EDITORIAL URRENT C OPINION
The Cancer Genome Atlas findings in head and neck cancer: a renewed hope Gilberto de Castro Jr. and Marcelo Vailati Negra˜o
Head and neck squamous cell carcinoma (HNSCC) remains as one of the leading causes of cancerrelated deaths worldwide [1], despite recent changes in HNSCC epidemiology (the increasing incidence of human papillomavirus (HPV)-related oropharyngeal SCC [2]) and the incorporation of some therapeutic advances into daily clinical practice (e.g. cisplatin-based concurrent chemoradiation for locally advanced HNSCC [3] and cetuximab for those patients with metastatic disease [4]). Indeed, no useful biomarker can be used nowadays as a predictive factor for treatment selection in these HNSCC patients. One exception is the presence of positive margins and/or extracapsular spread in patients submitted to radical surgery with curative intent, as indicators of adjuvant cisplatinbased chemoradiation [5]. The detection of HPV products has been shown as a positive prognostic factor [6] and some studies are exploring deintensification of multimodality therapies specifically in these patients diagnosed with HPV-related HNSCC [e.g. RTOG 1016 (NCT01302834) and E1308 (NCT01084083) trials]. In this scenario, there is an urgent need for exploring new potential biomarkers to better characterize prognosis and also to predict response to therapy. The Cancer Genome Atlas (TCGA) project was elaborated to study genetic alterations in different cancer subtypes for a better understanding of cancer pathophysiology and, more importantly, to identify signaling pathways that could be used as potential targets in cancer treatment. As of July 2013, the project has analyzed 7992 cases in 27 tumor subtypes. HNSCC is one of the cancer types being analyzed, accounting for 279 samples of the project. It figures as one of the cancers with a higher number of mutations per megabase [7]. The TCGA project includes DNA, RNA and microRNA sequencing along with DNA copy number profiling, quantification of mRNA expression, promoter methylation, and reverse-phase protein arrays. All samples analyzed were obtained during surgical resection of previously untreated patients with HNSCC. Among this population, 80% of HNSCC analyzed
were associated with tobacco consumption and 25% were considered as HPV-positive. Tobacco-related tumors presented a worse prognosis, suggesting that these tumors had indeed a different mutational profile when compared to those which were HPVpositive [8]. The first interesting finding of this study is the similarity between molecular signaling pathways between squamous cell lung cancer, which is another of the cancer types analyzed in the project, and HNSCC [9]. This interesting finding suggests that the carcinogens related to tobacco consumption may lead to similar mutational profiles in cancer cells of different locations. Another interesting finding occurred as a result of mRNA sequencing. As it occurred with other cancers, the mRNA profile determined four different subtypes of HNSCC, according to gene expression: atypical, basal, mesenchymal and classical, confirming previous reports [10]. This diversity in tumor subtypes is likely to be responsible for the different disease patterns we observe in clinical practice. Included in this clinical picture are the HPV-positive tumors, classified in the atypical subtype, which present a smaller mutational diversity. This finding could explain why HPV-positive tumors are more chemosensitive and radiosensitive, leading some authors to believe that the treatment for this tumor subtype could be less intensive. By contrast, alterations of the ‘antioxidant response elements’ transcription activators NFE2L2 and KEAP1 seem to be associated with the classical subtype of HNSCC, as has been shown in lung SCC. Indeed, co-occurrence of CASP8 and HRAS were detected in the basal subtype [8].
Clinical Oncology, Instituto do Caˆncer do Estado de Sa˜o Paulo, Sa˜o Paulo, Brazil Correspondence to Gilberto de Castro Jr., Clinical Oncology, Instituto do Caˆncer do Estado de Sa˜o Paulo, Av Dr Arnaldo 251 – 5th floor, Sa˜o Paulo – SP 01246-000, Brazil. Tel: +55 11 3893 2686; fax: +55 11 3083 1746; e-mail: [email protected] Curr Opin Oncol 2014, 26:245–246 DOI:10.1097/CCO.0000000000000075
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Head and neck
Several gene mutations were found to be of importance and could be considered as driver mutations. These mutations (false discovery rate
The Cancer Genome Atlas findings in head and neck cancer: a renewed hope Gilberto de Castro Jr. and Marcelo Vailati Negra˜o
Head and neck squamous cell carcinoma (HNSCC) remains as one of the leading causes of cancerrelated deaths worldwide [1], despite recent changes in HNSCC epidemiology (the increasing incidence of human papillomavirus (HPV)-related oropharyngeal SCC [2]) and the incorporation of some therapeutic advances into daily clinical practice (e.g. cisplatin-based concurrent chemoradiation for locally advanced HNSCC [3] and cetuximab for those patients with metastatic disease [4]). Indeed, no useful biomarker can be used nowadays as a predictive factor for treatment selection in these HNSCC patients. One exception is the presence of positive margins and/or extracapsular spread in patients submitted to radical surgery with curative intent, as indicators of adjuvant cisplatinbased chemoradiation [5]. The detection of HPV products has been shown as a positive prognostic factor [6] and some studies are exploring deintensification of multimodality therapies specifically in these patients diagnosed with HPV-related HNSCC [e.g. RTOG 1016 (NCT01302834) and E1308 (NCT01084083) trials]. In this scenario, there is an urgent need for exploring new potential biomarkers to better characterize prognosis and also to predict response to therapy. The Cancer Genome Atlas (TCGA) project was elaborated to study genetic alterations in different cancer subtypes for a better understanding of cancer pathophysiology and, more importantly, to identify signaling pathways that could be used as potential targets in cancer treatment. As of July 2013, the project has analyzed 7992 cases in 27 tumor subtypes. HNSCC is one of the cancer types being analyzed, accounting for 279 samples of the project. It figures as one of the cancers with a higher number of mutations per megabase [7]. The TCGA project includes DNA, RNA and microRNA sequencing along with DNA copy number profiling, quantification of mRNA expression, promoter methylation, and reverse-phase protein arrays. All samples analyzed were obtained during surgical resection of previously untreated patients with HNSCC. Among this population, 80% of HNSCC analyzed
were associated with tobacco consumption and 25% were considered as HPV-positive. Tobacco-related tumors presented a worse prognosis, suggesting that these tumors had indeed a different mutational profile when compared to those which were HPVpositive [8]. The first interesting finding of this study is the similarity between molecular signaling pathways between squamous cell lung cancer, which is another of the cancer types analyzed in the project, and HNSCC [9]. This interesting finding suggests that the carcinogens related to tobacco consumption may lead to similar mutational profiles in cancer cells of different locations. Another interesting finding occurred as a result of mRNA sequencing. As it occurred with other cancers, the mRNA profile determined four different subtypes of HNSCC, according to gene expression: atypical, basal, mesenchymal and classical, confirming previous reports [10]. This diversity in tumor subtypes is likely to be responsible for the different disease patterns we observe in clinical practice. Included in this clinical picture are the HPV-positive tumors, classified in the atypical subtype, which present a smaller mutational diversity. This finding could explain why HPV-positive tumors are more chemosensitive and radiosensitive, leading some authors to believe that the treatment for this tumor subtype could be less intensive. By contrast, alterations of the ‘antioxidant response elements’ transcription activators NFE2L2 and KEAP1 seem to be associated with the classical subtype of HNSCC, as has been shown in lung SCC. Indeed, co-occurrence of CASP8 and HRAS were detected in the basal subtype [8].
Clinical Oncology, Instituto do Caˆncer do Estado de Sa˜o Paulo, Sa˜o Paulo, Brazil Correspondence to Gilberto de Castro Jr., Clinical Oncology, Instituto do Caˆncer do Estado de Sa˜o Paulo, Av Dr Arnaldo 251 – 5th floor, Sa˜o Paulo – SP 01246-000, Brazil. Tel: +55 11 3893 2686; fax: +55 11 3083 1746; e-mail: [email protected] Curr Opin Oncol 2014, 26:245–246 DOI:10.1097/CCO.0000000000000075
1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-oncology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Head and neck
Several gene mutations were found to be of importance and could be considered as driver mutations. These mutations (false discovery rate
