Whole-Genome Sequencing and Target Validation Analysis of Mullerian Adenosarcoma: A Tumor With Complex but Specific Genetic Alterations
Whole-Genome Sequencing and Target Validation Analysis of Mullerian Adenosarcoma: A Tumor With Complex but Specific Genetic Alterations
复制标题
DOI：
10.3389/fonc.2020.00538
复制
发表时间：
2020-04-15
影响因子：
4.7
通讯作者：
Wei, Jian-Jun
中科院分区：
文献类型：
--
作者：
Ban, Yanli;Fischer, Jean V.;Wei, Jian-Jun
缪勒氏腺肉瘤（MAS）是一种带有恶性间质的双相肿瘤。它最常见的起源是子宫内膜，但偶尔起源于子宫颈、卵巢或其他盆腔/腹膜部位。典型的MAS是低度的，临床病程为无痛；然而，肉瘤过度生长（SO）或高级别肉瘤的肿瘤往往具有侵袭性。肿瘤病因在很大程度上是未知的。为了更好地了解MAS的全球基因组改变和基因突变，我们进行了全基因组测序（WGS）和靶标验证分析。MAS表现出显著的染色体拷贝数变异（CNV），即chr 1q、5p、12p、12q和17q增加，chr 3p、3q、9p和11q减少。50%的病例中存在chr 12q13-15的增加。通过免疫组织化学检测，在增益区选择的基因产物上调。HMGA2过表达与SO显著相关。虽然结构变异（SV）率总体上相对较低，但在chr 7处发现了不成比例的高断裂率，涉及6个帧内重排融合基因。在WGS检测到的40个常见突变基因中，通过下一代测序（NGS）在29个MAS中验证，KMT2C和bor在患有和不患有SO的MAS中都很常见，而MAGEC1和KDM6B与SO密切相关。总的来说，有SO的MAS患者的频繁基因突变率（33%）高于没有SO的MAS患者（11%）。本研究揭示了这种恶性肿瘤的复杂和特定的遗传改变。这些发现为未来研究肿瘤发生和靶向治疗中的这些分子变化提供了工具。
Mullerian adenosarcoma (MAS) is a biphasic tumor with malignant stroma. It is most commonly of endometrial origin but occasionally originates in the cervix, ovary, or other pelvic/peritoneal sites. The typical MAS is low grade with an indolent clinical course; however, tumors with sarcomatous overgrowth (SO) or a high-grade sarcoma tend to be aggressive. Tumor etiology is largely unknown. To better understand the global genome alterations and gene mutations in MAS, whole-genome sequencing (WGS) and target validation analysis were performed. MAS showed remarkable chromosome (chr) copy number variation (CNV), specifically, gains in chr 1q, 5p, 12p, 12q, and 17q and losses in chr 3p, 3q, 9p, and 11q. Gain of chr 12q13-15 was present in 50% of cases. The selected gene products in gain regions were upregulated as measured by immunohistochemistry. HMGA2 overexpression was significantly correlated with SO. While the structural variation (SV) rate was relatively low overall, a disproportionally high rate of break-ends at chr 7 was noted involving 6 in-frame rearrangement fusion genes. Among 40 frequently mutated genes detected by WGS and validated in 29 MAS by next generation sequencing (NGS), KMT2C, and BCOR were frequently seen in MAS both with and without SO, while MAGEC1 and KDM6B were strongly associated with SO. Overall, a higher rate of frequently mutated genes was found in MAS with SO (33%) than MAS without (11%). This study uncovers the complex and specific genetic alterations in this malignancy. The findings provide a tool for future investigation of these molecular changes in tumorigenesis and target therapies.