title: Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome.
abstract: Previous SNP array analyses have revealed genomic alterations of the Notch pathway as being the most frequent abnormality in adrenocortical tumors (ACTs). The aim of the present study was to evaluate the expression of components of Notch signaling in ACTs and to correlate them with clinical outcome. The mRNA expression of JAG1, NOTCH1, and selected target genes of NOTCH1 (HES1, HES5, and HEY2) was evaluated in 80 fresh frozen samples (28 normal adrenal glands (NAGs), 24 adenomas (ACAs), and 28 carcinomas (ACCs)) by quantitative RT-PCR. Immunohistochemistry was performed in 221 tissues on paraffin slides (16 NAGs, 27 ACAs, and 178 ACCs) for JAG1, activated NOTCH1 (aNOTCH1), and HEY2. An independent ACC validation cohort (n=77) was then also investigated. HEY2 mRNA expression was higher in ACCs than it was in ACAs (P<0.05). The protein expression of all of the factors was high (H-score 2-3) in a larger proportion of ACCs as compared to ACAs and NAGs (JAG1 in 27, 15, and 10%; aNOTCH1 in 13, 8, and 0%; HEY2 in 66, 61, and 33% respectively, all P<0.001). High JAG1 expression was associated with earlier tumor stages and lower numbers of metastases in ACCs (both P=0.08) and favorably impacted overall and progression-free survival (PFS) (131 vs 30 months, hazard ratio (HR) 0.45, and 37 vs 9 months, HR 0.51, both P<0.005). This impact on overall survival (OS) was confirmed in the validation cohort. No such association was observed for aNOTCH1 or HEY2. In conclusion, different components of the Notch1 signaling pathway are overexpressed in ACCs, which suggests a role for the pathway in malignant transformation. However, JAG1 is overexpressed in a subgroup of ACCs with a better clinical outcome.
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany Ronchi_C@ukw.de.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Ronchi
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Altieri
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Steinhauer
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wild
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Bekteshi
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kroiss
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Endocrine and Diabetes UnitDepartment of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, 97080 Wuerzburg, GermanyCentral LaboratoryUniversity Hospital of Wuerzburg, Wuerzburg, GermanyInstitute of PathologyUniversity of Wuerzburg, Wuerzburg, GermanyComprehensive Cancer Center MainfrankenWuerzburg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
mesh_terms: D000236:Adenoma / Q000378:metabolism; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C405693:HEY2 protein, human; C000606273:JAG1 protein, human; C497761:NOTCH1 protein, human
keywords: JAG1; Notch1 pathway; Wnt/β-catenin; adrenocortical tumors