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Objective:  Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to  KRAS  mutations. HES-1 has been proposed as harboring oncogenic activity in colorectal cancer but has not been investigated in adenocarcinoma of the small intestine, where the drivers of oncogenesis are not as well-understood.   Materials and Methods:  To investigate the clinicopathologic and prognostic implications of HES-1, HES-1 immunohistochemical expression was analyzed in digital images along with clinicopathological variables, including survival and  KRAS  genotype, in 185 small intestinal adenocarcinomas.   Results:  The loss of HES-1 expression (HES-1 Loss ) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category ( P  = 0.018), pancreatic invasion ( P  = 0.005), high grade ( P  = 0.043), and non-tubular histology ( P  = 0.004). Specifically, in tumors with mutant  KRAS  ( KRAS  MT ), HES-1 Loss  was related to proximal location ( P  = 0.024), high T and N categories ( P  = 0.005 and 0.047, respectively), and pancreatic invasion ( P  = 0.004). Patients with HES-1 Loss  showed worse overall survival compared to those with intact HES-1 (HES-1 Intact ) ( P  = 0.013). Patients with HES-1 Loss / KRAS  MT  (median, 17.3 months) had significantly worse outcomes than those with HES-1 Intact / KRAS  WT  (39.9 months), HES-1 Intact / KRAS  MT  (47.6 month), and HES-1 Loss / KRAS  WT  (36.2 months;  P  = 0.010). By multivariate analysis, HES-1 Loss  (hazard ratio = 1.55, 95% confidence interval (CI), 1.07–2.26;  P  = 0.022) remained an independent prognostic factor.   Conclusion:  HES-1expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.

Loss of HES-1 Expression Predicts a Poor Prognosis for Small Intestinal Adenocarcinoma Patients