背景:GLI1(12q13.3)扩增在具有不同嵌套圆形细胞/上皮样表型的间充质肿瘤的一个子集中被鉴定。MDM2和CDK4基因位于致癌的12q13-15片段,其扩增定义了高分化(WDLPS)/去分化脂肪肉瘤(DDLPS)。12q扩增子偶尔可以包括GLI1-与CDK4紧密接近的基因。我们在此描述第一组GLI1/MDM2/CDK4共扩增的WD/DDLPS。
方法:回顾性查询部门数据库中的所有WD/DDLPS病例,这些病例经过了经证实的MDM2、CDK4和GLI1共扩增的下一代(IMPACT)测序。临床病理数据是从医学图表和可用的组织学材料的回顾中获得的。
结果:486WD/DDLPS进行了DNA测序,92(19%),除MDM2和CDK4外,还具有GLI1基因座的扩增。这些包括原发性肿瘤(n=60),局部复发(n=29),和转移(n=3)。原发肿瘤多见于腹膜后(47/60,78%)纵隔(4/60,7%),和睾丸旁(3/60,5%)。平均年龄为63岁,男女比例为3:2。该队列由DDLPS组成(86/92[93%],其中6个由早期去分化的WDLPS组成),和WDLPS无任何去分化的纵向证据(6/92,7%)。五分之一(13/86,17%)的DDLPS病例在任何原发性,经常性,或转移标本。去分化区多表现为高级别未分化多形性肉瘤样(26/86,30%),)和高级黏液纤维肉瘤样(13/86,16%)形态。在16/86(19%)中,有/没有骨化生的脑膜上皮螺纹的发生率不成比例地增加是主要模式。在总共10/86(12%)的肿瘤中鉴定出如上所述的GLI1改变的形态。JUN(1p32.1),也涉及WD/DDLPS的发病机制,在7/91(8%)的病例中,与所有三个MDM2,CDK4和GLI1共同扩增。沿着染色体臂1p和6q的额外基因座,包括TNFAIP3,LATS1和ESR1在内的亚组病例也有扩增.
结论:在GLI1共扩增WD/DDLPS的大规模队列中,我们阐明了独特的复发特征,包括去分化区的脑膜上皮螺纹和GLI改变的形态。评估肿瘤位置(腹膜后或纵隔),鉴定分化良好的脂肪肉瘤成分,和其他空间离散基因组片段的共扩增(1p,6q)可能有助于区分具有真正驱动GLI1改变的肿瘤。
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 liposarcoma (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 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of 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 of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-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%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, 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 coamplified with all 3 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. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.