Fully accessible fitness landscape of oncogene negative lung adenocarcinoma

Multiple genetic mutations are needed for cancer to develop. This is even more pronounced in the case of oncogene negative cancer, where a single dominant oncogenic mutation that can start tumor growth is lacking and substituted by a combination of driver mutations. To shed light on how tumors can subsequently acquire these independent mutations and to test the predictability of cancer evolution, we have characterized the fitness landscapes of a triple-mutant oncogene negative genotype leading to potent lung adenocarcinoma formation. We found that, irrespective of the genetic background, landscapes are surprisingly accessible, where each additional mutation leads to growth advantage and hence prediction of the order of mutations in oncogene negative tumors cancer evolution is expected to be challenging. Overall design: Ultra-deep sequencing of DNA barcode amplicon