Variations in HPV function are associated with survival in squamous cell carcinoma

Gleber‐Netto, Frederico O.; Rao, Xiayu; Guo, Theresa; Xi, Yuanxin; Gao, Meng; Шен, Ли; Erikson, Kelly; Kalu, Nene N.; Xu, Guiyin; Fisch, Kathleen M.; Akagi, Keiko; Seiwert, Tanguy Y.; Gillison, Maura L.; Frederick, Mitchell J.; Johnson, Faye M.; Wang, Jing; Myers, Jeffrey N.; Califano, Joseph A.; Skinner, Heath D.; Pickering, Curtis R.

doi:10.1172/jci.insight.124762

Cited by 82 publications

(83 citation statements)

References 49 publications

(55 reference statements)

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“…The negative prognostic significance of reduced E2F target upregulation in this study adds to emerging evidence for oncogenic HPVs creating a greater imprint upon the host transcriptional landscape in the HPV+ HNSCCs that are readily curable. For instance, the poor prognosis HPV+ cases identified by us in TCGA using E2F target transcripts were nearly identical to a case cluster independently defined based on reduced HPV-driven dysregulation of a distinct set of genes ( Figure 6D) (7). Such evidence that multiple molecular traits are widely shared among atypical HPV+ cases that recur after definitive therapy holds promise for future development of clinically useful risk stratifiers based on levels of a limited set of host and/or viral proteins.…”

Section: Discussionmentioning

confidence: 57%

“…Furthermore, most of the 43 E2F targets that were significantly upregulated in HPV+ vs. HPV-oropharyngeal HNSCCs in TCGA lacked upregulation in TCGA_C2 (Supplemental Figure S8). The case composition of TCGA_C2 was then compared to another molecular subgroup of HPV+ oropharyngeal cases in TCGA reported recently to have worse prognosis (7). In that study, 19 cases with worse survival outcomes were clustered based on attenuation of a 38-gene expression profile that best distinguishes HPV+ from HPV-HNSCCs in TCGA.…”

Section: The E2f Target Gene Expression Pattern Is Prognostic In Hpv+mentioning

confidence: 99%

“…These factors are barriers both to identifying the optimal HPV+ HNSCC patients for therapy de-escalation and to developing distinct, more effective treatments for high risk cases. Among molecular prognostic features that could potentially guide treatment (7)(8)(9)(10), NOTCH1 loss of function is thus far the only mutation shown to predict poor outcomes in a published cohort of HPV+ HNSCCs (10).…”

Section: Introductionmentioning

confidence: 99%

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Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models

Facompre

Rajagopalan

Sahu

et al. 2019

Preprint

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Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate biomarkers and preclinical models. This study addressed both limitations using the largest panel of HPV+ HNSCC patient-derived xenografts (PDXs) and organoids described to date. Whole exome profiles of the PDXs were compared to those of HPV+ human tumors and cell lines, and genetic features of the models were analyzed relative to their growth properties and outcomes of their patients of origin. PDX engraftment enriched for negatively prognostic NOTCH1 mutations while preserving multiple features lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion, and absence of EGFR amplification. Observation of more mutations in faster-growing models facilitated identification of an association between mutational burden and local progression in both HPV+ and HPV-HNSCCs. Reduced E7 and p16INK4A levels found in a PDX from a lethal case led to detection of a similar profile among recurrent HPV+ HNSCCs in two patient cohorts, where low E2F target gene expression downstream of E7 predicted recurrence and mortality. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel applications for mutational burden and E2F target dysregulation in biomarker development.

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Section: Discussionmentioning

confidence: 57%

Section: The E2f Target Gene Expression Pattern Is Prognostic In Hpv+mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models

Facompre

Rajagopalan

Sahu

et al. 2019

Preprint

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“…The Cancer Genome Atlas (TCGA) data were obtained from the TCGA PanCancerAtlas Project (30) and analyzed for CASP8 mutations and RIP3 expression for HNSCC. Cell line RIP3 gene expression data is available through the Gene Expression Omnibus (GEO) (accession GSE122512) (31).…”

Section: Genomic Analysismentioning

confidence: 99%

Loss of Caspase-8 function in combination with SMAC mimetic treatment sensitizes Head and Neck Squamous Carcinoma to radiation through induction of necroptosis

Uzunparmak

2020

Preprint

Self Cite

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Abbreviations: HNSCC, head and neck squamous cell carcinoma; OSCC, oral squamous cell carcinoma; CASP8, Caspase-8; MOC1; mouse oral cancer-1; cIAP1/2, cellular inhibitor of apoptosis proteins-1/2; SMAC, second mitochondria-derived activator of caspase; RIP1, receptor-interacting serine/threonine-protein kinase-1; RIP3, receptor-interacting serine/threonine-protein kinase-3; MLKL, mixed lineage kinase domain-like; Z-VAD-FMK, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]fluoromethylketone; XRT, radiation therapy Conflicts of Interest: The authors have no potential conflicts of interest to disclose. Abstract Word Count: 250 Total Number of Figures and Tables: 6 Total Number of Supplementary Figures and Tables: 17 Significance: CASP8 status regulates necroptotic death in HNSCC and this pathway can be exploited therapeutically. AbstractCaspase-8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCC), and mutations of CASP8 are associated with poor overall survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a unique cell death mechanism. Here, we evaluated how CASP8 regulates necroptosis in HSNCC using cell line models and syngeneic mouse xenografts. In vitro, knockdown of CASP8 rendered HNSCCs susceptible to necroptosis induced by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, when combined with pan-caspase inhibitors Z-VAD-FMK or Emricasan. Strikingly, inhibition of CASP8 function via knockdown or Emricasan treatment was associated with enhanced radiation killing by Birinapant through induction of necroptosis. In a syngeneic mouse model of oral cancer, Birinapant, particularly when combined with radiation delayed tumor growth and enhanced survival under CASP8loss. Exploration of molecular underpinnings of necroptosis sensitivity confirmed that the level of functional receptor-interacting serine/threonine-protein kinase-3 (RIP3), a key enzyme in the necroptosis pathway was crucial in determining susceptibility to this mode of death. Although an in vitro screen revealed that many HNSCC cell lines were resistant to necroptosis due to low levels of RIP3, patient tumors maintain RIP3 expression and should therefore remain sensitive. Collectively, these results suggest that targeting the necroptosis pathway with SMAC mimetics, especially in combination with radiation, may be a relevant therapeutic approach in HNSCC with compromised CASP8 status, provided that RIP3 function is maintained.

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“…Four hundred and nineteen patients with histologically proven cervical carcinoma cases were prospectively recruited between 2013 and 2016 in 18 centers from seven European countries [7,8]. Fourty two patients were not eligible for analysis due to: inclusion error [26], death before start of treatment [1], investigator/patient decision [6], second cancer [4], lost to follow up [3], or missing data [2]. At a median follow up time of 22 months [min = 1•1max = 41•2], PFS data is available for 377 patients.…”

Section: Patient Population Eligible For Analysismentioning

confidence: 99%

Clinical and Genetic Landscape of Treatment Naive Cervical Cancer: Alterations in <i>PIK3CA</i> and in Epigenetic Modulators Associated with Sub-Optimal Outcome

et al. 2019

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HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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Variations in HPV function are associated with survival in squamous cell carcinoma

Cited by 82 publications

References 49 publications

Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models

Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models

Loss of Caspase-8 function in combination with SMAC mimetic treatment sensitizes Head and Neck Squamous Carcinoma to radiation through induction of necroptosis

Clinical and Genetic Landscape of Treatment Naive Cervical Cancer: Alterations in <i>PIK3CA</i> and in Epigenetic Modulators Associated with Sub-Optimal Outcome

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