Anti-BRAF V600E monoclonal antibody, clone SN9

Purpose Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs. Methods Next-generation sequencing was carried out on mucosal melanoma samples (n= 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescencein situhybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations inTERTwere detected by droplet digital polymerase chain reaction. Results In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein.TERTpromoter mutation was not detected in GMs (n= 40), but copy number variations in theTERTregion were observed in 20% (7/35) of the samples.TERTamplification was mutually exclusive with ALT (P< 0.05). Kaplan-Meier revealed that ALT relative toTERTamplification was associated with longer overall survival in GM patients without metastasis. Conclusion These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.

Carcinoma development in colorectal cancer is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of colorectal cancer metastatic disease, yet how RAS-ERK signaling regulates colorectal cancer metastasis remains unknown. In this study, we used an unbiased screening approach based on selection of highly liver metastatic colorectal cancer cells in vivo to determine genes associated with metastasis. From this, an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated with increased recurrence and reduced survival in patients with colorectal cancer tumors. Higher levels of EMGS expression were detected in the colorectal cancer subsets consensus molecular subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, two genes within the EMGS, were subjected to gain-of-function and loss-of-function studies in several colorectal cancer cell lines and then tested in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in colorectal cancer cells, which facilitated development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled the expression of cytokines IL10 and CXCL1, providing evidence for a causal role of IL10 in supporting liver colonization. In summary, these studies demonstrate that amplification of ERK1/2 signaling in KRAS-mutated colorectal cancer cells affects the cytokine milieu of the tumors, possibly affecting tumor-stroma interactions and favoring liver metastasis formation. Significance: These findings identify amplified ERK1/2 signaling in KRAS-mutated colorectal cancer cells as a driver of tumorstroma interactions that favor formation of metastases in the liver.