Same mutagenic insult, different destinies: genetic background directs cancer evolution

Abstract

In a recent study published in Nature, Aitken and colleagues experimentally replayed liver tumour evolution across divergent mouse genetic backgrounds and showed that the inherited genome does not merely modify cancer susceptibility. Instead, it determines which somatic drivers are selected, whether whole-genome duplication (WGD) occurs, and how early tumour clones survive or disappear. 1 These fi ndings place germline – somatic epistasis at the centre of cancer evolution and challenge the assumption that the same oncogenic mutation has an equivalent biological meaning in every individual. Human cancers emerge from interactions among inherited variation, environmental exposure and acquired mutations. Tumorigenesis is further shaped by the tumour microenvironment, cellular plasticity and epithelial – mesenchymal transition (EMT), and immune interactions. However, these components are dif fi cult to disentangle in patients because ancestry, lifestyle, mutagen exposure, age and socioeconomic context covary, while retrospective tumour sequencing captures only the endpoint of a long evolutionary process. Cancer genomic datasets have also underrepresented many ancestry groups, limiting the generalisa-bility of precision-oncology biomarkers. 2 Aitken et al. addressed this problem by holding sex, environment and carcinogenic exposure constant while varying genetic background. Male mice from four inbred backgrounds