Identification of TFG (TRK‐fused gene) as a putative metastatic melanoma tumor suppressor gene

Abstract

High density SNP arrays can be used to identify DNA copy number changes in tumors such as homozygous deletions of tumor suppressor genes and focal amplifications of oncogenes. Illumina Human CNV370 Bead chip arrays were used to assess the genome for unbalanced chromosomal events occurring in 39 cell lines derived from stage III metastatic melanomas. A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39). In addition, a number of focal homozygous deletions potentially targeting novel melanoma tumor suppressor genes were identified. Because of their likely functional significance for melanoma progression, FAS, CH25H, BMPR1A, ACTA2, and TFG were investigated in a larger cohort of melanomas through sequencing. Nonsynonymous mutations were identified in BMPR1A (1 of 43), ACTA2 (3 of 43), and TFG (5 of 103). A number of potentially important mutation events occurred in TFG including the identification of a mini mutation "hotspot" at amino acid residue 380 (P380S and P380L) and the presence of multiple mutations in two melanomas. Mutations in TFG may have important clinical relevance for current therapeutic strategies to treat metastatic melanoma.

TRIM68 Negatively Regulates IFN-β Production by Degrading TRK Fused Gene, a Novel Driver of IFN-β Downstream of Anti-Viral Detection Systems

“…Regarding its role in cancer, TFG has been found to be preferentially up-regulated in prostate cancer cell lines and tissues, with TFG expression being associated with a higher probability of tumour recurrence following surgery [46]. In addition TFG has been identified as a putative metastatic melanoma tumour suppressor gene [47] and is also thought to play a role in non-small cell lung cancer, acting as a translocation partner for anaplastic lymphoma kinase (ALK) [48]. Miranda et al were the first to suggest TFG may play a role in immune regulation, showing that TFG over-expression can enhance the effect of TNF-α, TANK, TRAF2 and TRAF6 in inducing NF-κB activity suggesting that TFG is part of a complex containing TANK and IKK-γ [32].…”

Somatic Mutations in MAP3K5 Attenuate Its Proapoptotic Function in Melanoma through Increased Binding to Thioredoxin

“…Additional tissue was collected and cell lines established at Queensland Institute of Medical Research (41 stage III and 46 stage IV (AJCC) early passage metastatic melanoma cell lines). All cell lines were established as described previously (Castellano et al, 1997; Dutton-Regester K, 2012; Pavey et al, 2004) with informed patient consent under a protocol approved by the Queensland Institute of Medical Research Human Research Ethics Committee.…”

Melanomas of unknown primary have a mutation profile consistent with cutaneous sun‐exposed melanoma

“…Melanoma of unknown primary cell lines used for exome sequencing were established at the Queensland Institute of Medical Research (QIMR) as previously described (Dutton‐Regester et al., ). These cell lines were profiled to confirm authenticity and matching status using an AmpFISTR Profiler Plus PCR amplification kit (Applied Biosystems, Foster City, CA, USA) and analyzed on a 3100 Genetic Analyzer (Applied Biosystems).…”