Cancer systems biology of TCGA SKCM: Efficient detection of genomic drivers in melanoma

Abstract

We characterized the mutational landscape of human skin cutaneous melanoma (SKCM) using data obtained from The Cancer Genome Atlas (TCGA) project. We analyzed next-generation sequencing data of somatic copy number alterations and somatic mutations in 303 metastatic melanomas. We were able to confirm preeminent drivers of melanoma as well as identify new melanoma genes. The TCGA SKCM study confirmed a dominance of somatic BRAF mutations in 50% of patients. The mutational burden of melanoma patients is an order of magnitude higher than of other TCGA cohorts. A multi-step filter enriched somatic mutations while accounting for recurrence, conservation, and basal rate. Thus, this filter can serve as a paradigm for analysis of genome-wide next-generation sequencing data of large cohorts with a high mutational burden. Analysis of TCGA melanoma data using such a multi-step filter discovered novel and statistically significant potential melanoma driver genes. In the context of the Pan-Cancer study we report a detailed analysis of the mutational landscape of BRAF and other drivers across cancer tissues. Integrated analysis of somatic mutations, somatic copy number alterations, low pass copy numbers, and gene expression of the melanogenesis pathway shows coordination of proliferative events by Gs-protein and cyclin signaling at a systems level.

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…High mutation burden has recently been defined as a key correlate to response to immune checkpoint therapy (Rizvi et al, 2015) (Snyder et al, 2014). Similar sharp high versus low clustering is seen for subgroups of breast and lung cancers and melanoma (Guan et al, 2015) (Figure S7d-f), the last being very responsive to immune checkpoint therapy (Topalian et al, 2015) (Hodi et al, 2010) (Weber et al, 2015).…”

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

“…However, BRAF mutations with paradoxical activation of the pathway via c-raf were also found in 4 patients, and in 1 of them (patient #41), 2 simultaneous BRAF mutations were identified: 1 at amino acid position 499 that has been suggested to be ERK activating and has been described in cardiofaciocutaneous syndrome, 51 and 1 in p.Glu695Lys, located in the protein kinase domain within the activator loop, previously reported in skin cutaneous melanoma. 52 In addition, a Gly503Arg mutation in PTPN11, another gene of the RAS pathway that has been reported as being frequently mutated in RAS-opathies (juvenile myelomonocytic leukemia, adult acute myelogenous leukemia, gastric cancer, glioblastoma, and anaplastic large cell lymphoma) was identified. 36,37,53 This gene is thought to play a role in acquired resistance to targeted therapy 54 and therefore represents a potential drug target.…”

Contemporary and potential future molecular diagnosis of melanoma

“…These observations supported the functional relevance of this mutation in melanoma . Overall TRRAP mutations prevalence across several large melanoma whole-exome studies is about 12% [8,24,33].…”

“…Since 2011, several studies exploited NGS technologies for a wide characterization of melanoma genetics [25,[28][29][30][31][32]. More recently, the landmark study from TCGA consortium reported the mutational screening by Whole Exome Sequencing (WES) coupled with RNA-seq and SNP-array data in 333 primary and metastatic cutaneous melanoma, providing one of the most comprehensive analysis on the somatic alterations underlying melanoma genesis to date [8,33].…”