title: Profiling immunohistochemical expression of NOTCH1-3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary.
abstract: Cancer of unknown primary (CUP) is a heterogeneous entity, managed on the basis of "one size fits all" therapeutic concepts; insights into the molecular biology of CUP are urgently needed. We retrospectively examined the immunohistochemical (IHC) expression of Notch1, 2, 3, Jagged1, cMET, and pMAPK biomolecules in 100 CUP tumors using tissue microarrays, aiming to study their correlation to clinicopathologic characteristics and prognostic utility for patient outcome. Notch3 and pMAPK were most frequently expressed (97 and 91 %, respectively). A linear correlation of Notch3 and cMET expression was found (p = 0.001), while pMAPK emerged as the major adverse prognostic factor (median overall survival OS 9 vs. 17 months, p = 0.016), carrying also a significantly positive predictive value (p = 0.02). Our study indicated a favorable prognostic impact of cMET expression in CUP, both in univariate (median OS 15 vs. 9 months, p = 0.05) and in multivariate analysis (Relative Risk RR for death 0.48, p = 0.025). cMET and Notch3 expression were found to be statistically more frequent in squamous carcinomas (positive in 90 % of cases), associated with a unique metastatic IHC pattern (cMET-high in soft tissue/lymph node metastases, p < 0.001, Notch3-high in visceral, peritoneal/pleural and soft tissue/lymph node metastases, p < 0.001). Our study points to the MAPK and cMET axes as crucial in defining cancer progression and outcome in CUP patients and, if validated, could justify attempts at their therapeutic modulation.
authors.affiliation: Department of Medical Oncology, Medical School, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Krikelis
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.forename: Anna
authors.initials: A
authors.lastname: Goussia
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Siozopoulou
authors.forename: Mattheos
authors.initials: M
authors.lastname: Bobos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Petrakis
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Stoyianni
authors.forename: Vassilios
authors.initials: V
authors.lastname: Golfinopoulos
authors.forename: Andres
authors.initials: A
authors.lastname: Cervantes
authors.forename: Tudor
authors.initials: T
authors.lastname: Ciuleanu
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Malamou-Mitsi
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pavlidis
mesh_terms: D000368:Aged; D002135:Calcium-Binding Proteins / Q000096:biosynthesis*; D002277:Carcinoma / Q000378:metabolism / Q000556:secondary*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D000072100:Jagged-1 Protein; D016014:Linear Models; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011237:Predictive Value of Tests; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis*; D051881:Receptor, Notch1 / Q000096:biosynthesis*; D051883:Receptor, Notch2 / Q000096:biosynthesis*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000096:biosynthesis*; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met