Abstract 2633: The effects of aberrant global methylation in hepatocellular carcinoma
Authors: Daniel C. Edelman, Fatma Shebl, Yonghong Wang, Holly Stevenson, Lawrence Sternberg, Joshua Sampson, Baiyu Yang, Paul S. Meltzer, Katherine McGlynn
Journal: Cancer Research (2018)

Abstract A better understanding of the molecular pathology of hepatocellular carcinomas (HCC), particularly in the United States of America (USA), could provide more effective biomarkers for early detection, diagnosis and treatment for this aggressive cancer. From two SEER Residual Tissue Repositories (Hawaii and Iowa), 483 surgical samples were obtained (223 cases of matched tumor/adjacent-normal); 30 were of OCT origin with the remaining FFPE. Purified genomic DNA was tested by the Illumina Infinium HumanMethylation450K BeadChip array according to the manufacturer's recommendations. Data were processed by using Lumi, methylumi, and other relevant R packages and also the Partek Genomics Suite. ANOVA results with FDR&amp;lt;0.01 between tumor and normal samples plus absolute beta value differences greater than 0.2 in FFPE or OCT, respectively, were compared and the overlapping 7279 targets generated the final gene list. In tumor, the genes MYH7 and TPO are hypomethylated, whereas OTX1 and C1orf70 are hypermethylated. Methyl2CGH aggregated patterns (FFPE only), showed that tumor was enriched for large chromosomal losses in Chr 8p and 17p with possible focal losses in Chr 4, 6, 8, 10, 12, 13, 17, 18 and 22. Large aberrations in chromosomal gains were seen in Chr 1q and 8q with possible focal gains seen in most chromosomes (excluding 9, 16, 21, 22). Importantly, 41 tumor suppressor genes are associated with copy number loss; these include RB1, TP53, MAP2K4 and CBFA2T3. However, identification of differentially methylated regions by using a segmentation method (NEXUS) suggested that tumor samples were more likely to be hypermethylated across the genome than hypomethylated (1q only). A possible limitation is that combining OCT and FFPE data is suspect due to at least 40 genes that specifically are hypermethylated in OCT samples but not FFPE. We previously reported that relative telomere length is prognostic for survival in HCC (Yang, et al., 2016). In this study we detected one gene, ZSCAN4, in the telomere maintenance pathway that is hypomethylated in tumor samples; the biological significance of this needs to be explored. In conclusion, for the under-studied USA HCC population, we have established strong preliminary methylation and copy number data indicating that there are specific epigenetic and chromosomal abnormalities that upon verification, could prove useful as biomarkers for improved understanding of the pathogenesis, early detection, and diagnosis of HCC. Citation Format: Daniel C. Edelman, Fatma Shebl, Yonghong Wang, Holly Stevenson, Lawrence Sternberg, Joshua Sampson, Baiyu Yang, Paul S. Meltzer, Katherine McGlynn. The effects of aberrant global methylation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2633.