1138PD - Activation status and prognostic significance of the Wnt/B Catenin and Hedgehog/Smoothened signalling pathways in patients with cancer of unknown p...

Date 29 September 2014
Event ESMO 2014
Session Neuroendocrine & endocrine tumours and CUP
Topics Carcinoma of Unknown Primary Site (CUP)
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter George Pentheroudakis
Citation Annals of Oncology (2014) 25 (suppl_4): iv394-iv405. 10.1093/annonc/mdu345
Authors G. Pentheroudakis1, G. Fotopoulos1, A. Gousia2, M. Bobos3, S. Chrysafi3, G. Fountzilas4, N. Pavlidis5
  • 1Oncology Secretariat B Building Ground Floor, University Hospital of Ioannina, 454 45 - Ioannina/GR
  • 2Data Office, Hellenic Cooperative Oncology Group (HeCOG), Athens/GR
  • 3Data Office, Hellenic Cooperative Oncology Group (HECOG), Athens/GR
  • 4Medical Oncology Clinic, Papageorgiou Hospital Aristotle University of Thessaloniki, 564 29 - Thessaloniki/GR
  • 5Medical Oncology, Ioannina University Hospital, 15 110 - Ioannina/GR



The Wnt/b catenin and Hedgehog/Smoothened signalling pathways regulate cellular proliferation, stemness, migratory and self-renewal potential, however their activation status and prognostic utility have not been investigated in Cancer of Unknown Primary.


Tissue microarrays from 87 CUP patients were constructed and immunohistochemistry (IHC) was succefully performed for Nuclear and cytoplasmic b-Catenin, nuclear TCF, LEF, Gli1, cytoplasmic and nuclear Smoothened (SMO) in 56 cases.


87 CUP patients harbouring CUP, mostly high-grade adenocarcinoma of visceral (28,32.1%), serous peritoneal (22,25.2%) or neuroendocrine (18, 20.7%) subgroups were retrospectively identified. Positive IHC expression (1% or more of staining cells) was seen in 1/3-1/4 of cases for each marker. Positively correlated expression was found for nuclear b-catenin with nuclear LEF, nuclear SMO. At a median follow-up of 85 months, only nuclear SMO was prognostic for overall survival (OS, SMO+ cases median OS 19 vs 12 months, p = 0.01). When complex profiles of activated pathways were examined, IHC activation of the Wnt pathway (positivity for any of the nuclear b-catenin and/or nuclear TCF and/or nuclear LEF) was significantly associated with improved PFS, OS, the significance mainly being driven by TCF and/or LEF nuclear expression (p = 0.04). In multivariate analysis, IHC expression of nuclear TCF and/or LEF carried significantly reduced risk of death (HR 0.15, p = 0.018).


Retrospective data suggest that activation of the Wnt pathway is associated with improved outcome of CUP patients, with the nuclear expression of TCF or LEF being the most reliable surrogate markers. In view of potential for therapeutic targeting, independent validation in larger series is warranted.


All authors have declared no conflicts of interest.