The Network of Cancer Genes (NCG) is a manually curated repository of 2372 genes whose somatic modifications have known or predicted cancer driver roles. These genes were collected from 275 publications, including two sources of known cancer genes and 273 cancer sequencing screens of more than 100 cancer types from 34,905 cancer donors and multiple primary sites. This represents a more than 1.5-fold content increase compared to the previous version. NCG also annotates properties of cancer genes, such as duplicability, evolutionary origin, RNA and protein expression, miRNA and protein interactions, and protein function and essentiality. NCG is accessible at http://ncg.kcl.ac.uk/.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1612-0) contains supplementary material, which is available to authorized users.

PurposePegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) –negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non–small-cell lung cancer (NSCLC).Patients and MethodsUsing a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM.ResultsNo dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM.ConclusionTarget engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.

Background Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear and hampers our understanding of tissue homeostasis and cancer development. Results Here, we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and non-cancer somatic evolution in 122 cancer types and 12 non-cancer tissues. Mapping the alterations of these genes in 7953 pan-cancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and non-cancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. Conclusions Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and non-cancer somatic drivers, their literature support, and properties are accessible in the Network of Cancer Genes and Healthy Drivers resource at http://www.network-cancer-genes.org/.

The Network of Cancer Genes (NCG) is a manually curated repository of 2,372 genes whose somatic modifications have a known or predicted cancer driver role.These genes were collected from 275 publications, including two sources of known cancer genes and 273 cancer sequencing screens of 119 cancer types in 31 primary sites from 34,905 cancer donors. This represents a more than 1.5-fold increase in content as compared to the previous version. NCG also annotates properties of cancer genes, such as duplicability, evolutionary origin, RNA and protein expression, miRNA and protein interactions, protein function and essentiality. NCG is accessible at http://ncg.kcl.ac.uk/.