title: TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.
abstract: The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.
authors.affiliation: Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100, Varese, Italy. stefano.larosa@ospedale.varese.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bernasconi
authors.affiliation: Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.affiliation: Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100, Varese, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tibiletti
authors.affiliation: Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Furlan
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Nora
authors.initials: N
authors.lastname: Sahnane
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vanoli
authors.affiliation: Pathology Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Albarello
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Kurashiki Central Hospital, Kurashiki, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Notohara
authors.affiliation: Centre de Pathologie, Strasbourg, France.
authors.forename: Selenia
authors.initials: S
authors.lastname: Casnedi
authors.affiliation: Department of Pathology, Hospital De Hautepierre, Strasbourg, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Chenard
authors.affiliation: Department of Pathology, Emory University, Atlanta, GA, USA.
authors.forename: Volkan
authors.initials: V
authors.lastname: Adsay
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Asioli
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
mesh_terms: D000328:Adult; D000368:Aged; D018267:Carcinoma, Acinar Cell / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D057089:Pathology, Molecular / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics
keywords: Acinar cell carcinoma; Pancreas; TP53; p53