Proteoglycan-based diversification of disease outcome in head and neck cancer patients identifies NG2/CSPG4 and syndecan-2 as unique relapse and overall survival predicting factors.
BACKGROUND
Tumour relapse is recognized to be the prime fatal burden in patients affected by head and neck squamous cell carcinoma (HNSCC), but no discrete molecular trait has yet been identified to make reliable early predictions of tumour recurrence. Expression of cell surface proteoglycans (PGs) is frequently altered in carcinomas and several of them are gradually emerging as key prognostic factors.


METHODS
A PG expression analysis at both mRNA and protein level, was pursued on primary lesions derived from 173 HNSCC patients from whom full clinical history and 2 years post-surgical follow-up was accessible. Gene and protein expression data were correlated with clinical traits and previously proposed tumour relapse markers to stratify high-risk patient subgroups.


RESULTS
HNSCC lesions were indeed found to exhibit a widely aberrant PG expression pattern characterized by a variable expression of all PGs and a characteristic de novo transcription/translation of GPC2, GPC5 and NG2/CSPG4 respectively in 36%, 72% and 71% on 119 cases. Importantly, expression of NG2/CSPG4, on neoplastic cells and in the intralesional stroma (Hazard Ratio [HR], 6.76, p = 0.017) was strongly associated with loco-regional relapse, whereas stromal enrichment of SDC2 (HR, 7.652, p = 0.007) was independently tied to lymphnodal infiltration and disease-related death. Conversely, down-regulated SDC1 transcript (HR, 0.232, p = 0.013) uniquely correlated with formation of distant metastases. Altered expression of PGs significantly correlated with the above disease outcomes when either considered alone or in association with well-established predictors of poor prognosis (i.e. T classification, previous occurrence of precancerous lesions and lymphnodal metastasis). Combined alteration of all three PGs was found to be a reliable predictor of shorter survival.


CONCLUSIONS
An unprecedented PG-based prognostic portrait is unveiled that incisively diversifies disease course in HNSCC patients beyond the currently known clinical and molecular biomarkers.
Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy. farnedi@hotmail.com.
Anna
A
Farnedi
COMT - Centre for Molecular Translational Oncology & Department of Life Sciences, University of Parma, Parma, Italy. silvia.rossi1@unipr.it.
Silvia
S
Rossi
COMT - Centre for Molecular Translational Oncology & Department of Life Sciences, University of Parma, Parma, Italy. nicoletta.bertani@unipr.it.
Nicoletta
N
Bertani
Department of Life Sciences, Division of Genetics and Environmental Biotechnology, University of Parma, Parma, Italy. mariolina.gulli@unipr.it.
Mariolina
M
Gulli
COMT - Centre for Molecular Translational Oncology & Department of Life Sciences, University of Parma, Parma, Italy. enricomaria.silini@unipr.it.|Department of Pathology and Laboratory Medicine, University of Parma, Parma, Italy. enricomaria.silini@unipr.it.
Enrico Maria
EM
Silini
S.O.C. of Experimental Oncology 2, The National Tumour Institute Aviano - CRO-IRCCS, Aviano, Pordenone, Italy. mtmucignat@cro.it.
Maria Teresa
MT
Mucignat
Maxillofacial Surgery Section, Head and Neck Department, University of Parma, Parma, Italy. tito.poli@unipr.it.
Tito
T
Poli
Maxillofacial Surgery Section, Head and Neck Department, University of Parma, Parma, Italy. enrico.sesenna@unipr.it.
Enrico
E
Sesenna
Maxillofacial Surgery Section, Head and Neck Department, University of Parma, Parma, Italy. lanfranco82@yahoo.it.
Davide
D
Lanfranco
Unit of Maxillo-Facial Surgery, Department of Oral Sciences, University of Bologna, Bellaria Hospital, Bologna, Italy. lucio.montebugnoli@unibo.it.
Lucio
L
Montebugnoli
Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy. elisa.leonardi4@unibo.it.
Elisa
E
Leonardi
Department of Biomedical and Neuromotor Sciences, Unit of Maxillo-Facial Surgery, University of Bologna, S. Orsola Hospital, Bologna, Italy. claudio.marchetti@unibo.it.
Claudio
C
Marchetti
Unit of Maxillo-facial Surgery at Bellaria Hospital, Bologna, Italy. roberto.cocchi@ausl.bologna.it.|Unit of Maxillo-facial Surgery, "Casa Sollievo della Sofferenza", San Giovanni in Rotondo, Italy. roberto.cocchi@ausl.bologna.it.
Renato
R
Cocchi
Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy. andreaambrosini@yahoo.it.
Andrea
A
Ambrosini-Spaltro
Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy. mariapia.foschini@unibo.it.
Maria Pia
MP
Foschini
COMT - Centre for Molecular Translational Oncology & Department of Life Sciences, University of Parma, Parma, Italy. roberto.perris@unipr.it.|S.O.C. of Experimental Oncology 2, The National Tumour Institute Aviano - CRO-IRCCS, Aviano, Pordenone, Italy. roberto.perris@unipr.it.
Roberto
R
Perris
D000328:Adult; D000941:Antigens / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009055:Mouth / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control; D016016:Proportional Hazards Models; D011509:Proteoglycans / Q000378:metabolism*; D053669:Syndecan-2 / Q000378:metabolism; D016896:Treatment Outcome; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D014408:Biomarkers, Tumor; D011508:Chondroitin Sulfate Proteoglycans; D008565:Membrane Proteins; D011509:Proteoglycans; D053669:Syndecan-2; D000099216:Chondroitin Sulfate Proteoglycan 4; C101390:CSPG4 protein, human