Hibberts N A, Simpson D J, Bicknell J E, Broome J C, Hoban P R, Clayton R N, Farrell W E
Centre for Cell and Molecular Medicine, School of Postgraduate Medicine, Keele University, North Staffordshire Hospital, Stoke on Trent, United Kingdom.
Clin Cancer Res. 1999 Aug;5(8):2133-9.
Cyclin D1 plays an important role in the regulation of cell progression through G1 of the cell cycle and has been demonstrated to have oncogenic properties. Using RFLP-PCR, an A/G polymorphism within the cyclin D1 (CCND1) gene was analyzed in 151 sporadic human pituitary tumors, of which 60 were informative at this locus. Further analysis showed that in 15 of 60 (25%) tumors, there was evidence of allelic imbalance, which is indicative of gene amplification. Allelic imbalance was observed more frequently in invasive tumors (11 of 29 tumors; 38%) than in their noninvasive counterparts (4 of 31 tumors; 13%; P = 0.02). Forty-six of the tumors informative for the polymorphism were available for immunohistochemical analysis. Cyclin D1 expression (nuclear and/or cytoplasmic) was detected in 25 of 46 (54%) tumors. Of these cases, expression of nuclear cyclin D1 was detected in 9 of 46 (20%) tumors, whereas 16 of 46 (35%) tumors showed cyclin D1 staining exclusively confined to the cytoplasm. Neither nuclear staining nor cytoplasmic staining was observed in any of the normal pituitaries or in the negative control. Expression of cyclin D1 was observed in significantly more nonfunctional tumors (18 of 27 tumors; 67%) than in somatotrophinomas (7 of 19 tumors; 37%; P = 0.046). Nuclear cyclin D1 expression was observed more frequently in nonfunctional tumors (8 of 27 tumors; 30%) than in somatotrophinomas (1 of 19 tumors; 5%; P = 0.04). There was no correlation between cyclin D1 expression and tumor grade or between allelic imbalance of CCND1 and cyclin D1 expression. We conclude that amplification of CCND1 occurs in pituitary tumors and that the overexpression of cyclin D1 may be an early event in tumorigenesis. Cyclin D1 overexpression occurring in the absence of CCND1 allelic imbalance suggests that additional mechanisms responsible for deregulated cyclin D1 expression are involved in human pituitary tumorigenesis.
细胞周期蛋白D1在调控细胞通过细胞周期的G1期进程中发挥重要作用，并且已被证明具有致癌特性。利用限制性片段长度多态性聚合酶链反应（RFLP-PCR），在151例散发性人类垂体瘤中分析了细胞周期蛋白D1（CCND1）基因内的A/G多态性，其中60例在该位点具有信息性。进一步分析表明，在60例肿瘤中的15例（25%）中，有等位基因失衡的证据，这表明基因扩增。等位基因失衡在侵袭性肿瘤（29例肿瘤中的11例；38%）中比在非侵袭性肿瘤（31例肿瘤中的4例；13%；P = 0.02）中更频繁地观察到。46例对该多态性具有信息性的肿瘤可用于免疫组织化学分析。在46例肿瘤中的25例（54%）中检测到细胞周期蛋白D1表达（核和/或细胞质）。在这些病例中，在46例肿瘤中的9例（20%）中检测到核细胞周期蛋白D1表达，而46例肿瘤中的16例（35%）显示细胞周期蛋白D1染色仅局限于细胞质。在任何正常垂体或阴性对照中均未观察到核染色或细胞质染色。在无功能肿瘤（27例肿瘤中的18例；67%）中观察到细胞周期蛋白D1表达明显多于生长激素瘤（19例肿瘤中的7例；37%；P = 0.046）。在无功能肿瘤（27例肿瘤中的8例；30%）中比在生长激素瘤（19例肿瘤中的1例；5%；P = 0.04）中更频繁地观察到核细胞周期蛋白D1表达。细胞周期蛋白D1表达与肿瘤分级之间或CCND1的等位基因失衡与细胞周期蛋白D1表达之间均无相关性。我们得出结论，CCND1在垂体瘤中发生扩增，并且细胞周期蛋白D1的过表达可能是肿瘤发生的早期事件。在不存在CCND1等位基因失衡的情况下发生的细胞周期蛋白D1过表达表明，负责细胞周期蛋白D1表达失调的其他机制参与了人类垂体瘤的发生。
