Jacobsen Frank, Kohsar Jacob, Gebauer Florian, Kluth Martina, Hube-Magg Claudia, Simon Ronald, Bockhorn Maximilian, Hinsch Andrea, Burandt Eike, Lübke Andreas M, Steurer Stefan, Tachezy Michael, Sauter Guido, Izbicki Jacob R, Wilczak Wildemar, Melling Nathaniel
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
These authors contributed equally to this work.
Oncotarget. 2020 Mar 24;11(12):1007-1016. doi: 10.18632/oncotarget.27507.
The p16 tumor suppressor is coded by (9p21) and plays an important role during carcinogenesis and tumor progression in numerous tumor entities. The aim of our study was to evaluate the prognostic role of p16 expression and CDKN2A deletion in esophageal cancer (EC). Therefore, we analyzed p16 and KI67 expression by immunohistochemistry and 9p21 deletion by fluorescence hybridization on a tissue microarray including 398 adenocarcinomas (AC) and 293 squamous cell carcinomas (SCC) with clinical follow up-data. p16 positivity was found in 30.2% of AC and 13.9% of SCC and CDKN2A deletion in 32.1% of AC and 33.5% of SCC. In SCC p16 immunostaining correlated with low tumor stage ( = 0.014). In AC Ki67 positivity was associated with high tumor stage ( = 0.001), presence of lymph node metastasis ( = 0.009), high UICC stage ( = 0.001) and poor grading ( = 0.005). Overall survival (OS) was shorter for patients with high Ki67 labeling index (Ki67LI; = 0.009) and negative p16 immunostaining ( = 0.026). In both histological tumor types, CDKN2A deletion showed no association with phenotype or outcome. Proportional cox-regression modeling revealed patients' age, tumor stage, lymph node metastasis and Ki67 labeling index as independent prognostic markers in AC. In SCC, only patients' age and tumor stage proved to be independent prognosticators. In summary, our study shows that loss of p16 expression and high Ki67LI is linked to shortened OS in AC. CDKN2A deletion shows no relevant association with tumor phenotype and patient outcome.
p16肿瘤抑制基因由（9p21）编码，在众多肿瘤实体的致癌过程和肿瘤进展中发挥重要作用。我们研究的目的是评估p16表达和CDKN2A缺失在食管癌（EC）中的预后作用。因此，我们通过免疫组织化学分析了p16和KI67的表达，并通过荧光原位杂交分析了398例腺癌（AC）和293例鳞状细胞癌（SCC）组织芯片上的9p21缺失情况，这些病例均有临床随访数据。在AC中，30.2%呈p16阳性，在SCC中为13.9%；在AC中，32.1%存在CDKN2A缺失，在SCC中为33.5%。在SCC中，p16免疫染色与低肿瘤分期相关（P = 0.014）。在AC中，Ki67阳性与高肿瘤分期（P = 0.001）、淋巴结转移（P = 0.009）、高UICC分期（P = 0.001）和高分级（P = 0.005）相关。高Ki67标记指数（Ki67LI；P = 0.009）和p16免疫染色阴性的患者总生存期（OS）较短（P = 0.026）。在两种组织学肿瘤类型中，CDKN2A缺失与表型或预后均无关联。比例cox回归模型显示，患者年龄、肿瘤分期、淋巴结转移和Ki67标记指数是AC的独立预后标志物。在SCC中，只有患者年龄和肿瘤分期被证明是独立的预后因素。总之，我们的研究表明，p16表达缺失和高Ki67LI与AC患者的OS缩短有关。CDKN2A缺失与肿瘤表型和患者预后无显著关联。
