Nature | 遗传背景塑造肿瘤演化轨迹

TL;DR - A Nature study using 581 DEN-induced liver tumors across four inbred mouse strains shows that germline genetic background shapes cancer susceptibility and evolutionary trajectories. It influences which somatic drivers are selected, whether whole-genome duplication occurs, and how readily early clones become malignant.

• About 95% of tumors converged on MAPK activation through Braf, Hras, Egfr, or Kras, but driver and amino-acid preferences differed markedly by genetic background.
• Mutation burden did not explain tumor latency: the most susceptible C3H mice developed tumors earlier despite lower overall substitution burdens than BL6 and CAST.
• Germline–somatic epistasis altered the transcriptional effects and selective advantage of identical drivers; C3H tumors typically needed one driver, whereas other strains often required multiple events.
• CAROLI tumors frequently underwent early whole-genome duplication, while lineage reconstruction showed that genetic background also determined early clone survival and the threshold for malignant transformation.