1729P - Heterogenity of Epigenetic and EMT Marks Observed in Hepatocellular Carcinoma with Keratin 19 Proficiency

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Hepatobiliary Cancers
Translational Research
Presenter Takeshi Nagasaka
Citation Annals of Oncology (2017) 28 (suppl_5): v595-v604. 10.1093/annonc/mdx391
Authors T. Nagasaka1, T. Okada1, N. Yokomichi2, F. Taniguchi1, T. Toshima1, K. YASUI1, T. Fuji1, Y. Mori1, T. Kawai1, Y. Umeda1, T. Yagi1, T. Fujiwara1, A. Goel3
  • 1Department Of Gastroenterological Surgery, Okayama University Hospital, 700-8558 - Okayama/JP
  • 2Palliative Medicine, Seirei Mikatahara General Hospital-Hamamatsu, 4338558 - Hamamatsu/JP
  • 3Center For Gastrointestinal Research Center For Translational Genomics And Oncology, CeBaylor Scott & White Research Institutenter for Translational Genomics and Oncology, 75246 - Texas/US

Abstract

Background

The expression of keratin 19 (K19) has been proposed as a novel predictor for poor prognosis in patients with hepatocellular carcinoma (HCC). However, the cell origin of K19-proficient HCC remains unclear. Herein we tried to reveal the cell origin of K19-proficient HCC by tracing epigenetic footprints in cultured cells and clinical materials.

Methods

The KRT19 gene, which encodes K19, has a CpG island in promoter region and therefore implicates DNA methylation as a potential epigenetic process for K19 expression. Firstly, we examined epigenetic alterations in K19-positive HCC cell lines. Next, from a panel of 564 surgically resected HCCs, we clarify the clinicopathological relevance of K19-preficent HCCs by analyzing robust methylation analyses in KRT19 promoter region and LINE-1 in comparison with other cholangiocytic (K7), hepatocytic markers (HepPar-1 and Arginase-1), EMT markers (E-cadherin and vimentin), and a signal pathway associate with biliary differentiation (NOTCH-1).

Results

In vitro, although methylation in KRT19 promoter was associated with K19 deficiency, 5-aza-dC treatment failed to re-expression of K19. From 564 surgically resected HCCs, a cohort of 125 HCC patients was selected and analyzed after exclusion of HCC with recurrence, TNM stage as IIIB or more, preoperative therapy, transplantation, and combined hepatocellular-cholangiocarcinoma. In this cohort, K19 expression was found in 29 HCCs (23.2%), and corresponded with poor survival following surgery (P = 0.025) and extrahepatic recurrence free survival (P = 0.017). Compared with K19-deficient HCCs, the lower methylation level in KRT19 promoter was observed in K19-proficient HCCs (P

Conclusions

K19-proficient HCC showed the poor prognosis owing to extrahepatic recurrence and the molecular signatures were different from K19-deficeint HCC, providing novel insights of heterogeneity underlying development of HCC with extrahepatic metastasis.

Clinical trial identification

Legal entity responsible for the study

Takeshi Nagasaka

Funding

None

Disclosure

All authors have declared no conflicts of interest.