AUTHOR=Kim Jeong Won , Jun Sun-Young , Ylaya Kris , Chang Hee-Kyung , Oh Young-Ha , Hong Seung-Mo , Chung Joon-Yong , Hewitt Stephen M. 

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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01427

DOI=10.3389/fonc.2020.01427

ISSN=2234-943X

ABSTRACT=<p><bold>Objective:</bold> Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to <italic>KRAS</italic> 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.</p><p><bold>Materials and Methods:</bold> 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 <italic>KRAS</italic> genotype, in 185 small intestinal adenocarcinomas.</p><p><bold>Results:</bold> The loss of HES-1 expression (HES-1<sup>Loss</sup>) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category (<italic>P</italic> = 0.018), pancreatic invasion (<italic>P</italic> = 0.005), high grade (<italic>P</italic> = 0.043), and non-tubular histology (<italic>P</italic> = 0.004). Specifically, in tumors with mutant <italic>KRAS</italic> (<italic>KRAS</italic><sup>MT</sup>), HES-1<sup>Loss</sup> was related to proximal location (<italic>P</italic> = 0.024), high T and N categories (<italic>P</italic> = 0.005 and 0.047, respectively), and pancreatic invasion (<italic>P</italic> = 0.004). Patients with HES-1<sup>Loss</sup> showed worse overall survival compared to those with intact HES-1 (HES-1<sup>Intact</sup>) (<italic>P</italic> = 0.013). Patients with HES-1<sup>Loss</sup>/<italic>KRAS</italic><sup>MT</sup> (median, 17.3 months) had significantly worse outcomes than those with HES-1<sup>Intact</sup>/<italic>KRAS</italic><sup>WT</sup> (39.9 months), HES-1<sup>Intact</sup>/<italic>KRAS</italic><sup>MT</sup> (47.6 month), and HES-1<sup>Loss</sup>/<italic>KRAS</italic><sup>WT</sup> (36.2 months; <italic>P</italic> = 0.010). By multivariate analysis, HES-1<sup>Loss</sup> (hazard ratio = 1.55, 95% confidence interval (CI), 1.07–2.26; <italic>P</italic> = 0.022) remained an independent prognostic factor.</p><p><bold>Conclusion:</bold> HES-1expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.</p>