Ann Hepatobiliary Pancreat Surg.  2018 Nov;22(4):305-309. 10.14701/ahbps.2018.22.4.305.

ALKBH5 gene is a novel biomarker that predicts the prognosis of pancreatic cancer: A retrospective multicohort study

Affiliations
  • 1Department of Surgery, Pusan National University Yangsan Hospital, Yangsan, Korea.
  • 2Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea. hedgehog@pusan.ac.kr

Abstract

BACKGROUNDS/AIMS
Discovery of new prognostic factors for cases in which the pancreatic cancer scoring and staging system does not result in a clear definition is imperative. We examined the role of Human AlkB homolog H5 (ALKBH5) as a prognostic marker for pancreatic cancer.
METHODS
Patient data were extracted from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). The prognostic value of ALKBH5 was confirmed via analysis of ALKBH5 and other clinical factors, such as age, sex, and stage, using the time-dependent area under the curve (AUC) of Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at three years, the Kaplan-Meier survival curve, and multivariate analysis.
RESULTS
ALKBH5 showed excellent prognosis prediction in comparison with existing markers in the two independent cohorts (n=262). Kaplan-Meier survival analysis showed that ALKBH5 expression was positively associated with overall survival (log-rank test, ICGC, p=0.001; TCGA, p=0.01). Notably, comparison of C-index and AUC values in ROC analysis showed that ALKBH5 was associated with high C-index and AUC values compared with other clinical variables (C-index: ICGC, 0.621; TCGA, 0.614 and AUC at three years: ICGC, 0.609; TCGA, 0.558). Multivariate analysis demonstrated thatALKBH5 is an independent prognostic factor (ICGC, p=0.0123; TCGA, p < 0.001).
CONCLUSIONS
These findings contribute to the study of RNA methylation in pancreatic cancer. We believe that ALKBH5 is a new prognostic marker for pancreatic cancer.

Keyword

ALKBH5; RNA methylation; Pancreatic cancer; Prognosis

MeSH Terms

Area Under Curve
Cohort Studies
Genome
Humans
Methylation
Multivariate Analysis
Pancreatic Neoplasms*
Prognosis*
Retrospective Studies*
RNA
ROC Curve
RNA

Figure

  • Fig. 1 Overview of the study workflow.

  • Fig. 2 Survival analyses of the ICGC and TCGA cohorts. (A, D) Kaplan-Meier estimates of overall survival of pancreatic cancer patients according to ALKBH5 gene expression. (B, E) Time dependent area under the curve (AUC) according to ALKBH5 gene expression. (C, F) Receiver operating characteristic (ROC) curve at three years according to ALKBH5 gene expression.


Reference

1. Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006; 20:197–209.
Article
2. Eto S, Ishikawa M, Asanoma M, Tashiro Y, Matsuyama K, Oshio T. A long-term survival case of advanced biliary cancer with repeated resection due to recurrence in the pancreaticogastrostomy site after pancreaticoduodenectomy. Ann Hepatobiliary Pancreat Surg. 2018; 22:173–177.
Article
3. Kim HS, Jang JY, Han Y, Lee KB, Joo I, Lee DH, et al. Survival outcome and prognostic factors of neoadjuvant treatment followed by resection for borderline resectable pancreatic cancer. Ann Surg Treat Res. 2017; 93:186–194.
Article
4. Wei P, Tang H, Li D. Insights into pancreatic cancer etiology from pathway analysis of genome-wide association study data. PLoS One. 2012; 7:e46887.
Article
5. Jaffrey SR, Kharas MG. Emerging links between m6A and misregulated mRNA methylation in cancer. Genome Med. 2017; 9:2.
Article
6. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013; 49:18–29.
Article
7. Xu C, Liu K, Tempel W, Demetriades M, Aik W, Schofield CJ, et al. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation. J Biol Chem. 2014; 289:17299–17311.
Article
8. Neureiter D, Jäger T, Ocker M, Kiesslich T. Epigenetics and pancreatic cancer: pathophysiology and novel treatment aspects. World J Gastroenterol. 2014; 20:7830–7848.
Article
9. Feng C, Liu Y, Wang G, Deng Z, Zhang Q, Wu W, et al. Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition. J Biol Chem. 2014; 289:11571–11583.
Article
10. Cancer Genome Atlas Research Network. Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013; 45:1113–1120.
Article
11. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2:401–404.
12. Zhang J, Baran J, Cros A, Guberman JM, Haider S, Hsu J, et al. International Cancer Genome Consortium Data Portal--a one-stop shop for cancer genomics data. Database (Oxford). 2011; 2011:bar026.
Article
13. Kleeff J, Michalski C, Friess H, Büchler MW. Pancreatic cancer: from bench to 5-year survival. Pancreas. 2006; 33:111–118.
14. Sato N, Goggins M. The role of epigenetic alterations in pancreatic cancer. J Hepatobiliary Pancreat Surg. 2006; 13:286–295.
Article
15. Kern S, Hruban R, Hollingsworth MA, Brand R, Adrian TE, Jaffee E, et al. A white paper: the product of a pancreas cancer think tank. Cancer Res. 2001; 61:4923–4932.
16. Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg. 1995; 221:721–731.
Article
17. Winter JM, Yeo CJ, Brody JR. Diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. J Surg Oncol. 2013; 107:15–22.
Article
18. Fong ZV, Winter JM. Biomarkers in pancreatic cancer: diagnostic, prognostic, and predictive. Cancer J. 2012; 18:530–538.
19. Nalls D, Tang SN, Rodova M, Srivastava RK, Shankar S. Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One. 2011; 6:e24099.
Article
20. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, et al. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 2017; 18:2622–2634.
21. Batista PJ. The RNA modification N6-methyladenosine and its implications in human disease. Genomics Proteomics Bioinformatics. 2017; 15:154–163.
22. Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017; 31:591–606.e6.
23. Zhang C, Zhi WI, Lu H, Samanta D, Chen I, Gabrielson E, et al. Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells. Oncotarget. 2016; 7:64527–64542.
Article
Full Text Links
  • AHBPS
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr