Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15.
Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15.
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发表时间：
2003-03
期刊：
影响因子：
11.2
通讯作者：
B. Quade;S. Weremowicz;David M. Neskey;R. Vanni;C. Ladd;P. Dal Cin;C. Morton
中科院分区：
文献类型：
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作者：
B. Quade;S. Weremowicz;David M. Neskey;R. Vanni;C. Ladd;P. Dal Cin;C. Morton
子宫平滑肌瘤是几种良性肿瘤之一，其特征是涉及 12q15 的频繁染色体重排。平滑肌瘤中的 12q15 重排通常表现为 t(12;14)(q15;q23-24)，假设其产生源自 HMGA2 和 RAD51L1 的具有病理生物学意义的融合转录本。为了进一步探索这一假设，我们利用荧光原位杂交绘制了 38 个子宫平滑肌瘤中涉及 12q15 重排的染色体断点。大多数肿瘤 (n = 26) 含有 der(14)t(12;14)(q15;q23-24)，而 1、5、8 和 10 号染色体参与 6 个肌瘤中 12q15 的重排。另外 6 例有更复杂的重排，包括 12q15 或 14q23-24 以外的断点、12 号染色体倒位、12q15 插入 14 号染色体或额外的易位伙伴。 24 例和 9 例断点分别位于 HMGA2 基因座的 5'（着丝粒）或 3'（端粒）；一种肿瘤是具有 5' 或 3' 断点的细胞镶嵌体。在 6 个病例中发现了基因 5' 和 3' 区域侧翼的断点。通过 3' 快速扩增 cDNA 末端对一个肿瘤进行的分析显示，转录物发生了改变，其中 HMGA2 的外显子 1-3 异常剪接到 12 号染色体上的隐秘位点，或者通过 3' 非翻译区的一部分包含 HMGA2 完整编码序列的转录物与 14 号染色体的序列融合。对一组 10 个具有 t(12;14) 的子宫平滑肌瘤进行了专门测试融合转录本。未检测到 RAD51L1-HMGA2 转录本。然而，在四种肿瘤中检测到 HMGA2-RAD51L1 转录本；其中两个肿瘤在 HMGA2 的 3' 区域有不常见的重排，另外两个肿瘤有 5' 重排。尽管源自具有5'断点的肿瘤的融合转录物的机制尚不清楚，但这些发现表明融合转录物的形成并不是子宫平滑肌瘤的主要病理生物学机制。重排模式表明 HMGA2 表达失调，最常见的原因是 14 号染色体序列易位至该基因的 5'。
Uterine leiomyomata are one of several benign tumors characterized by frequent chromosomal rearrangement involving 12q15. The 12q15 rearrangement in leiomyomata typically is manifested as t(12;14)(q15;q23-24), which has been hypothesized to create pathobiologically significant fusion transcripts derived from HMGA2 and RAD51L1. To explore further this hypothesis, we mapped chromosomal breakpoints in 38 uterine leiomyomata with rearrangements involving 12q15 using fluorescence in situ hybridization. Most tumors (n = 26) harbored der(14)t(12;14)(q15;q23-24), whereas chromosomes 1, 5, 8, and 10 were involved in rearrangements with 12q15 in six myomas. An additional six cases had more complex rearrangements, including breakpoints other than 12q15 or 14q23-24, inversions of chromosome 12, insertions of 12q15 into chromosome 14, or additional translocation partners. Breakpoints were mapped either 5' (centromeric) or 3' (telomeric) in the HMGA2 locus in 24 and nine cases, respectively; one tumor was a mosaic of cells with either 5' or 3' breakpoints. Breakpoints flanking the gene in both 5' and 3' regions were found in six cases. Analysis of one tumor by 3' rapid amplification of cDNA ends showed altered transcripts in which either exons 1-3 of HMGA2 were aberrantly spliced to cryptic sites in chromosome 12 or transcripts encompassing the full coding sequence of HMGA2 through a portion of the 3' untranslated region were fused to sequence from chromosome 14. A panel of 10 uterine leiomyomata with t(12;14) was specifically tested for fusion transcripts. RAD51L1-HMGA2 transcripts were not detected. HMGA2-RAD51L1 transcripts, however, were detected in four tumors; two of these tumors had uncommon rearrangements in the 3' region of HMGA2 and two had 5' rearrangements. Although the mechanism of fusion transcripts derived from tumors with 5' breakpoints is unclear, these findings indicate that formation of a fusion transcript is not the principle pathobiological mechanism in uterine leiomyomata. The pattern of rearrangements suggests dysregulated expression of HMGA2, most often by translocation of chromosome 14 sequence 5' to this gene.