Ipilimumab improves the survival of metastatic melanoma patients.,Despite documented, durable objective responses, a significant number of patients fails to benefit from treatment.,The aim of this study was to identify an upfront marker for treatment benefit.,A total of 187 metastatic melanoma patients treated in three Italian Institutions with 3 mg kg−1 ipilimumab, and 27 patients treated with 10 mg kg−1 ipilimumab, were evaluated.,Neutrophil-to-lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts.,Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied, adjusting for confounders and other prognostic factors.,In the training cohort of 69 patients treated at European Institute of Oncology, pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses.,Patients with baseline NLR<5 had a significantly improved PFS (HR=0.38; 95% CI: 0.22-0.66; P=0.0006) and OS (HR=0.24; 95% CI: 0.13-0.46; P<0.0001) compared with those with a NLR⩾5.,Associations of low NLR with improved survival were confirmed in three validation cohorts of patients.,Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve to identify patients most likely to benefit from this therapy.
Aberrations of protein-coding genes are a focus of cancer genomics; however, the impact of oncogenes on expression of the ∼50% of transcripts without protein-coding potential, including long noncoding RNAs (lncRNAs), has been largely uncharacterized.,Activating mutations in the BRAF oncogene are present in >70% of melanomas, 90% of which produce active mutant BRAFV600E protein.,To define the impacts of oncogenic BRAF on the melanocyte transcriptome, massively parallel cDNA sequencing (RNA-seq) was performed on genetically matched normal human melanocytes with and without BRAFV600E expression.,To enhance potential disease relevance by verifying expression of altered genes in BRAF-driven cancer tissue, parallel RNA-seq was also undertaken of two BRAFV600E-mutant human melanomas.,BRAFV600E regulated expression of 1027 protein-coding transcripts and 39 annotated lncRNAs, as well as 70 unannotated, potentially novel, intergenic transcripts.,These transcripts display both tissue-specific and multi-tissue expression profiles and harbor distinctive regulatory chromatin marks and transcription factor binding sites indicative of active transcription.,Coding potential analysis of the 70 unannotated transcripts suggested that most may represent newly identified lncRNAs.,BRAF-regulated lncRNA 1 (BANCR) was identified as a recurrently overexpressed, previously unannotated 693-bp transcript on chromosome 9 with a potential functional role in melanoma cell migration.,BANCR knockdown reduced melanoma cell migration, and this could be rescued by the chemokine CXCL11.,Combining RNA-seq of oncogene-expressing normal cells with RNA-seq of their corresponding human cancers may represent a useful approach to discover new oncogene-regulated RNA transcripts of potential clinical relevance in cancer.