Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers
Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers
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DOI：
10.1073/pnas.1518752113
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发表时间：
2016-02-02
影响因子：
11.1
通讯作者：
Aaltonen, Lauri A.
中科院分区：
文献类型：
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作者：
Mehine, Miika;Kaasinen, Eevi;Aaltonen, Lauri A.
子宫平滑肌瘤是一种常见的良性平滑肌肿瘤，对妇女的健康造成了很大的负担。最近的测序研究揭示了平滑肌瘤的复发性和互斥性突变，表明参与分子不同的途径。在这项研究中，我们探讨了具有不同遗传驱动因素的平滑肌瘤的转录差异，包括高迁移率组AT-hook 2 （HMGA2）重排、介质复合体亚基12 （MED12）突变、富马酸水合酶（FH）双等位基因失活、胶原型IV、α 5和胶原型IV、α 6 （COL4A5-COL4A6）缺失。我们还探讨了7q22、22q和1p缺失的转录后果，旨在确定可能的靶基因。我们使用外显子阵列、全基因组测序和SNP阵列研究了94个平滑肌瘤和60个相应的子宫肌瘤组织。这种综合方法揭示了关键驱动通路中亚型特异性表达的变化，包括Wnt/ β -连环蛋白、催乳素和胰岛素样生长因子（IGF） 1信号传导。HMGA2异常的平滑肌瘤显示出原癌基因多形性腺瘤基因1 （PLAG1）的高度显著上调，表明HMGA2通过激活PLAG1促进肿瘤发生。这一发现得到了遗传PLAG1改变的支持，这种改变导致了HMGA2畸变的平滑肌瘤的表达特征。HMGA2的优先易位伴侣RAD51 para B （RAD51B）在MED12突变病变中上调，提示该基因在平滑肌瘤的发生中起作用。fh缺陷平滑肌瘤的独特特征是核因子红系2相关因子2 （NRF2）靶基因的激活，这支持了富马酸积累导致致癌转录因子NRF2激活的假设。本研究强调了分子分层在平滑肌瘤研究以及可能在临床实践中的必要性。需要进一步的研究来确定本文提出的候选生物标志物是否可以为管理数百万受这些病变影响的患者提供指导。
Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women's health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions. We also explored the transcriptional consequences of 7q22, 22q, and 1p deletions, aiming to identify possible target genes. We investigated 94 leiomyomas and 60 corresponding myometrial tissues using exon arrays, whole genome sequencing, and SNP arrays. This integrative approach revealed subtype-specific expression changes in key driver pathways, including Wnt/beta-catenin, Prolactin, and insulin-like growth factor (IGF) 1 signaling. Leiomyomas with HMGA2 aberrations displayed highly significant up-regulation of the proto-oncogene pleomorphic adenoma gene 1 (PLAG1), suggesting that HMGA2 promotes tumorigenesis through PLAG1 activation. This was supported by the identification of genetic PLAG1 alterations resulting in expression signatures as seen in leiomyomas with HMGA2 aberrations. RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas. FH-deficient leiomyomas were uniquely characterized by activation of nuclear factor erythroid 2-related factor 2 (NRF2) target genes, supporting the hypothesis that accumulation of fumarate leads to activation of the oncogenic transcription factor NRF2. This study emphasizes the need for molecular stratification in leiomyoma research and possibly in clinical practice as well. Further research is needed to determine whether the candidate biomarkers presented herein can provide guidance for managing the millions of patients affected by these lesions.