Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain.
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.
Sobottka
S B
SB
Department of Neurosurgery, Technical University of Dresden, Germany. sobottka@rcs.urz.tu-dresden.de
Haase
M
M
Fitze
G
G
Hahn
M
M
Schackert
H K
HK
Schackert
G
G
D000091162:AMP-Activated Protein Kinase Kinases; D001483:Base Sequence / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases