Seemann N, Kuhn D, Wrocklage C, Keyvani K, Hackl W, Buchfelder M, Fahlbusch R, Paulus W
Institute of Neuropathology, University of Münster, Domagkstrasse 19, D-48129 Münster, Germany.
J Pathol. 2001 Apr;193(4):491-7. doi: 10.1002/path.833.
p16 (CDKN2A, MTS1, INK4A) status at genomic and protein levels was analysed and correlated with clinico-pathological features in 72 pituitary adenomas. Methylation of CpG islands of promoter/exon 1 sequences was found in most gonadotroph, lactotroph, plurihormonal, and null cell adenomas (36 of 44, 82%), but it was rare in somatotroph (1 of 13 cases, 8%) and corticotroph adenomas (1 of 15 cases, 7%). Homozygous CDKN2A deletion was restricted to rare somatotroph (15%) and corticotroph adenomas (13%). Immunohistochemical p16 protein expression was observed in the normal adenohypophysis, whereas it was absent in 60 of 72 (83%) tumours and reduced in another ten (14%) tumours. Staining for p16 was only seen in 5 of 15 (33%) corticotroph, 3 of 13 (23%) somatotroph, 3 of 5 (60%) plurihormonal, and 1 of 19 (5%) null cell adenomas. p16 immunonegativity without CDKN2A methylation or deletion occurred in 22 tumours, including most somatotroph and corticotroph adenomas (15 of 28, 54%). Both CDKN2A alterations and p16 negativity were related to larger tumour size. Patients with p16-negative tumours were older than patients with p16-positive tumours. These data suggest that p16 down-regulation is common in all adenoma types. The mechanisms of p16 down-regulation probably involve CDKN2A methylation in most types, but remain to be determined in somatotroph and corticotroph adenomas. These findings also suggest that p16 down-regulation is usually not an initial event, but is acquired during adenoma progression.
分析了72例垂体腺瘤中p16（CDKN2A、MTS1、INK4A）在基因组和蛋白质水平的状态，并将其与临床病理特征进行关联。在大多数促性腺激素细胞、催乳素细胞、多激素和无功能细胞腺瘤（44例中的36例，82%）中发现启动子/外显子1序列的CpG岛甲基化，但在生长激素细胞腺瘤（13例中的1例，8%）和促肾上腺皮质激素细胞腺瘤（15例中的1例，7%）中罕见。纯合性CDKN2A缺失仅限于罕见的生长激素细胞（15%）和促肾上腺皮质激素细胞腺瘤（13%）。免疫组化p16蛋白表达在正常腺垂体中可见，而在72例肿瘤中的60例（83%）中缺失，在另外10例（14%）肿瘤中减少。仅在15例促肾上腺皮质激素细胞腺瘤中的5例（33%）、13例生长激素细胞腺瘤中的3例（23%）、5例多激素腺瘤中的3例（60%）和19例无功能细胞腺瘤中的1例（5%）中见到p16染色。22例肿瘤中出现无CDKN2A甲基化或缺失的p16免疫阴性，包括大多数生长激素细胞和促肾上腺皮质激素细胞腺瘤（28例中的15例，54%）。CDKN2A改变和p16阴性均与肿瘤体积较大有关。p16阴性肿瘤患者比p16阳性肿瘤患者年龄更大。这些数据表明p16下调在所有腺瘤类型中都很常见。p16下调的机制在大多数类型中可能涉及CDKN2A甲基化，但在生长激素细胞和促肾上腺皮质激素细胞腺瘤中仍有待确定。这些发现还表明p16下调通常不是初始事件，而是在腺瘤进展过程中获得的。
