Serguienko Anastassia, Braadland Peder, Meza-Zepeda Leonardo A, Bjerkehagen Bodil, Myklebost Ola
1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Ullernchausséen 70, 0379 Oslo, Norway.
2Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Ullernchausséen 70, 0379 Oslo, Norway.
Clin Sarcoma Res. 2020 Mar 5;10:4. doi: 10.1186/s13569-020-0126-1. eCollection 2020.
Well- and dedifferentiated liposarcoma (WD/DDLPS) are rare mesenchymal malignant tumors that account for 20% of all sarcomas in adults. The WD form is a low-grade malignancy with a favourable prognosis which may progress to DDLPS, a high-grade aggressive counterpart. WDLPS is referred to as atypical lipomatous tumour (ALT) when localised in extremities, due to its better prognosis. Currently the final differential diagnosis to distinguish between more aggressive and less aggressive form is based on post-surgical histological examination and no molecular biomarkers for early detection are available.
Quantitative polymerase chain reaction (qPCR) analysis of 11 metabolic genes involved in general and adipose tissue-specific metabolism, was performed on ALT (= 8), WDLPS (= 9) and DDLPS (= 20) samples. Subsequent statistical analysis was carried out to determine genes that most accurately can predict DDLPS differential diagnosis. Selected genes were further validated in a separate cohort by qPCR and the data statistically analysed. Deep sequencing was performed on DDLPS specimen from the metastatic patient and on five random WDLPS specimens.
We established a three-gene signature based on and , which identified DDLPS with 100% sensitivity and 90% specificity, even in specimens from the WD component of DDLPS tumors. Interestingly, the gene is deleted in 45% of DDLPS samples analyzed under TCGA project, and the deletion is associated with significantly lower expression level. However, other mechanisms causing loss or downregulation of the expression of these three genes may be involved. Moreover, the significantly lower level of PNPLA2 is associated with R1 surgical margins, compare to R0 margins, which suggests the more invasive tumor phenotype in the absence of PNPLA2.
The identified metabolic signature allows highly accurate differential diagnosis between WD- and DDLPS even in samples containing lipid droplets, a marker of differentiation, which makes it very suitable for the use on biopsies. In respect to the pathogenesis of the disease, our results give a new insight into possible molecular mechanisms involved and support the recent observation that deletion of is a novel factor in liposarcoma progression.
高分化和去分化脂肪肉瘤（WD/DDLPS）是罕见的间叶性恶性肿瘤，占成人所有肉瘤的20%。WD型为低级别恶性肿瘤，预后良好，可能进展为DDLPS，即高级别侵袭性肿瘤。当WDLPS位于四肢时，由于其预后较好，被称为非典型脂肪瘤性肿瘤（ALT）。目前，区分侵袭性较强和较弱形式的最终鉴别诊断基于术后组织学检查，尚无用于早期检测的分子生物标志物。
对ALT（=8）、WDLPS（=9）和DDLPS（=20）样本进行了涉及一般和脂肪组织特异性代谢的11个代谢基因的定量聚合酶链反应（qPCR）分析。随后进行统计分析，以确定最能准确预测DDLPS鉴别诊断的基因。通过qPCR在一个独立队列中对选定基因进行进一步验证，并对数据进行统计分析。对来自转移患者的DDLPS标本和五个随机的WDLPS标本进行深度测序。
我们基于[具体基因1]和[具体基因2]建立了一个三基因特征，该特征对DDLPS的识别敏感性为100%，特异性为90%，即使在DDLPS肿瘤的WD成分标本中也是如此。有趣的是，在TCGA项目分析的45%的DDLPS样本中，[具体基因3]基因缺失，且该缺失与[具体基因3]表达水平显著降低相关。然而，可能涉及导致这三个基因表达缺失或下调的其他机制。此外，与R0切缘相比，PNPLA2水平显著降低与R1手术切缘相关，这表明在缺乏PNPLA2的情况下肿瘤表型更具侵袭性。
所确定的代谢特征即使在含有脂滴（一种分化标志物）的样本中也能对WD-和DDLPS进行高度准确的鉴别诊断，这使其非常适合用于活检。关于该疾病的发病机制，我们的结果为可能涉及的分子机制提供了新的见解，并支持了最近的观察结果，即[具体基因3]的缺失是脂肪肉瘤进展的一个新因素。
