Whole-genome landscapes of major melanoma subtypes

Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The identification of therapeutic targets in metastatic melanoma

Metastatic melanoma, a cancer historically refractory to chemotherapeutic strategies, has a poor prognosis and accounts for the majority of skin cancer related mortality. Although the recent approval of two new drugs combating this disease, Ipilimumab and Vemurafenib (PLX4032), has demonstrated for the first time in decades an improvement in overall survival; the clinical efficacy of these drugs has been marred by severe adverse immune reactions and acquired drug resistance in patients, respectively. Thus, understanding the etiology of metastatic melanoma will contribute to the improvement of current therapeutic strategies while leading to the development of novel drug approaches. In order to identify recurrently mutated genes of therapeutic relevance in metastatic melanoma, a panel of stage III local lymph node melanomas were extensively characterised using high-throughput genomic technologies. This led to the identification of mutations in TFG in 5% of melanomas from a candidate gene sequencing approach using SNP array analysis, 24% of melanomas with mutations in MAP3K5 or MAP3K9 though unbiased whole-exome sequencing strategies, and inactivating mutations in NF1 in BRAF/NRAS wild type tumours though pathway analysis. Lastly, this thesis describes the development of a melanoma specific mutation panel that can rapidly identify clinically relevant mutation profiles that could guide effective treatment strategies through a personalised therapeutic approach. These findings are discussed in respect to a number of important issues raised by this study including the current limitation of next-generation sequencing technology, the difficulty in identifying ‘driver’ mutations critical to the development of melanoma due to high carcinogenic exposure by UV radiation, and the ultimate application of mutation screening in a personalised therapeutic setting. In summary, a number novel genes involved in metastatic melanoma have been identified that may have relevance for current therapeutic strategies in treating this disease

Whole genome and exome sequencing of melanoma: a step toward personalized targeted therapy

Melanoma has historically been refractive to traditional therapeutic approaches. As such, the development of novel drug strategies has been needed to improve rates of overall survival in patients with melanoma, particularly those with late stage or disseminated disease. Recent success with molecularly based targeted drugs, such as Vemurafenib in BRAF-mutant melanomas, has now made “personalized medicine” a reality within some oncology clinics. In this sense, tailored drugs can be administered to patients according to their tumor “mutation profiles.” The success of these drug strategies, in part, can be attributed to the identification of the genetic mechanisms responsible for the development and progression of metastatic melanoma. Recently, the advances in sequencing technology have allowed for comprehensive mutation analysis of tumors and have led to the identification of a number of genes involved in the etiology of metastatic melanoma. As the methodology and costs associated with next-generation sequencing continue to improve, this technology will be rapidly adopted into routine clinical oncology practices and will significantly impact on personalized therapy. This review summarizes current and emerging molecular targets in metastatic melanoma, discusses the potential application of next-generation sequencing within the paradigm of personalized medicine, and describes the current limitations for the adoption of this technology within the clinic

The next generation's Frankenstein films (Letter)

In Mary Shelley's Frankenstein, Victor Frankenstein's well-intentioned research goes awry, creating a monster. The novel was first adapted to film in 1910, and many movie remakes and variations followed. We asked young scientists to craft their own Frankenstein-inspired science fiction by pitching a movie plot answering this question: What modern research could serve as the basis for the next box office hit? According to the responses, the research discoveries most likely to play a part in this year's blockbuster are gene-editing technology, xenotransplantation, and artificial intelligence. Microbes and viruses also played a starring role. Several scripts were set in the future against a backdrop of extreme climate change. Read on for a selection of our scientific Oscar line-up

Melanoma cell invasiveness is regulated by miR-211 suppression of the BRN2 transcription factor

To identify microRNAs potentially involved in melanomagenesis, we compared microRNA expression profiles between melanoma cell lines and cultured melanocytes. The most differentially expressed microRNA between the normal and tumor cell lines was miR-211. We focused on this pigment-cell-enriched miRNA as it is derived from the microphthalmia-associated transcription factor (MITF)-regulated gene, TRPM1 (melastatin). We find that miR-211 expression is greatly decreased in melanoma cells and melanoblasts compared to melanocytes. Bioinformatic analysis identified a large number of potential targets of miR-211, including POU3F2 (BRN2). Inhibition of miR-211 in normal melanocytes resulted in increased BRN2 protein, indicating that endogenous miR-211 represses BRN2 in differentiated cells. Over-expression of miR-211 in melanoma cell lines changed the invasive potential of the cells in vitro through directly targeting BRN2 translation. We propose a model for the apparent non-overlapping expression levels of BRN2 and MITF in melanoma, mediated by miR-211 expression

BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: implications for melanoma staging and adjuvant therapy

Background: 5-year survival for melanoma metastasis to regional lymph nodes (American Joint Committee on Cancer stage III) i

MC1R Is a potent regulator of PTEN after UV exposure in melanocytes

The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis