Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz-Jeghers syndrome

• Published in: Carcinogenesis (New York) 2013-07, Vol.34 (7), p.1611-1619
• Main Authors: Korsse, Susanne E, Biermann, Katharina, Offerhaus, G Johan A, Wagner, Anja, Dekker, Evelien, Mathus-Vliegen, Elisabeth M H, Kuipers, Ernst J, van Leerdam, Monique E, van Veelen, Wendy
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Cohort Studies; DNA Mutational Analysis; Female; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - pathology; Gene Expression Regulation, Neoplastic; Germ-Line Mutation; Hamartoma - genetics; Hamartoma - pathology; Humans; Immunohistochemistry; Loss of Heterozygosity; Male; Middle Aged; Netherlands; Pedigree; Peutz-Jeghers Syndrome - genetics; Peutz-Jeghers Syndrome - pathology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Smad4 Protein - genetics; Smad4 Protein - metabolism; Transforming Growth Factor beta - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgt068

Peutz-Jeghers syndrome (PJS) is caused by mutations in the LKB1 gene. It is characterized by gastrointestinal polyposis and an increased cancer risk, mainly in the gastrointestinal tract. Mechanisms of PJS-associated carcinogenesis are unclear. We investigated the involvement of candidate genes and molecular pathways in PJS-associated gastrointestinal cancers and dysplastic hamartomas. Cases were selected from the Dutch PJS cohort. Available tissue was immunostained for phospho-S6, β-catenin, P53 and SMAD4. DNA was isolated from carcinoma tissue and dysplastic and non-dysplastic areas of hamartomas specifically. Mutation analyses were done for BRAF, KRAS and P53, and loss of heterozygosity (LOH) analyses for LKB1 and P53. Twenty-four of 144 patients (17%) developed 26 gastrointestinal malignancies at a median age of 49 years (interquartile range: 35-60). Eleven of 792 hamartomas (1.4%) of 9 patients were classified as dysplastic. LOH of LKB1 was detected in three of six (50%) carcinomas and in the dysplastic part of three of five (60%) hamartomas. Aberrant P53 expression was observed in 8 of 15 (53%) carcinomas. Six carcinomas with P53 overexpression harboured a P53 mutation, with loss of the remaining wild-type allele in four. Two hamartomas showing P53 overexpression in high-grade dysplastic foci harboured a P53 mutation with LOH. Loss of nuclear SMAD4 was observed in high-grade dysplastic foci of two of four (50%) hamartomas, in contrast to low-grade dysplastic foci (0/4) and non-dysplastic epithelium. Our findings suggest a role for mutant P53 in PJS-associated gastrointestinal carcinogenesis. Inactivation of transforming growth factor-β/bone morphogenetic protein signalling and complete loss of LKB1 might be involved in dysplastic transformation of gastrointestinal hamartomas specifically.