Abstract
BackgroundTumour 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.MethodsA 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.ResultsHNSCC 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.ConclusionsAn unprecedented PG-based prognostic portrait is unveiled that incisively diversifies disease course in HNSCC patients beyond the currently known clinical and molecular biomarkers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1336-4) contains supplementary material, which is available to authorized users.
Highlights
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
Transcriptional profiles of PGs in primary oral cavity HNSCC lesions Analyses of the relative mRNA expression levels of the eleven prevalent cell surface-associated PGs conducted on a total of 119 primary oral cavity HNSCC lesions revealed that 3 of the PGs, including NG2/CSPG4, GPC2 and GPC5, were de novo expressed in neoplastic cells, i.e. were not detectable in the healthy control tissues, but were detectable in cancer cells
SDC2, SDC3 and SDC4 were up-regulated in 79-84% of the patients, whereas GPC4 was enhanced in 11% and GPC3 in 57% of the specimens
Summary
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. The currently adopted methods to predict disease recurrence, such as staging and grading, are too arbitrary and do not allow for a sufficiently accurate clinical stratification of the patients [14,15]. This deficit calls upon the need to identify distinct molecular markers that more reliably would predict disease progression, recurrence and metastasis formation, and many such have been proposed over the last decade (Table 1). Only three such markers have been considered as meaningful, i.e. HPV infection, TP53 mutation status and overexpression of EGFR [16,17,18,19,20], but their full independence from clinical parameters is still dubious
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