HEY1 is expressed independent of NOTCH1 and is associated with poor prognosis in head and neck squamous cell carcinoma

Eleni M. Rettig, Justin A. Bishop, Nishant Agrawal, Christine H. Chung, Rajni Sharma, Fernando Zamuner, Ryan Li, Wayne M. Koch, Joseph A. Califano, Theresa Guo, Daria A. Gaykalova, Carole Fakhry

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Abstract

Objectives: Notch signaling is frequently altered in head and neck squamous cell carcinoma (HNSCC). However, the nature and clinical implications of this dysregulation are not well understood. We previously described an association of transcriptionally active NOTCH1 Intracellular Domain (NICD1) immunohistochemical (IHC) expression pattern with high-risk pathologic characteristics. Here we further characterize Notch signaling in HNSCC. Materials and methods: IHC expression patterns and clinicopathologic associations of Notch pathway molecules were evaluated among 78 tumors with known NOTCH1 mutation status. IHC was performed for JAG1, a NOTCH1 activating ligand, and HEY1, an NICD1 transcriptional target and Notch pathway activation marker. IHC pattern and H-score (% staining × intensity) were recorded and compared to clinicopathologic characteristics and survival. Survival was analyzed using Kaplan Meier method and Cox proportional hazards models (HR). Results: JAG1 and NICD1 expression patterns were highly concordant among tumors without truncating NOTCH1 mutations (p < 0.001), but were dissimilar among tumors with truncating NOTCH1 mutations (p = 0.24). There was evidence for JAG1-independent NOTCH1 activation among seven tumors, all with wild-type NOTCH1. HEY1 expression was associated with neither JAG1 nor NICD1 expression, but was associated with NOTCH1 mutation status (p = 0.03). Twelve (16%) tumors expressed HEY1 but not NICD1. Higher HEY1 H-score was significantly associated with worse overall (adjusted hazard ratio [aHR] 2.0, 95% CI = 1.0–4.2) and disease-specific (aHR = 3.3, 95% CI = 1.4–7.9) survival, whereas JAG1 and NICD1 expression were not associated with survival. Conclusions: These findings suggest both NOTCH1-dependent and -independent HEY1 regulation, and imply a previously unrecognized prognostic role for HEY1 in HNSCC.

Original languageEnglish (US)
Pages (from-to)168-175
Number of pages8
JournalOral Oncology
Volume82
DOIs
StatePublished - Jul 1 2018

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Mutation
Neoplasms
Proportional Hazards Models
Carcinoma, squamous cell of head and neck
Staining and Labeling
Ligands

Keywords

  • Head and neck cancer
  • Head and neck squamous cell carcinoma
  • HEY1
  • JAG1
  • Notch signaling
  • Survival

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research

Cite this

Rettig, E. M., Bishop, J. A., Agrawal, N., Chung, C. H., Sharma, R., Zamuner, F., ... Fakhry, C. (2018). HEY1 is expressed independent of NOTCH1 and is associated with poor prognosis in head and neck squamous cell carcinoma. Oral Oncology, 82, 168-175. https://doi.org/10.1016/j.oraloncology.2018.05.017

HEY1 is expressed independent of NOTCH1 and is associated with poor prognosis in head and neck squamous cell carcinoma. / Rettig, Eleni M.; Bishop, Justin A.; Agrawal, Nishant; Chung, Christine H.; Sharma, Rajni; Zamuner, Fernando; Li, Ryan; Koch, Wayne M.; Califano, Joseph A.; Guo, Theresa; Gaykalova, Daria A.; Fakhry, Carole.

In: Oral Oncology, Vol. 82, 01.07.2018, p. 168-175.

Research output: Contribution to journalArticle

Rettig, EM, Bishop, JA, Agrawal, N, Chung, CH, Sharma, R, Zamuner, F, Li, R, Koch, WM, Califano, JA, Guo, T, Gaykalova, DA & Fakhry, C 2018, 'HEY1 is expressed independent of NOTCH1 and is associated with poor prognosis in head and neck squamous cell carcinoma', Oral Oncology, vol. 82, pp. 168-175. https://doi.org/10.1016/j.oraloncology.2018.05.017
Rettig, Eleni M. ; Bishop, Justin A. ; Agrawal, Nishant ; Chung, Christine H. ; Sharma, Rajni ; Zamuner, Fernando ; Li, Ryan ; Koch, Wayne M. ; Califano, Joseph A. ; Guo, Theresa ; Gaykalova, Daria A. ; Fakhry, Carole. / HEY1 is expressed independent of NOTCH1 and is associated with poor prognosis in head and neck squamous cell carcinoma. In: Oral Oncology. 2018 ; Vol. 82. pp. 168-175.
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abstract = "Objectives: Notch signaling is frequently altered in head and neck squamous cell carcinoma (HNSCC). However, the nature and clinical implications of this dysregulation are not well understood. We previously described an association of transcriptionally active NOTCH1 Intracellular Domain (NICD1) immunohistochemical (IHC) expression pattern with high-risk pathologic characteristics. Here we further characterize Notch signaling in HNSCC. Materials and methods: IHC expression patterns and clinicopathologic associations of Notch pathway molecules were evaluated among 78 tumors with known NOTCH1 mutation status. IHC was performed for JAG1, a NOTCH1 activating ligand, and HEY1, an NICD1 transcriptional target and Notch pathway activation marker. IHC pattern and H-score ({\%} staining × intensity) were recorded and compared to clinicopathologic characteristics and survival. Survival was analyzed using Kaplan Meier method and Cox proportional hazards models (HR). Results: JAG1 and NICD1 expression patterns were highly concordant among tumors without truncating NOTCH1 mutations (p < 0.001), but were dissimilar among tumors with truncating NOTCH1 mutations (p = 0.24). There was evidence for JAG1-independent NOTCH1 activation among seven tumors, all with wild-type NOTCH1. HEY1 expression was associated with neither JAG1 nor NICD1 expression, but was associated with NOTCH1 mutation status (p = 0.03). Twelve (16{\%}) tumors expressed HEY1 but not NICD1. Higher HEY1 H-score was significantly associated with worse overall (adjusted hazard ratio [aHR] 2.0, 95{\%} CI = 1.0–4.2) and disease-specific (aHR = 3.3, 95{\%} CI = 1.4–7.9) survival, whereas JAG1 and NICD1 expression were not associated with survival. Conclusions: These findings suggest both NOTCH1-dependent and -independent HEY1 regulation, and imply a previously unrecognized prognostic role for HEY1 in HNSCC.",
keywords = "Head and neck cancer, Head and neck squamous cell carcinoma, HEY1, JAG1, Notch signaling, Survival",
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T1 - HEY1 is expressed independent of NOTCH1 and is associated with poor prognosis in head and neck squamous cell carcinoma

AU - Rettig, Eleni M.

AU - Bishop, Justin A.

AU - Agrawal, Nishant

AU - Chung, Christine H.

AU - Sharma, Rajni

AU - Zamuner, Fernando

AU - Li, Ryan

AU - Koch, Wayne M.

AU - Califano, Joseph A.

AU - Guo, Theresa

AU - Gaykalova, Daria A.

AU - Fakhry, Carole

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Objectives: Notch signaling is frequently altered in head and neck squamous cell carcinoma (HNSCC). However, the nature and clinical implications of this dysregulation are not well understood. We previously described an association of transcriptionally active NOTCH1 Intracellular Domain (NICD1) immunohistochemical (IHC) expression pattern with high-risk pathologic characteristics. Here we further characterize Notch signaling in HNSCC. Materials and methods: IHC expression patterns and clinicopathologic associations of Notch pathway molecules were evaluated among 78 tumors with known NOTCH1 mutation status. IHC was performed for JAG1, a NOTCH1 activating ligand, and HEY1, an NICD1 transcriptional target and Notch pathway activation marker. IHC pattern and H-score (% staining × intensity) were recorded and compared to clinicopathologic characteristics and survival. Survival was analyzed using Kaplan Meier method and Cox proportional hazards models (HR). Results: JAG1 and NICD1 expression patterns were highly concordant among tumors without truncating NOTCH1 mutations (p < 0.001), but were dissimilar among tumors with truncating NOTCH1 mutations (p = 0.24). There was evidence for JAG1-independent NOTCH1 activation among seven tumors, all with wild-type NOTCH1. HEY1 expression was associated with neither JAG1 nor NICD1 expression, but was associated with NOTCH1 mutation status (p = 0.03). Twelve (16%) tumors expressed HEY1 but not NICD1. Higher HEY1 H-score was significantly associated with worse overall (adjusted hazard ratio [aHR] 2.0, 95% CI = 1.0–4.2) and disease-specific (aHR = 3.3, 95% CI = 1.4–7.9) survival, whereas JAG1 and NICD1 expression were not associated with survival. Conclusions: These findings suggest both NOTCH1-dependent and -independent HEY1 regulation, and imply a previously unrecognized prognostic role for HEY1 in HNSCC.

AB - Objectives: Notch signaling is frequently altered in head and neck squamous cell carcinoma (HNSCC). However, the nature and clinical implications of this dysregulation are not well understood. We previously described an association of transcriptionally active NOTCH1 Intracellular Domain (NICD1) immunohistochemical (IHC) expression pattern with high-risk pathologic characteristics. Here we further characterize Notch signaling in HNSCC. Materials and methods: IHC expression patterns and clinicopathologic associations of Notch pathway molecules were evaluated among 78 tumors with known NOTCH1 mutation status. IHC was performed for JAG1, a NOTCH1 activating ligand, and HEY1, an NICD1 transcriptional target and Notch pathway activation marker. IHC pattern and H-score (% staining × intensity) were recorded and compared to clinicopathologic characteristics and survival. Survival was analyzed using Kaplan Meier method and Cox proportional hazards models (HR). Results: JAG1 and NICD1 expression patterns were highly concordant among tumors without truncating NOTCH1 mutations (p < 0.001), but were dissimilar among tumors with truncating NOTCH1 mutations (p = 0.24). There was evidence for JAG1-independent NOTCH1 activation among seven tumors, all with wild-type NOTCH1. HEY1 expression was associated with neither JAG1 nor NICD1 expression, but was associated with NOTCH1 mutation status (p = 0.03). Twelve (16%) tumors expressed HEY1 but not NICD1. Higher HEY1 H-score was significantly associated with worse overall (adjusted hazard ratio [aHR] 2.0, 95% CI = 1.0–4.2) and disease-specific (aHR = 3.3, 95% CI = 1.4–7.9) survival, whereas JAG1 and NICD1 expression were not associated with survival. Conclusions: These findings suggest both NOTCH1-dependent and -independent HEY1 regulation, and imply a previously unrecognized prognostic role for HEY1 in HNSCC.

KW - Head and neck cancer

KW - Head and neck squamous cell carcinoma

KW - HEY1

KW - JAG1

KW - Notch signaling

KW - Survival

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