Rettig Eleni M, Chung Christine H, Bishop Justin A, Howard Jason D, Sharma Rajni, Li Ryan J, Douville Christopher, Karchin Rachel, Izumchenko Evgeny, Sidransky David, Koch Wayne, Califano Joseph, Agrawal Nishant, Fakhry Carole
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Prev Res (Phila). 2015 Apr;8(4):287-95. doi: 10.1158/1940-6207.CAPR-14-0366. Epub 2015 Jan 29.
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 disruptive mutations 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.
Notch信号通路在头颈部鳞状细胞癌（HNSCC）中常发生改变；然而，NOTCH1失调的临床意义却知之甚少。本研究旨在表征HNSCC中转录活性NOTCH1细胞内结构域（NICD1）的表达，并评估其与NOTCH1突变状态及临床参数的相关性。对79例先前已测序且已知NOTCH1突变状态的存档HNSCC进行NICD1免疫组化检测。识别出三种不同的免疫组化染色模式：阳性/周边型（47%）、阳性/非周边型（34%）和阴性（19%）。NICD1表达与NOTCH1突变状态相关（P < 0.001）。大多数NOTCH1野生型肿瘤为周边型（55%），而NOTCH1突变型肿瘤最常见为阴性（47%）。非周边型肿瘤比周边型肿瘤更易发生包膜外扩散[校正比值比（aOR），16.01；95%置信区间（CI），1.92 - 133.46；P = 0.010]且分化差（aOR，5.27；95% CI，0.90 - 30.86；P = 0.066）。阴性染色肿瘤往往分化差（aOR，24.71；95% CI，1.53 - 399.33；P = 0.024）且人乳头瘤病毒（HPV）阳性可能性较小（aOR，0.043；95% CI，0.001 - 1.59；P = 0.087）。NOTCH1诱变与HPV状态显著相关，NOTCH1野生型肿瘤比NOTCH1突变型肿瘤更易为HPV阳性（aOR，19.06；95% CI，1.31 - 276.15；P = 0.031）。TP53破坏性突变与NICD1表达或NOTCH1突变无关。总之，NICD1在HNSCC中以三种不同模式表达，这些模式与高危特征显著相关。这些发现进一步支持NOTCH1在HNSCC中兼具肿瘤抑制因子和癌基因的双重作用。有必要进一步研究以阐明NOTCH1在HNSCC中的作用，并了解其中的临床和治疗意义。
