In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4012-4012
Kurzfassung:
Metastasis is the leading cause of caner-related death for solid tumors including gastric carcinoma (GC). An epigenetic biomarker panel for prediction GC metastasis will have clinical impact on the care of GC patients. In order to characterize the methylation differences between GCs with and without metastasis, genome-wide DNA methylation profiles were compared between 4 metastatic and 4 non-metastatic GCs and their surgical margins (SM). The GC genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared to SMs. From the list of differentially methylated CpG islands (CGIs), 63 candidate genes and 10 known tumor-related genes were selected for further analysis based on their known functions. Significant differential methylation was validated in the CGIs of 15 genes (Ps & lt;0.05) and confirmed using bisulfite-sequencing. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Hypermethylation of CGIs in several genes resulted in inactivation of their transcription; however, hypomethylation of GFRA1 correlated with an increase in expression. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations were inversely and coordinately associated with GC metastasis and the patients' overall survival throughout discovery and validation cohorts in China (n=108 and 222), and two independent validation cohorts in Japan and Korea (n=129 and 153). Multivariate analysis showed that the number of combined methylation changes of GFRA1, SRF, and ZNF382 was an independent predictor of overall survival for GC patients in the above 4 patient cohorts (n=246) after adjusting for the pTNM stage, GC location, differentiation, vascular embolus, age, and sex (HR=0.753; 95%CI [0.584-0.972]). The metastasis-prediction values of GFRA1 and SRF methylation are stronger than those of MMP7. In conclusion, methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of GC metastasis. Citation Format: Zhaojun Liu, Jun Zhang, Yanhong Gao, Lirong Pei, Naoko Hattori, Budong Zhu, Jiafu Ji, Yasuhito Yuasa, Wooho Kim, Toshikazu Ushijima, Huidong Shi, Dajun Deng. Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4012. doi:10.1158/1538-7445.AM2014-4012
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-4012
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2014
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
