. To further examine the possibility that group 1 LMS constitutes a small part of cases diagnosed as UPS, we examined the expression of the top 500 genes from the group 1 LMS expression signature in 29 UPSs by complementary DNA microarray. Unsupervised hierarchical clustering of 29 UPS expression showed that 2 (7%) had coordinated high levels of expression of genes from the group 1 LMS signature, a rate similar to that seen by IHC analysis. These findings show that group 1 LMS IHC markers smooth muscle gamma actin, calsequestrin 2, human muscle cofilin2, myosin light chain kinase, and sarcolemmal membrane associated protein when coordinately expressed have specificity for a subset of LMS when compared with other sarcomas, and may be useful for the recognition of group 1 LMS cases within cases diagnosed as UPS.
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, CA, USA. AnneMills1@gmail.com
authors.forename: Anne M
authors.initials: AM
authors.lastname: Mills
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.forename: Kelli D
authors.initials: KD
authors.lastname: Montgomery
authors.forename: Shirley X
authors.initials: SX
authors.lastname: Zhu
authors.forename: Inigo
authors.initials: I
authors.lastname: Espinosa
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D003937:Diagnosis, Differential; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007890:Leiomyosarcoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D018203:Sarcoma, Endometrial Stromal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm