title: Analysis of LKB1 mutations and other molecular alterations in pancreatic acinar cell carcinoma.
abstract: Acinar cell carcinoma is a rare non-ductal neoplasm of the pancreas with poorly defined molecular genetic features. Recently, biallelic inactivation of LKB1 was described in an acinar cell carcinoma of a Peutz-Jeghers patient carrying a heterozygous germline LKB1 mutation, and inhibition of mTOR signaling resulted in partial remission of the tumor. To explore the potential of mTOR inhibitors in sporadic acinar cell carcinoma, the LKB1 gene was investigated in five sporadic acinar cell carcinomas by sequence analysis, methylation analysis and mRNA expression. In addition, microsatellite instability and methylation of a number of tumor suppressor genes were investigated and KRAS, TP53, CDKN1A, SMAD4 and CTNNB1 were studied by mutation analysis and immunohistochemistry. No mutations, deletions or promoter hypermethylation of LKB1 were found in any of the sporadic acinar cell carcinomas, and mRNA expression of LKB1 was not altered. Amplifications at chromosome 20q and 19p were found in 100 and 80% of the cases, respectively. In addition, hypermethylation of one or more tumor suppressor genes was found in 80% of cases. One case harbored a TP53 mutation, and expression of SMAD4 and CTNNB1 was altered in one case each. No KRAS mutations or microsatellite instability were found. To conclude, no evidence for a role for LKB1 in tumorigenesis of sporadic pancreatic acinar cell carcinoma was found. However, copy number variations and hypermethylation were found in a majority of cases. Molecular pathways involved in acinar cell carcinoma-tumorigenesis differ from those involved in ductal pancreatic neoplasms. Further studies are needed to increase our understanding of molecular pathogenesis of acinar cell carcinoma, which may eventually result in development of new therapeutic targets.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roeland F
authors.initials: RF
authors.lastname: de Wilde
authors.forename: Niki A
authors.initials: NA
authors.lastname: Ottenhof
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.forename: Folkert H M
authors.initials: FH
authors.lastname: Morsink
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: de Leng
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Lodewijk A A
authors.initials: LA
authors.lastname: Brosens
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D018267:Carcinoma, Acinar Cell / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D060885:Multiplex Polymerase Chain Reaction; D010190:Pancreatic Neoplasms / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases