Molecular insights into Peutz-Jeghers syndrome: two probands with a germline mutation of LKB1

LKB1 encodes a serine/threonine protein kinase that is defective in patients with Peutz-Jeghers syndrome (PJS), a hereditary disorder characterized by gastrointestinal hamartomatous polyposis and an increased risk of cancer development. Although a tentative molecular classification of PJS patients was recently made according to their LKB1 mutation status, it is difficult to clarify the genotype-phenotype relationship because of the rarity and genetic heterogeneity of this disease. Here we report on two probands with PJS whose intestinal hamartomatous polyposis was treated by laparoscopyassisted polypectomy. Direct sequencing analyses revealed a nonsense mutation at codon 240 in exon 5 in one patient, and a mutation at a splicing donor site in intron 5 in the other patient. No additional somatic mutations were detected in the resected hamartomas in either case. Immunohistochemical analysis revealed an elevated expression of cyclooxygenase-2, and almost complete loss of LKB1 expression in the polyps, suggesting that a biallelic inactivation of the LKB1 gene was responsible for the hamartoma formation. Methylation-specific polymerase chain reaction analysis revealed no hypermethylation of the LKB1 promoter. Mutation analysis is useful in making a precise diagnosis of PJS in candidate probands, and may in the near future provide valuable information for predicting cancer risk based on genotype-phenotype correlations.