Multi-platform genome-wide analysis of melanoma progression to brain metastasis

AbstractMelanoma has a high tendency to metastasize to brain tissue. The understanding about the molecular alterations of early-stage melanoma progression to brain metastasis (MBM) is very limited. Identifying MBM-specific genomic and epigenomic alterations is a key initial step in understanding its aggressive nature and identifying specific novel druggable targets. Here, we describe a multi-platform dataset generated with different stages of melanoma progression to MBM. This data includes genome-wide DNA methylation (Illumina HM450K BeadChip), gene expression (Affymetrix HuEx 1.0 ST array), single nucleotide polymorphisms (SNPs) and copy number variation (CNV; Affymetrix SNP 6.0 array) analyses of melanocyte cells (MNCs), primary melanoma tumors (PRMs), lymph node metastases (LNMs) and MBMs. The analysis of this data has been reported in our recently published study (Marzese et al., 2014)

Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment

Toll-like receptors (TLRs) play a crucial role in the innate immune response and the subsequent induction of adaptive immune responses against microbial infection or tissue injury. Recent findings show that functional TLRs are expressed not only on immune cells but also on cancer cells. TLRs play an active role in carcinogenesis and tumor progression during chronic inflammation that involves the tumor microenvironment. Damage-associated molecular patterns (DAMPs) derived from injured normal epithelial cells and necrotic cancer cells appear to be present at significant levels in the tumor microenvironment, and their stimulation of specific TLRs can foster chronic inflammation. This review discusses how carcinogenesis, cancer progression, and site-specific metastasis are related to interactions between cancer cells, immune cells, and DAMPs through TLR activation in the tumor microenvironment

Genome–Wide Hypomethylation and Specific Tumor-Related Gene Hypermethylation are Associated with Esophageal Squamous Cell Carcinoma Outcome

IntroductionEsophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood.MethodsWe explored genome-wide DNA methylation data from The Cancer Genome Atlas project and identified a panel of tumor-related genes hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n = 140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n = 28) using a quantitative methylation-specific polymerase chain reaction.ResultsHypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55%, 24%, 20%, 19%, 14%, and 8% of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p = 0.02) and American Joint Committee on Cancer stage (p = 0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (p < 0.0001), and lower in greater than or equal to T2 (n = 69) than T1 tumors (n = 45; p = 0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p = 0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; p = 0.006 and p = 0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (greater than two genes) presented worse OS (p = 0.003).ConclusionsThis study demonstrates that epigenetic alterations of a panel of tumor-related genes and the noncoding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients