Abstract
The Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder caused by inactivating germline mutations in the serine–threonine kinase gene LKB1, is characterized by mucocutaneous pigmentation, multiple gastrointestinal hamartomatous polyps, and by an increased risk for developing tumors involving several different organs. To date, no brain tumors have been described in PJS patients. In this report, we describe a case of ganglioglioma in a 22-year-old PJS patient. Single-strand conformation polymorphism-Heteroduplex analysis evidenced an abnormal pattern in exon 6 of the LKB1 gene. Sequencing revealed a 821delTinsAC mutation creating a termination codon 29 nucleotides downstream (p.Asn274fsX11). RNA studies showed an out-of-frame LKB1 isoform derived from the wild type allele and generated by exon 4 skipping. Since the LKB1 gene is expressed in the fetal and adult brain, our data would suggest its likely involvement in the pathogenesis of a subset of gangliogliomas.
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References
Blümcke I, Wiestler OD (2002) Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. J Neuropathol Exp Neurol 61:575–584
Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18:1533–1538
Entius MM, Keller JJ, Westerman AM, Van Rees BP, Van Velthuysen ML, de Goeij AF, Wilson JH, Giardiello FM, Offerhaus GJ (2001) Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J Clin Pathol 54:126–131
Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–187
Iborra FJ, Jackson DA, Cook PR (2001) Coupled transcription and translation within nuclei of mammalian cells. Science 29:1139–1142
Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M (1998) Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18:38–43
Kam R, Chen J, Blumcke I, Normann S, Fassunke J, Elger CE, Schramm J, Wiestler OD, Becker AJ (2004) The reelin pathway components disabled-1 and p35 in gangliogliomas—a mutation and expression analysis. Neuropathol Appl Neurobiol 30:225–232
Mehenni H, Lin-Marq N, Buchet-Poyau K, Reymond A, Collart MA, Picard D, Antonarakis SE (2005) LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum Mol Genet 14:2209–2219
Nelson JS, Bruner JM, Wiestler OD, Vandenberg SR (2000) Ganglioglioma and gangliocytoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics. Tumours of the nervous system. IARC Press, Lyon, pp 96–98
Parry L, Maynard JH, Patel A, Hodges AK, von Deimling A, Sampson JR, Cheadle JP (2000) Molecular analysis of the TSC1 and TSC2 tumour suppressor genes in sporadic glial and glioneuronal tumours. Hum Genet 107:350–356
Resta N, Simone C, Mareni C, Montera M, Gentile M, Susca F, Gristina R, Pozzi S, Bertario L, Bufo P, Carlomagno N, Ingrosso M, Rossini FP, Tenconi R, Guanti G (1998) STK11 mutations in Peutz-Jeghers syndrome and sporadic colon cancer. Cancer Res 58:4799–4801
Resta N, Stella A, Susca FC, Di Giacomo M, Forleo G, Miccolis I, Rossini FP, Genuardi M, Piepoli A, Grammatico P, Guanti G (2002) Two novel mutations and a new STK11/LKB1 gene isoform in Peutz-Jeghers patients. Hum Mutat 20:78–79
Spicer J, Ashworth A (2004) LKB1 kinase: master and commander of metabolism and polarity. Curr Biol 14:R383–R385
Trojan J, Brieger A, Raedle J, Esteller M, Zeuzem S (2000) 5′-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer. Gut 47:272–276
Yoo LI, Chung DC, Yuan J (2002) LKB1—a master tumour suppressor of the small intestine and beyond. Nat Rev Cancer 2:529–535
Zerbe LK, Pino I, Pio R, Cosper PF, Dwyer-Nield LD, Meyer AM, Port JD, Montuenga LM, Malkinson AM (2004). Relative amounts of antagonistic splicing factors, hnRNP A1 and ASF/SF2, change during neoplastic lung growth: implications for pre-mRNA processing. Mol Carcinog 41:87–96
Acknowledgments
The authors are grateful to Dr. Rosanna Bagnulo for her skilful technical assistance. This work is partially supported by Fondazione Cassa di Risparmio di Puglia “Progetto integrato per la salvaguardia della salute dell’uomo” and R.S. 2005.
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Resta, N., Lauriola, L., Puca, A. et al. Ganglioglioma arising in a Peutz-Jeghers patient: a case report with molecular implications. Acta Neuropathol 112, 106–111 (2006). https://doi.org/10.1007/s00401-006-0084-6
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DOI: https://doi.org/10.1007/s00401-006-0084-6