Clayton R N, Pfeifer M, Atkinson A B, Belchetz P, Wass J A, Kyrodimou E, Vanderpump M, Simpson D, Bicknell J, Farrell W E
Centre for Cell and Molecular Medicine, School of Postgraduate Medicine, Keele University, Stoke on Trent, Staffordshire, United Kingdom.
Clin Cancer Res. 2000 Oct;6(10):3973-82.
Sporadic human pituitary tumors are benign adenomas of monoclonal origin. This implies that they arise from de novo somatic mutation(s) within a single pituitary cell. The availability of original and recurrent/regrown tumors from the same patient allowed testing of the prediction that recurrent/regrown tumors have identical genetic abnormalities as the original tumor sample. We used PCR amplification, from archival slide-extracted DNA, to allelotype microsatellite polymorphisms as an indication of clonality and confirmed this by X chromosome inactivation analysis in samples from women. Tumors from 33 of 49 (67%) patients with two or more specimens showed loss of heterozygosity (LOH) of at least one marker in at least one of their samples. Two patterns of LOH were observed. In pattern A in 14 of 33 (42%) of patients, the LOH pattern of the first tumor was preserved in the second recurrent sample, with some recurrent tumors also showing additional LOH. In these patients, the original and second tumors are presumed to arise from the same original clone with or without progressive accumulation of LOH. In pattern B [19 of 33 (58%) patients], LOH seen in the first tumor was not preserved in the second or subsequent tumors, as evidenced by retention of heterozygosity compared with the first tumor. The simplest explanation is that the second tumor, although still monoclonal, arises from another independently abnormal clone. This was confirmed by X chromosome inactivation analysis in all 11 women where this was informative. These results show that initial and recurrent tumors, of a benign tumor type, are frequently derived from separate independent clones. This suggests that either: (a) more than one abnormal clone is present from the outset though only one dominates; or (b) several clones arise independently at different times. In both scenarios, the initiating event(s) that predisposes to transformation might result in multiclonal hyperplasia, possibly as a consequence of exogenous stimulation.
散发性人类垂体瘤是单克隆起源的良性腺瘤。这意味着它们源于单个垂体细胞内的新生体细胞突变。同一患者的原发性肿瘤和复发/再生长肿瘤的获取，使得能够检验复发/再生长肿瘤与原发性肿瘤样本具有相同基因异常这一预测。我们使用从存档玻片提取的DNA进行PCR扩增，以等位基因分型微卫星多态性作为克隆性的指标，并通过对女性样本进行X染色体失活分析来证实这一点。49例有两个或更多标本的患者中，33例（67%）的肿瘤在其至少一个样本中显示至少一个标记的杂合性缺失（LOH）。观察到两种LOH模式。在33例患者中的14例（42%）呈现模式A，第一个肿瘤的LOH模式在第二个复发样本中得以保留，一些复发肿瘤还显示出额外的LOH。在这些患者中，原发性肿瘤和第二个肿瘤被推测源于同一个原始克隆，伴有或不伴有LOH的渐进性积累。在模式B [33例患者中的19例（58%）]中，第一个肿瘤中出现的LOH在第二个或后续肿瘤中未保留，与第一个肿瘤相比杂合性得以保留即可证明。最简单的解释是，第二个肿瘤虽然仍是单克隆的，但源于另一个独立异常的克隆。在所有11例有信息价值的女性中，通过X染色体失活分析证实了这一点。这些结果表明，良性肿瘤类型的初始肿瘤和复发肿瘤常常源自不同的独立克隆。这表明要么：（a）从一开始就存在不止一个异常克隆，尽管只有一个占主导；要么（b）几个克隆在不同时间独立出现。在这两种情况下，易引发转化的起始事件可能导致多克隆增生，这可能是外源性刺激的结果。
