The Cancer Genome Atlas findings in head and neck cancer: a renewed hope.

Head and neck squamous cell carcinoma (HNSCC)remains as one of the leading causes of cancer-related deaths worldwide [1], despite recentchanges in HNSCC epidemiology (the increasingincidence of human papillomavirus (HPV)-relatedoropharyngeal SCC [2]) and the incorporationof some therapeutic advances into daily clinicalpractice (e.g. cisplatin-based concurrent chemo-radiation for locally advanced HNSCC [3] andcetuximabforthosepatientswithmetastaticdisease[4]). Indeed, no useful biomarker can be usednowadays as a predictive factor for treatment selec-tion in these HNSCC patients. One exception is thepresence of positive margins and/or extracapsularspread in patients submitted to radical surgery withcurative intent, as indicators of adjuvant cisplatin-based chemoradiation [5]. The detection of HPVproducts has been shown as a positive prognosticfactor [6] and some studies are exploring deintensi-fication of multimodality therapies specifically inthese patients diagnosed with HPV-related HNSCC[e.g. RTOG 1016 (NCT01302834) and E1308(NCT01084083) trials]. In this scenario, there is an urgent need forexploring new potential biomarkers to bettercharacterize prognosis and also to predict responseto therapy. The Cancer Genome Atlas (TCGA)project was elaborated to study genetic alterationsin different cancer subtypes for a better under-standing of cancer pathophysiology and, moreimportantly, to identify signaling pathways thatcould be used as potential targets in cancer treat-ment. As of July 2013, the project has analyzed7992 cases in 27 tumor subtypes.HNSCC is one of the cancer types beinganalyzed, accounting for 279 samplesof theproject.Itfiguresasoneofthecancerswithahighernumberof mutations per megabase [7]. The TCGA projectincludes DNA, RNA and microRNA sequencingalong with DNA copy number profiling, quantifi-cation of mRNA expression, promoter methylation,and reverse-phase protein arrays. All samplesanalyzed were obtained during surgical resectionof previously untreated patients with HNSCC.Among this population, 80% of HNSCC analyzedwereassociatedwithtobaccoconsumptionand25%were considered as HPV-positive. Tobacco-relatedtumorspresented aworse prognosis,suggestingthatthese tumors had indeed a different mutationalprofile when compared to those which were HPV-positive [8]. The first interesting finding of this study isthe similarity between molecular signaling path-ways between squamous cell lung cancer, which isanother of the cancer types analyzed in the project,and HNSCC [9]. This interesting finding suggeststhat the carcinogens related to tobacco consump-tion may lead to similar mutational profiles incancer cells of different locations.Another interesting finding occurred as a resultof mRNA sequencing. As it occurred with othercancers,themRNAprofiledeterminedfourdifferentsubtypes of HNSCC, according to gene expression:atypical,basal,mesenchymalandclassical,confirm-ing previous reports [10]. This diversity in tumorsubtypes is likely to be responsible for the differentdisease patterns we observe in clinical practice.IncludedinthisclinicalpicturearetheHPV-positivetumors, classified in the atypical subtype, whichpresent a smaller mutational diversity. This findingcould explain why HPV-positive tumors are morechemosensitive and radiosensitive, leading someauthors to believe that the treatment for thistumor subtype could be less intensive. By contrast,alterations of the ‘antioxidant response elements’transcription activators NFE2L2 and KEAP1 seemto be associated with the classical subtype ofHNSCC, as has been shown in lung SCC. Indeed,co-occurrence of CASP8 and HRAS were detected inthe basal subtype [8].