Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation

Tinhofer, Ingeborg; Budach, Volker; Saki, Mohammad; Konschak, Robert; Niehr, Franziska; Jöhrens, Korinna; Weichert, Wilko; Linge, Annett; Lohaus, Fabian; Krause, Mechthild; Neumann, Konrad; Endris, Volker; Sak, Ali; Stuschke, Martin; Balermpas, Panagiotis; Rödel, Claus; Avlar, Melanie; Grosu, Anca L.; Abdollahi, Amir; Debus, Jürgen; Belka, Claus; Pigorsch, Steffi; Combs, Stephanie E.; Mönnich, David; Zips, Daniel; Baumann, Michaël

doi:10.1016/j.ejca.2016.01.003

Cited by 64 publications

(66 citation statements)

References 37 publications

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“…Mutated TP53 was found to be of prognostic value for survival in HPV-negative OPSCC in one, but not in another study (38,39). This discrepancy might be due to differences in sequencing methods, classification of TP53 mutation as well as number and type of patients included in the analysis (38,39).…”

Section: Studies Focusing On Immunological and Stem Cell Markers In Tmentioning

confidence: 93%

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Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma

Näsman

Bersani

Lindquist

et al. 2017

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Abstract. Human papillomavirus (HPV)-positive tonsillarand base of tongue cancer is increasing epidemically and has much better outcome than corresponding HPV-negativeIn 2007, human papillomavirus (HPV) was recognized as a risk factor for oropharyngeal squamous cell carcinoma (OPSCC) by the International Agency for Research against Cancer (IARC), besides the traditional risk factors smoking and alcohol (1-4). Concurrently, an increased incidence of OPSCC, more specifically tonsillar and base of tongue cancer (TSCC and BOTSCC, the two main HPV-positive OPSCC sites) was described in many developed countries, and found to be due to a sharp rise of HPV-positive cases (5-18). These HPV-positive tumors had a much better clinical outcome than their HPV-negative counterparts and head and neck squamous cell carcinoma (HNSCC) in general when treated with radiotherapy and surgery (1-3, 15-17, 19, 20). Treatment of HNSCC including OPSCC has, however, gradually become more intensified with induction chemotherapy or concurrent chemo-radiotherapy and sometimes the administration of Erbitux, leading to more severe side effects (16, 20, 21). This is likely unnecessary for most HPV-positive TSCC and BOTSCC patients since they generally respond well to less therapy and furthermore, intensified therapy does not improve survival of [15][16][17] 20, 22, 23). It is, therefore, important to identify patients with HPV-positive TSCC and BOTSCC eligible for less treatment or targeted therapy and efforts focus now on finding predictive and targetable markers for these patients (24-39).Here, a short background of the field and an update on recent attempts to find predictive and targetable markers with different methodologies for individualized therapy is presented. Human Papillomavirus in Tonsillar and Base of Tongue Squamous Cell Carcinoma and an Epidemic Increase of these TumorsIn 2000, an association between HPV and OPSCC and TSCC was reported, and with radiotherapy and surgery, these HPVpositive cases had much better outcome than corresponding HPV-negative cases (80% vs. 40-50% 5-year survival) (1, 2). In 2004, a similar relationship of HPV to BOTSCC, but not to mobile tongue cancer was disclosed (40). Based on 5319

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Section: Studies Focusing On Immunological and Stem Cell Markers In Tmentioning

confidence: 93%

“…This discrepancy might be due to differences in sequencing methods, classification of TP53 mutation as well as number and type of patients included in the analysis (38,39). PRIMA-1 MET is the only drug currently under clinical trials targeting mutant p53 (93).…”

Section: Studies Focusing On Immunological and Stem Cell Markers In Tmentioning

confidence: 99%

Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma

Näsman

Bersani

Lindquist

et al. 2017

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“…Mucosal HPV types can be then divided into high-risk and low-risk groups. There are almost 15 high-risk HPV types, identified in precancerous and cancerous lesions, as well as those well established as causing cervical cancers [6], including types 16,18,31,33,34,35,39,45,51,52,56,58,59,66,68, and 70. On the other hand, the most important of low-risk HPVs, which are mainly associated with benign genital warts and other nonmalignant lesions, such as respiratory papillomatosis and oral focal epithelial hyperplasia, are HPV6, 11, 42, 43, and 44 [5,7].…”

Section: The Genomic Organization Of Hpv and Viral Gene Productsmentioning

confidence: 99%

“…While classical alcohol-and smoking-related HNSCCs show p53 mutations, including "disruptive p53 mutation," resulting in worse clinical outcomes with more aggressive behavior [49,50], HPV-positive HNSCCs basically harbor the wild-type p53 [51,52]. The inactivation of p53 by HPV16 E6 results in p53 mutations being quite rare.…”

Section: Hpv-induced Carcinogenesis Of Hnsccmentioning

confidence: 99%

“…Furthermore, HPV-positive HNSCCs generally display less genomic complexity than do traditional HPV-negative HNSCCs, as indicated by several whole-exome sequencing analyses of HNSCC [55,56]. Interestingly, two independent reports based on next-generation sequencing studies have indicated that mutations in the PIK3CA genes are more frequent in HPVpositive than in HPV-negative HNSCCs [51,52]. Although the significance of this finding remains obscure, the phosphoinositide 3-kinase pathway might provide a potential treatment target for patients with HPV-OPC.…”

Section: Hpv-induced Carcinogenesis Of Hnsccmentioning

confidence: 99%

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The molecular mechanism of human papillomavirus-induced carcinogenesis in head and neck squamous cell carcinoma

Sano

Oridate

2016

Int J Clin Oncol

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Recently, the incidence of oropharyngeal cancer (OPC) has increased markedly in comparison to that of HNSCC, which is associated with the use of tobacco or alcohol or both. This increase has resulted mainly from the global rise in the number of human papillomavirus (HPV)-related oropharyngeal cancers (HPV-OPCs). HPV-OPC has several unique characteristics, including presentation in younger patients, better response rates to treatment, and better prognosis compared to alcohol- and smoking-related HNSCC. HPV infection status is now an independent prognostic factor for survival in patients with OPC. In general, HPV oncoproteins E6 and E7 are the primary viral factors responsible for the initiation and progression of HPV-related cancers via the inactivation of p53 and pRb. However, alterations in additional factors, including genomic instability, HPV DNA integration, and epigenetic alterations, could be equally important for neoplastic transformation and tumor progression. The impact of genomic instability and external environmental factors on the initiation of cervical cancer development through high-risk HPV infection has been well characterized, although less is known about the mechanism underlying HPV-induced carcinogenesis in HNSCC. This review provides an overview of the biology and molecular mechanisms of HPV-related cancers, including a particular focus on several recent studies on the comprehensive characterization of genomic alterations in HPV-associated HNSCC.

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Novel landscape of HLA‐G isoforms expressed in clear cell renal cell carcinoma patients

et al. 2017

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Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (HLA‐G), a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor‐infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anticancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in‐depth the HLA‐G isoforms expressed in these tumors. We found that the expression of HLA‐G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter‐ and intratumor heterogeneity. Moreover, our results generate an inventory of novel HLA‐G isoforms which includes spliced forms that have an extended 5′‐region and lack the transmembrane and alpha‐1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA‐G in ccRCC and reveals data that should prove suitable for the tailoring of future clinical applications.

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Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation

Abstract: Distinct mutation profiles in HPV- and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.

Cited by 64 publications

References 37 publications

Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma

Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma

The molecular mechanism of human papillomavirus-induced carcinogenesis in head and neck squamous cell carcinoma

Novel landscape of HLA‐G isoforms expressed in clear cell renal cell carcinoma patients

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