Census of cancer genes from a comprehensive review of cancer gene panels

Abstract

Background: The field of personalised cancer medicine and the supporting diagnostic tools are growing rapidly. Several research projects and many molecular diagnostic companies have selected relevant or clinically actionable genes for targeted next-generation sequencing (NGS) panels. However, there is no consensus in the scientific literature about which genes these are, and what the logic of their selection is (based on their biological function, actionability, mutational frequency and prognostic/therapeutic relevance). Our aim was to compile a comprehensive list of cancer genes and analyse their function and potential clinical relevance. Methods: We collected commercially available cancer gene panels (focusing on NGS panels for SNV detection) and also cancer gene lists defined in the scientific literature. Our study included 34 different NGS-based cancer panels of 22 institutes or diagnostic companies. Solid, haematology, or pan-cancer indication panels and cancer predisposition panels were included. This list was extended with 11 ‘cancer gene’ lists based on literature search such as COSMIC Cancer Gene Census, The Cancer Genomics Resource List 2014, and driver genes according to Vogelstein et al, 2013. We categorised the union of the genes based on their association with solid or haematology indications, their functions, and we explored actionable targets and related compounds based on data from publicly available databases (like ChEMBL and Genomics of Drug Sensitivity in Cancer). Results: Panel sizes vary between 8 and 710, with the average of 162 genes. More than half of the panels (18/34) contain <100 genes, 9 panels contain 117-160 genes and the rest (7 panels) contain ≥315 genes. The cumulated gene list of these panels and literature-based collections includes 2040 cancer-related genes. TP53 and KIT, the most frequent genes are listed in 32 panels, while ∼500 genes are listed in one panel only. More than 250 of the genes are reported to be relevant in solid tumours only, while about 140 genes in haematology only. The rest is either not specified or is relevant in pan-cancer indications. 41 ‘ADME-TOX’ genes are included, which are important in pharmacogenomics (ABC and CYP genes). Other functional groups can be defined, for example enzymes (600<genes), and within that: kinases (300<genes). More than 300 out of 2040 genes can be linked to clinically relevant compounds according to at least one of the databases investigated. Conclusions: A universal ‘cancer gene’ list, which have been selected by the scientific community so far for targeted re-sequencing, contains about 2000 genes. No comprehensive targeted cancer gene panel is available for molecular diagnostics which could cover all these somatic and germline alterations associated with cancer. It is highly important to acknowledge the functional and clinical relevance of these cancer genes in order to find the optimal molecular test for an individual in a specific clinical situation, to help the interpretation of the test Results and to enhance the delivery of genomically-informed therapeutic decisions. This might also help researchers towards novel biomarker discovery and targeted drug design. Legal entity responsible for the study: NA Funding: National Oncogenomic and Precision Oncotherapy Program Funded by the Hungarian Innovation Agency. Disclosure: All authors have declared no conflicts of interest.