Expression of ATF6 as a marker of pre-cancerous atypical change in ulcerative colitis-associated colorectal cancer: a potential role in the management of dysplasia

Marie Hanaoka,Akifumi Kikuchi,Toshiaki Ishikawa,Michiyo Tokura,Tatsuyuki Kawano,Shinichi Yamauchi,Hiroyuki Uetake,Megumi Ishiguro,Masamichi Yasuno

doi:10.1007/s00535-017-1387-1

Marie Hanaoka, Akifumi Kikuchi + Show 7 more

Open Access

https://doi.org/10.1007/s00535-017-1387-1

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Abstract

BackgroundDiagnosis of low-grade dysplasia (LGD) is important in the management of ulcerative colitis (UC), but it is often difficult to distinguish LGD from inflammatory regenerative epithelium. The unfolded protein response (UPR) is activated in inflammatory bowel disease and malignancies. We aimed to identify a UPR-related gene that is involved in the development of non-UC and UC-associated colorectal cancer (CRC), and to investigate whether the target gene is useful for the diagnosis of LGD.MethodsUsing our microarray gene expression database of 152 CRCs, we identified activating transcription factor 6 (ATF6) as a target gene. Immunohistochemistry (IHC) of ATF6 were analyzed in 137 surgically resected CRCs, 95 endoscopically resected adenomas and pTis cancers, and 136 samples from 51 UC patients (93 colitis without neoplasia, 31 dysplasia, and 12 UC-associated CRC). The diagnostic accuracy of ATF6 and p53 as markers of LGD was assessed.ResultsATF6 expression was detectable in all CRCs but not in normal colonic mucosa, was elevated with increase in cellular atypia (adenoma with moderate atypia < severe atypia < pTis CRC, p < 0.001), and higher in dysplasia and CRC than in non-neoplastic colitis (p < 0.001). Notably, the difference between colitis and LGD was significant. Compared to p53-IHC, ATF6-IHC had better diagnostic accuracy for distinguishing LGD from background inflammatory mucosa (sensitivity 70.8 vs. 16.7%, specificity 78.5 vs.71.0%, respectively).ConclusionsATF6 was expressed in lesions undergoing pre-cancerous atypical change in both non-UC and UC-associated CRC and may be used to distinguish LGD from inflammatory regenerative epithelium in UC patients.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.The incidence of ulcerative colitis (UC) is significantly increasing around the world [1]
We aimed to identify a unfolded protein response (UPR)-related gene that is involved in the development of non-UC and UCassociated colorectal cancer (CRC), and to investigate whether the target gene is useful for the diagnosis of low-grade dysplasia (LGD)
activating transcription factor 6 (ATF6) expression was detectable in all CRCs but not in normal colonic mucosa, was elevated with increase in cellular atypia, and higher in dysplasia and CRC than in non-neoplastic colitis (p \ 0.001)

Summary

Introduction

The incidence of ulcerative colitis (UC) is significantly increasing around the world [1]. The risk of developing UC-associated CRC increases 0.5–1% per year for patients with disease duration in excess of 8–10 years [2]. Detection of UC-associated CRC is essential for successful management of long-standing UC [3]. Endoscopic and histologic detection of dysplasia (i.e., precancerous lesions) is often difficult due to. Diagnosis of low-grade dysplasia (LGD) is important in the management of ulcerative colitis (UC), but it is often difficult to distinguish LGD from inflammatory regenerative epithelium. We aimed to identify a UPR-related gene that is involved in the development of non-UC and UCassociated colorectal cancer (CRC), and to investigate whether the target gene is useful for the diagnosis of LGD

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