Further research found that 33 percent of young people with spitzoid melanoma screened in this study carried novel mutations, including rearrangements, in the same gene, MAP3K8. Analogous mutations were also found in 1.5 percent of the almost 500 adult melanoma patients tested.
These results indicate that MAP3K8 is the most commonly mutated gene in pediatric spitzoid melanoma.
MAP3K8 surfaced as an oncogene that initiated spitzoid melanoma through the St.
"Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas." Newman turned his attention to the dozens of other rearrangements and other mutations that sequencing revealed, including a novel fusion gene created when MAP3K8, a kinase, fused with part of another gene.
MAP3K8 is known to regulate MEK, a gene that promotes cell division and is deregulated in other cancers.
When another novel MAP3K8 mutation was discovered in a second St.
Newman and his colleagues mined the transcriptome sequencing data in the Cancer Genome Atlas and to their surprise found 1.5 percent of the 472 adult melanoma patients carried similar MAP3K8 mutations.
So far, heterozygous pathogenic variants have been documented in seventeen genes (PTPN11, SOS1, SOS2, KRAS, NRAS, RAF1, SHOC2, CBL, RRAS, RIT1, RASA2, MAP3K8
, SPRY1, MYST4, LZTR1, A2ML1, and PP1CB) that underlie this disorder or clinically related phenotypes [1, 2].
These genes encoded cytokines (CSF3, CSF2, CCL3, TNF, CCR1, IL13, KIT, CCL5, CCL4, IL10, CXCL10, IL12RB2, IFNG, IL1B, IL1A, IL8, MET, CD40, HGF, LEP, CXCL16, CX3CR1, CCR2, PDGFRA, IL12B, IL2), lipid metabolism related genes (CD36, GPX4, LPIN1, LPL, LPB), transcription regulators (BCL3, FOS and NFKBIA), receptors (TNF, IL8, RELA, TLR1, TIRAP, TLR2, NFKBIA, NFKB1, TLR4, CD40, CCL5, CXCL10, FOS, JUN, MAP3K8
, IL1B, LBP, IL12B, CD14, SPP1), and others such as SELP, SELL, and SOD1, all play a role in some aspect of the immune response including cytokine activity (IL10, TNF, IL8, and IL1B), cell adhesion (SELL and SELP), immune activation (CD14 and TLR2), acute phase reaction (TNF, IL1B, and SAA3), apoptosis (BCL2, BAX).
Endochondral Actin Focal ossification cytoskeleton adhesion VEGFA FGF2 COL11A1 ADAMTS4 FGFR1 COL3A1 PLAT4 TMSB4X COL4A1 COL10A1 GNA13 COL4A2 TGFB2 PDGFA COL4A4 PTHrP FGF1 COL5A1 FGF2 ENAH COL5A2 C4ST1 MSN COL1A1 FGFR1 GSN LAMC2 PDGFRB PDGFRB THBS2 COL1 KRAS CAV2 MRAS ARHGAP5 SOS2 PTEN AKT3 PDGFA PDGFC PGF ITGA2 PDGFRB RAP1B MAPK8 TGF[beta] MAPK signaling signaling Adipogenesis SMURF1 MAPK8 FOXO1A MAPK8 NGFB TRIB3 SKP1 PDGFRB PCK2 NEDD9 RASA2 EGR2 ETS1 SOS2 DDIT3 KLF11 KRAS GADD45A ATF3 MRAS GADD45B FOSB NF1 HIF1A SKIL RAP1B IRS1 SMURF1 DUSP1 MEF2D ZFYVE16 DDIT3 FAS HSPB1 SPOCK IL1A FAS TGFB2 MAP313 ZAK AKT3 MAP3K8
GADD45A Table 2: Genes involved in osteogenesis-related pathways that are downregulated in CYD-treated hMSCs.
GPX3, TLR2, BDKRB1, FBXO5, BRCA1, MAP3K8
, SCARB1, and 6 lncRNAs (XR_111050, NR_024031, FR374455, FR401275, FR406817, and FR148647) played a key role in osteogenic process, and lncRNA XR_111050 promoted osteogenic differentiation of mesenchymal stromal cells .