Comprehensive patient-level classification and quantification of driver events in TCGA PanCanAtlas cohorts

BackgroundThere is a growing need to develop novel therapeutics for targeted treatment of cancer. The prerequisite to success is the knowledge about which types of molecular alterations are predominantly driving tumorigenesis - single nucleotide (SNA) or copy number (CNA), in oncogenes or in tumour suppressors, gains or losses of full chromosomes or chromosomal arms (aneuploidy). However, the number and proportion of various types of driver events per tumour is still not clear, neither for cancer in general, nor for individual cancer types, stages and patient demographics (age and gender). MethodsTo shed light onto this subject, we have utilized the largest database of human cancer mutations - TCGA PanCanAtlas, multiple established algorithms for cancer driver prediction (2020plus, CHASMplus, CompositeDriver, dNdScv, DriverNet, HotMAPS, IntOGen Plus, OncodriveCLUSTL, OncodriveFML) and developed four novel computational pipelines: SNADRIF (SNA DRIver Finder), GECNAV (Gene Expression-based CNA Validator), ANDRIF (ANeuploidy DRIver Finder) and PALDRIC (PAtient-Level DRIver Classifier). A unified workflow integrating all these pipelines, algorithms and datasets at cohort and patient levels was created. ResultsBy integrating results of various driver prediction algorithms, we have found that there are on average 20 driver events per tumour, of which 1.5 are hyperactivating SNAs in oncogenes, 10.5 are amplifications of oncogenes, 2 are homozygous inactivating SNAs or deletions of tumour suppressors, 1.5 are driver chromosome losses, 2 are driver chromosome gains, 1 is a driver chromosome arm loss, and 1.5 are driver chromosome arm gains. The average number of driver events per tumour varies strongly between cancer types, from 1.7 in thyroid carcinoma to 42.4 in ovarian carcinoma. In females, the number of driver events increases most dramatically until the age of menopause (50 y.o.), whereas in males until 70 y.o. Moreover, in females, the number of driver events increases abruptly from Stage I to Stage II, after which stays more or less constant, and this increase is due to CNAs and aneuploidy but not due to SNAs. In tumours having only one driver event, this event is a SNA in an oncogene. However, with increasing number of driver events per tumour, the contribution of SNAs and tumour suppressor events decreases, whereas the contribution of oncogene amplifications and aneuploidy events increases. Patients with two driver events per tumour are the most frequent, and there are very few patients with more than 50 events. ConclusionsAs half of all driver events in a patients tumour appear to be amplifications of oncogenes, we suggest that future therapeutics development efforts should be focused on targeting this alteration type. Therapies aimed at gains and losses of chromosomal arms and whole chromosomes also appear very promising. On the other hand, drugs aiming at point mutations and tumour suppressors are predicted to be less successful. Overall, our results provide valuable insights into the extent of driver alterations of different types in human tumours and suggest optimal targets for candidate therapeutics.