The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers

Abstract

The Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) is an expert-curated description of the genes driving human cancer that is used as a standard in cancer genetics across basic research, medical reporting and pharmaceutical development. After a major expansion and complete re-evaluation, the 2018 CGC describes in detail the effect of 719 cancer-driving genes. The recent expansion includes functional and mechanistic descriptions of how each gene contributes to disease generation in terms of the key cancer hallmarks and the impact of mutations on gene and protein function. These functional characteristics depict the extraordinary complexity of cancer biology and suggest multiple cancer-related functions for many genes, which are often highly tissue-dependent or tumour stage-dependent. The 2018 CGC encompasses a second tier, describing an expanding list of genes (currently 145) from more recent cancer studies that show supportive but less detailed indications of a role in cancer.

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Figure 1. Functional classes of genes involved in fusions and their classification within the Cancer Gene Census.

(A) As a result of gene fusion, a tumour suppressor gene (TSG) may lose its suppressive abilities and a proto-oncogene may be transformed into an oncogene; e.g. QKI-MYB: in angiocentric glioma MYB is activated by truncation and the influence of the QKI enhancer; QKI loses its TSG function. (B) Genes that, after fusion, upregulate an oncogene through donation of regulatory element (e.g. active promoter, enhancer, or activating domain) are included in Tier 1; e.g. BCR-ABL1: in this fusion (also known as the Philadelphia chromosome), BCR, which is neither TSG nor oncogene, simply provides an oligomerisation domain, which enables constitutive activation of ABL1. (C) A fusion partner which only deactivates a TSG by disrupting its sequence is classified as a Tier 2 Cancer Gene Census (CGC) gene if it is recurrently involved in a fusion; e.g. CIITA-RALGDS: in Hodgkin lymphoma this fusion results in the N-terminal part of CIITA, which loses its TSG function, fused in an out-of-frame fashion to RALGDS, which is neither TSG nor oncogene in this case . (D) A fusion may also result in hyperactivation of an oncogene due to loss of an autoinhibitory domain, which is replaced by a fusion partner; e.g. KIAA1549-BRAF: in pilocytic astrocytoma the N-terminal BRAF autoregulatory domain is lost in the fusion protein, resulting in constitutively active BRAF expressed under the control of the KIAA1549 promoter. A fusion gene, such as KIAA1549, acting solely and recurrently through replacing a functional fragment of the other partner is included into Tier 2.

Figure 2. Tiers of the Cancer Gene Census.

Genes are classified into either Tier 1 or Tier 2 of the Cancer Gene Census (CGC) based on two criteria: a) the evidence of functional involvement in oncogenesis via impact on hallmarks of cancer, and b) the presence of patterns of somatic mutations in cancer samples that are concordant with the gene function determined by the literature curation (i.e. gene fusions; highly recurrent missense mutation in oncogenes; or a high proportion of inactivating mutations in tumour suppressor genes (TSGs)). Only strong evidence from both functional and mutational analyses qualify a gene to Tier 1. Genes with mutational patterns typical for cancer drivers but not functionally characterised, as well as genes with published mechanistic description of their involvement in cancer but without a proof of being somatically mutated in cancer comprise Tier 2 of the CGC.

Figure 3. Quantification of the 3 classes of cancer genes in the Cancer Gene Census tiers.

The figure shows Tier 1 (A), and both Tier 1 and Tier 2 combined (B). The role of Cancer Gene Census (CGC) genes in cancer differs, depending on disease type as demonstrated by the overlap between annotation sets. In Tier 1 69 genes can act as tumour suppressor genes (TSGs) or oncogenes. The majority of genes involved in gene fusions promote cancer by gaining oncogenic or losing tumour suppressing activity. However, about one third of the genes that act as fusion partners acts exclusively through modifying the function of their fusion partner. Numbers correspond to the number of genes in each of the categories.

Figure 4. Graphical summary of hallmarks of cancer-related functions of PTEN presented on the CGC website

(A) New gene summaries concisely integrate manually curated information on the impact of proteins (in this case PTEN) coded by cancer genes on the hallmarks of cancer in simple graphical form. If the wild-type (WT) protein function promotes a process related to cancer, it is marked within the green outer ring. The protein suppressing a hallmark of cancer in its WT form is marked within the blue outer ring. [modified from Hanahan & Weinberg, Cell, 2011] (B) The alternative presentation of the summary of PTEN functions shows how an alteration resulting in gain- or loss-of-function of a gene may impact each of the hallmarks. As WT PTEN promotes (P) growth suppression, an inactivating PTEN mutation will lead to increased proliferation of mutant cells. (S = suppresses)