Sobottka S B, Haase M, Fitze G, Hahn M, Schackert H K, Schackert G
Department of Neurosurgery, Technical University of Dresden, Germany.
J Neurooncol. 2000 Sep;49(3):187-95. doi: 10.1023/a:1006442024874.
Inactivating germline mutations of the novel putative tumor-suppressor gene LKB1/STK11 at 19p13.3 have been shown to cause Peutz-Jeghers syndrome (PJS), an autosomal dominantly inherited disease characterized by a predisposition to mucocutaneous pigmentations, as well as various benign and malignant neoplasms. To elucidate the role of LKB1/STK11 in the carcinogenesis of primary and secondary human brain tumors, a total of 309 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, DI9S878, and D19S565. Low LOH rates were observed for glioma (17.3%, n = 139), meningioma (5.3%, n = 57), schwannoma (0%, n = 21), pituitary adenoma (18.8%, n = 16), primary CNS lymphoma, neuroblastoma, plasmocytoma, medulloblastoma, germinoma, and papilloma of the choroid plexus (6.6%, n = 15). In contrast, brain metastases exhibited a mean LOH frequency of 42.6% (n = 61), with breast (56.3%) and lung cancer metastases (58.3%) being most frequently affected. Genomic DNA sequencing of the complete coding region of LKB1/STK11 was performed in all brain metastases exhibiting LOH (n = 26); no mutation was revealed, but we did find a germline mutation in a PJS patient. Despite high LOH fiequencies at the 19p13.3 locus in carcinoma metastases to the brain and occasional mutations reported for certain primary carcinomas, there are no mutations in LKB1/STK11. This fact suggests that alterations of LKB1/STK11 occur relatively early in tumorigenesis and are rarely involved in the development of carcinoma metastases. Based on these findings, the genes adjacent to LKB1/STK11 may be relevant for the development of metastases to the brain from certain carcinomas.
位于19p13.3的新型假定肿瘤抑制基因LKB1/STK11的种系失活突变已被证明会导致黑斑息肉综合征（PJS），这是一种常染色体显性遗传病，其特征为易患黏膜皮肤色素沉着以及各种良性和恶性肿瘤。为了阐明LKB1/STK11在原发性和继发性人脑肿瘤发生中的作用，对总共309个肿瘤进行了微卫星位点D19S886、DI9S878和D19S565的杂合性缺失（LOH）分析。胶质瘤（17.3%，n = 139）、脑膜瘤（5.3%，n = 57）、神经鞘瘤（0%，n = 21）、垂体腺瘤（18.8%，n = 16）、原发性中枢神经系统淋巴瘤、神经母细胞瘤、浆细胞瘤、髓母细胞瘤、生殖细胞瘤和脉络丛乳头状瘤（6.6%，n = 15）的LOH率较低。相比之下，脑转移瘤的平均LOH频率为42.6%（n = 61），其中乳腺癌转移瘤（56.3%）和肺癌转移瘤（58.3%）受影响最为频繁。对所有表现出LOH的脑转移瘤（n = 26）进行了LKB1/STK11完整编码区的基因组DNA测序；未发现突变，但我们在一名PJS患者中发现了一个种系突变。尽管癌转移至脑时19p13.3位点的LOH频率较高，且某些原发性癌偶尔有突变报道，但LKB1/STK11未发生突变。这一事实表明，LKB1/STK11的改变在肿瘤发生过程中相对较早出现，很少参与癌转移的发生。基于这些发现，与LKB1/STK11相邻的基因可能与某些癌转移至脑的发生有关。
