Prognostic significance of WNT and hedgehog pathway activation markers in cancer of unknown primary.
BACKGROUND
Cancer of unknown primary (CUP) possesses distinct biology and peculiar natural history, in which the roles of the winged and hedgehog signalling pathways are unclear.


METHODS
We constructed tissue microarrays and studied the immunohistochemical (IHC) expression of β-catenin, smoothened (SMO) and the transcription factors TCF, LEF, GLI1 in 87 CUP cases for prognostic significance.


RESULTS
A low rate of IHC expression of proteins was seen, the cut-off used being any expression in ≥ 1% of tumour cells. At univariate analysis, only nuclear IHC SMO expression displayed a statistically significant association with favourable outcome [median Overall survival (OS) of 19 months in SMO-positive vs. 12 months in SMO-negative cases, P = 0·01]. An activated Wnt pathway, defined as IHC expression of any of nuclear β-catenin, TCF and LEF, was significantly associated with favourable progression free survival (median 9 vs. 5 months, P = 0·037) and OS (median 19 vs. 13 months, P = 0·04). This prognostic impact on OS was mainly driven by nuclear expression of TCF and/or LEF (P = 0·03). No prognostic significance of the hedgehog pathway activation status, defined as IHC expression of SMO or nuclear GLI1, could be established. A favourable prognostic impact of the concurrent activation of both pathways was observed. A trend for association of activated Wnt with response to chemotherapy (responders 67% among activated Wnt cases vs. 35% among nonactivated Wnt cases, P = 0·07) was observed in CUP adenocarcinomas.


CONCLUSIONS
Activation of the Wnt pathway was a positive prognostic factor in a small CUP series, possibly via enhanced chemosensitivity. Independent validation is warranted.
Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.
George
G
Fotopoulos
Department of Pathology, Medical School, University of Ioannina, Ioannina, Greece.
Anna
A
Gousia
Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.
Eleni
E
Bareta
Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.
Epameinondas
E
Koumpis
Department of Medical Oncology, Medical School, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Sofia
S
Chrisafi
Department of Pathology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Matthaios
M
Bobos
Department of Pathology, Medical School, University of Ioannina, Ioannina, Greece.
Vassiliki
V
Malamou-Mitsi
Department of Medical Oncology, Medical School, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
George
G
Fountzilas
Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.
Nicholas
N
Pavlidis
Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.
George
G
Pentheroudakis
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality; D005260:Female; D053823:Hedgehog Proteins; D006801:Humans; D007150:Immunohistochemistry; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009382:Neoplasms, Unknown Primary / Q000378:metabolism* / Q000401:mortality; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012189:Retrospective Studies; D000072086:Smoothened Receptor; D051820:TCF Transcription Factors / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000378:metabolism
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D051820:TCF Transcription Factors; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin
Cancer of unknown primary; WNT pathway; hedgehog; immunohistochemistry; prognostic; wingless