Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma
Prognostic significance of the MDM2/HMGA2 ratio and histological tumor grade in dedifferentiated liposarcoma
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DOI：
10.1002/gcc.22899
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发表时间：
2020-10-28
影响因子：
3.7
通讯作者：
Oda, Yoshinao
中科院分区：
文献类型：
--
作者：
Yamashita, Kyoko;Kohashi, Kenichi;Oda, Yoshinao
去分化脂肪肉瘤（DDLPS）是一种相对常见的软组织肉瘤，是由分化良好的脂肪肉瘤（WDLPS）进展引起的。本研究旨在探讨DDLPS的进展过程，并阐明与预后不良相关的病理和遗传因素。在32例DDLPS病例和5例WDLPS病例中，通过定制比较基因组杂交（CGH）阵列分析遗传因素，该阵列旨在密集覆盖已知在WD/DDLPS中频繁扩增的基因区域。比较原发性和转移性病变的分析以及比较同一肿瘤中组织学不同区域的分析揭示了肿瘤内遗传异质性和进展。根据预后良好组和预后不良组的预后分析，我们选择MDM 2和HMGA 2分别作为与预后不良和预后良好相关的候选基因。MDM 2和HMGA 2的扩增或增益水平的比值以对数比表示（log[MDM 2/HMGA 2] = log[MDM 2]-log[HMGA 2]）与预后显著相关。MDM 2的扩增或增益水平超过HMGA 2的两倍（MDM 2/HMGA 2> 2，log[MDM 2/HMGA 2] > 1）与OS差（P < .001）和无远处转移生存（DMFS）差（P < .001）密切相关。在44例DDLPS的病理分析中，组织学肿瘤分级、细胞浸润和MDM 2免疫反应性与总生存期（OS）相关，而HMGA 2免疫反应性倾向于与OS相关，细胞浸润也与DMFS相关。总之，组织学分级和MDM 2表达被确定为在病理学上重要的，并且通过定制CGH阵列分析发现MDM 2/HMGA 2扩增或增益比具有显著的预后价值。
Dedifferentiated liposarcoma (DDLPS) is a relatively common soft tissue sarcoma that results from the progression of well-differentiated liposarcoma (WDLPS). This study aimed to investigate the progression process and to clarify the pathological and genetic factors related to poor prognosis in DDLPS. In 32 DDLPS cases and five WDLPS cases, genetic factors were analyzed by custom comparative genomic hybridization (CGH) array, which was designed to densely cover gene regions known to be frequently amplified in WD/DDLPS. The analyses comparing primary and metastatic lesions and those comparing histologically different areas in the same tumor revealed intra-tumoral genetic heterogeneity and progression. According to a prognostic analysis comparing the good-prognosis and the poor-prognosis groups, we selected MDM2 and HMGA2 as candidate genes associated with poor and good prognosis, respectively. The ratios of the amplification or gain levels of MDM2 and HMGA2 expressed in log ratios (log[MDM2/HMGA2] = log[MDM2]-log[HMGA2]) were significantly associated with prognosis. An amplification or gain level of MDM2 that was more than twice that of HMGA2 (MDM2/HMGA2 > 2, log[MDM2/HMGA2] > 1) was strongly related to poor OS (P < .001) and poor distant metastasis-free survival (DMFS) (P < .001). In the pathological analysis of 44 cases of DDLPS, histological tumor grade, cellular atypia, and MDM2 immunoreactivity were related to overall survival (OS), while HMGA2 immunoreactivity tended to be associated with OS. Cellular atypia was also associated with DMFS. In conclusion, histological grade and MDM2 expression were determined to be prognostically important, and the MDM2/HMGA2 amplification or gain ratio was found to have significant prognostic value by the custom CGH array analysis.