Cleaved NOTCH1 expression pattern in head and neck squamous cell carcinoma is associated with NOTCH1 mutation, HPV status, and high-risk features

Eleni M. Rettig, Christine H. Chung, Justin A. Bishop, Jason D. Howard, Rajni Sharma, Ryan Li, Christopher Douville, Rachel Karchin, Evgeny Izumchenko, David Sidransky, Wayne Koch, Joseph Califano, Nishant Agrawal, Carole Fakhry

Research output: Contribution to journalArticle

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Abstract

The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P <0.001). Most NOTCH1-wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31-276.15; P = 0.031). TP53 disruptivemutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein.

Original languageEnglish (US)
Pages (from-to)287-295
Number of pages9
JournalCancer Prevention Research
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

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Mutation
Odds Ratio
Confidence Intervals
Neoplasms
Negative Staining
Carcinoma, squamous cell of head and neck
Oncogenes
Mutagenesis
Staining and Labeling
Research
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cleaved NOTCH1 expression pattern in head and neck squamous cell carcinoma is associated with NOTCH1 mutation, HPV status, and high-risk features. / Rettig, Eleni M.; Chung, Christine H.; Bishop, Justin A.; Howard, Jason D.; Sharma, Rajni; Li, Ryan; Douville, Christopher; Karchin, Rachel; Izumchenko, Evgeny; Sidransky, David; Koch, Wayne; Califano, Joseph; Agrawal, Nishant; Fakhry, Carole.

In: Cancer Prevention Research, Vol. 8, No. 4, 01.04.2015, p. 287-295.

Research output: Contribution to journalArticle

Rettig, EM, Chung, CH, Bishop, JA, Howard, JD, Sharma, R, Li, R, Douville, C, Karchin, R, Izumchenko, E, Sidransky, D, Koch, W, Califano, J, Agrawal, N & Fakhry, C 2015, 'Cleaved NOTCH1 expression pattern in head and neck squamous cell carcinoma is associated with NOTCH1 mutation, HPV status, and high-risk features', Cancer Prevention Research, vol. 8, no. 4, pp. 287-295. https://doi.org/10.1158/1940-6207.CAPR-14-0366
Rettig, Eleni M. ; Chung, Christine H. ; Bishop, Justin A. ; Howard, Jason D. ; Sharma, Rajni ; Li, Ryan ; Douville, Christopher ; Karchin, Rachel ; Izumchenko, Evgeny ; Sidransky, David ; Koch, Wayne ; Califano, Joseph ; Agrawal, Nishant ; Fakhry, Carole. / Cleaved NOTCH1 expression pattern in head and neck squamous cell carcinoma is associated with NOTCH1 mutation, HPV status, and high-risk features. In: Cancer Prevention Research. 2015 ; Vol. 8, No. 4. pp. 287-295.
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abstract = "The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47{\%}), positive/nonperipheral (34{\%}), and negative (19{\%}). NICD1 expression was associated with NOTCH1 mutation status (P <0.001). Most NOTCH1-wild-type tumors were peripheral (55{\%}), whereas mutated NOTCH1 tumors were most commonly negative (47{\%}). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95{\%} confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95{\%} CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95{\%} CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95{\%} CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95{\%} CI, 1.31-276.15; P = 0.031). TP53 disruptivemutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein.",
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AU - Bishop, Justin A.

AU - Howard, Jason D.

AU - Sharma, Rajni

AU - Li, Ryan

AU - Douville, Christopher

AU - Karchin, Rachel

AU - Izumchenko, Evgeny

AU - Sidransky, David

AU - Koch, Wayne

AU - Califano, Joseph

AU - Agrawal, Nishant

AU - Fakhry, Carole

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N2 - The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P <0.001). Most NOTCH1-wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31-276.15; P = 0.031). TP53 disruptivemutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein.

AB - The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P <0.001). Most NOTCH1-wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31-276.15; P = 0.031). TP53 disruptivemutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein.

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