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Frequent Loss of Heterozygosity at the 19p13.3 Locus Without LKB1/STK11 Mutations in Human Carcinoma Metastases to the Brain

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Abstract

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/STK11in 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.

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Authors and Affiliations

  1. Department of Neurosurgery, Technical University of Dresden, Dresden, Germany

    Stephan B. Sobottka, Markus Haase & Gabriele Schackert

  2. Department of Pediatric Surgery, Technical University of Dresden, Dresden, Germany

    Guido Fitze

  3. Department of Surgical Research, Technical University of Dresden, Dresden, Germany

    Matthias Hahn & Hans K. Schackert

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  1. Stephan B. Sobottka
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Sobottka, S.B., Haase, M., Fitze, G. et al. Frequent Loss of Heterozygosity at the 19p13.3 Locus Without LKB1/STK11 Mutations in Human Carcinoma Metastases to the Brain. J Neurooncol 49, 187–195 (2000). https://doi.org/10.1023/A:1006442024874

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