title: Molecular characteristics and predictors of survival in patients with malignant neuroendocrine tumors.
abstract: To better understand the molecular pathogenesis of neuroendocrine tumors (NET), we investigated the molecular and clinical characteristics of malignant poorly differentiated colorectal NET and compared these findings with sporadic CRC and well-differentiated benign and malignant fore-/midgut NET. Tumors were analyzed and correlated for microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). NET were scored for proliferation using Ki-67. A total of 34 malignant poorly differentiated colorectal NET, 38 well-differentiated benign and malignant fore-/midgut-NET and 150 sporadic colorectal cancers (CRC) with known MSI status were investigated. Among the sporadic CRC, CIMP was significantly correlated with MSI-high (MSI-H) (p < 0.001). Of the 34 colorectal NET, 0/1 of the MSI-H, 3/5 (60%) of the MSI-L and 13/19 (68%) of the MSS tumors were CIMP+ (p = 0.17). Of the fore-/midgut-NET, none was MSI-H. 20/34 (59%) colorectal NET vs. 11/38 (29%) fore-/midgut-NET were CIMP+ (p = 0.01). The Ki-67 index was significantly higher in poorly differentiated colorectal NET compared to the less malignant fore-/midgut-NET (p < 0.0001). Besides the location in the colon, Ki-67 predicted poor outcome in NET (p < 0.0001). CIMP status did not affect survival. In NET, p16 methylation predicted a poor outcome (p = 0.0004). We conclude that molecular pathogenesis in sporadic CRC and poorly differentiated colorectal NET is different despite some similarities. Main differences between malignant well-differentiated and poorly differentiated NET are the Ki-67 proliferation rate and differential methylation in tumor-associated genes. Predictors of a poor outcome in patients with NET are poor differentiation, a high Ki-67 index and p16 methylation.
authors.affiliation: Department of Internal Medicine II, University of Freiburg, D-79106 Freiburg, Germany. christian.arnold@uniklinik-freiburg.de
authors.forename: Christian N
authors.initials: CN
authors.lastname: Arnold
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.forename: Iris
authors.initials: I
authors.lastname: Scharf
authors.forename: Patricia
authors.initials: P
authors.lastname: Grabowski
authors.forename: Andrea
authors.initials: A
authors.lastname: Sosnowski
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Gräff
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Rudolf
authors.initials: R
authors.lastname: Arnold
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002454:Cell Differentiation; D002874:Chromosome Mapping; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D016133:Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor