High Frequency of HES1 Loss in Colorectal Adenocarcinomas with RAS/BRAF Mutations

Background and objectives: Hes1 is the downstream target of the canonical Notch-signaling pathway, which plays an essential role in maintaining intestinal proliferative crypts and regulating enterocyte differentiation. Loss of Hes1 expression is frequently observed in right-sided colon cancers. This study aims to present the relationship between the dysregulated Notch pathway and the status of RAS or BRAF mutations. Methods: Forty-three cases of primary colorectal adenocarcinomas were collected in a tertiary teaching hospital. Hes1 expression was assessed by the immunohistochemical stain. The RAS (KRAS and NRAS) and APC status were determined by the next-generation sequencing study. In addition, BRAF V600E was tested by PCR-based mutation analysis. Results: Overall, loss of Hes1 expression was observed more frequently in colorectal cancer specimens with either RAS or BRAF mutations than in the wild type (78.6% vs. 40.0%, p < 0.05). All the right-side tumors with RAS or BRAF mutations showed loss of Hes1 expression (12/12, 100%) (p < 0.05), compared to only 62.5% (10/16) of leftsided tumors. In addition, patients with Hes1 loss in tumor tissue were less likely to have immediate metastasis (59.1%, 13/22) compared to those with preserved Hes1 expression (83.3%, 5/6) (p = 0.37). Conclusion: The high frequency of Hes1 loss in colorectal adenocarcinoma is associated with either RAS or BRAF mutations, suggesting that synergistic effects by dysregulated Notch and RAS/BRAF mutation might play a vital role in colon carcinogenesis in some forms, especially the right-sided tumors. This finding might help guide future treatments for a subset of colon cancers.