Tumor Suppressor genes (TSGs) often locate at chromosomal regions with frequent deletions in tumors. Loss of 16q23 occurs frequently in multiple tumors, indicating the presence of critical TSGs at this locus, such as the well-studied WWOX. Herein we found that ADAMTS18, located next to WWOX, was significantly downregulated in multiple carcinoma cell lines. No deletion of ADAMTS18 was detected with multiplex differential DNA-PCR or high resolution 1-Mb array-based CGH analysis. Instead, methylation of the ADAMTS18 promoter CpG Island was frequently detected with methylation-specific PCR and bisulfite genome sequencing in multiple carcinoma cell lines and primary carcinomas, but not in any non-tumor cell line and normal epithelial tissue. Both pharmacological and genetic demethylation dramatically induced ADAMTS18 expression, indicating that CpG methylation directly contributes to the tumor-specific silencing of ADAMTS18. Ectopic ADAMTS18 expression leads to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells lacking the expression. Thus, through functional epigenetics, we identified ADAMTS18 as a novel functional tumor suppressor, being frequently inactivated epigenetically in multiple carcinomas.

Aberrant promoter methylation is an epigenetic mechanism for silencing tumor suppressor genes (TSG), and is also a biomarker for early cancer diagnosis and prognosis prediction. Recently, we and others identified DLC1 (ARHGAP7) as a functional TSG frequently methylated in multiple carcinomas. Here, we further uncovered DLC1 as one of the up-regulated genes in lymphoma cell lines after pharmacologic demethylation with 5-aza-2'-deoxycytidine (Aza). Transcriptional silencing and methylation of DLC1 was detected in most Hodgkin (HL) and non-Hodgkin lymphoma (NHL) cell lines, including 4/6 Hodgkin, 4/4 nasal NK/T-cell, 6/6 Burkitt and 5/5 diffuse large B-cell lymphoma cell lines. Aza treatment led to DLC1 promoter demethylation and transcriptional reactivation in silenced cell lines, indicating a methylation-mediated silencing. Aberrant methylation was further detected in 44% (14/37) Hodgkin, 77% (34/44) nasal NK/T-cell and 60-90% of various types of primary NHLs, but not in any normal lymph node or PBMC sample, and is thus tumor-specific. Analysis of microdissected Hodgkin/Reed-Sternberg (HRS) cells from HL cases confirmed the site of methylation as tumor cells. Moreover, DLC1 methylation was detected in 4/14 (29%) serum samples from HL patients. Our results indicate that DLC1 methylation is a frequent event in multiple lymphomagenesis and could serve as a tumor-specific biomarker for future lymphoma diagnosis.

In this study, we looked for potential gene-gene interaction in susceptibility to schizophrenia by an exhaustive searching for SNP–SNP interactions in 3 GWAS datasets (phs000021:phg000013, phs000021:phg000014, phs000167) using our recently published algorithm. The search space for SNP–SNP interaction was confined to 8 biologically plausible ways of interaction under dominant-dominant or recessive-recessive modes. First, we performed our search of all pair-wise combination of 729,454 SNPs after filtering by SNP genotype quality. All possible pairwise interactions of any 2 SNPs (5 × 10 11 ) were exhausted to search for significant interaction which was defined by p -value of chi-square tests. Nine out the top 10 interactions, protein coding genes were partnered with non-coding RNA (ncRNA) which suggested a new alternative insight into interaction biology other than the frequently sought-after protein–protein interaction. Therefore, we extended to look for replication among the top 10,000 interaction SNP pairs and high proportion of concurrent genes forming the interaction pairs were found. The results indicated that an enrichment of signals over noise was present in the top 10,000 interactions. Then, replications of SNP–SNP interaction were confirmed for 14 SNPs-pairs in both replication datasets. Biological insight was highlighted by a potential binding between FHIT (protein coding gene) and LINC00969 (lncRNA) which showed a replicable interaction between their SNPs. Both of them were reported to have expression in brain. Our study represented an early attempt of exhaustive interaction analysis of GWAS data which also yield replicated interaction and new insight into understanding of genetic interaction in schizophrenia.