GLI1 Co-Amplification in Well-differentiated/Dedifferentiated Liposarcomas: Clinicopathologic and Molecular Analysis of 92 Cases.

BACKGROUND:GLI1 (12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1 - a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 co-amplified WD/DDLPS. MATERIALS AND METHODS:The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next generation (IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 co-amplification. Clinicopathologic data was obtained from review of the medical chart and available histologic material. RESULTS:486 WD/DDLPS underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to MDM2 and CDK4. These included primary tumors (n=60), local recurrences (n=29), and metastases (n=3). Primary tumors were most frequently retroperitoneal (47/60,78%) mediastinal (4/60,7%), and paratesticular (3/60, 5%). Average age was 63 years with a male: female ratio of 3:2. The cohort was comprised by DDLPS (86/92 [93%], 6 of which were comprised by WDLPS with early dedifferentiation) , and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%%). A fifth (13/86,17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86, 30%),) and high-grade myxofibrosarcoma-like (13/86, 16%)) morphology. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%), and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was co-amplified with all three of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1 and ESR1, were also amplified in a subset of cases. CONCLUSIONS:In this large-scale cohort of GLI1 co-amplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorls and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and co-amplification of other spatially discrete genomic segments (1p, 6q) might aid in distinction from tumors with true driver GLI1 alterations.