Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma

Proc Natl Acad Sci U S A. 2023 Sep 19;120(38):e2303224120. doi: 10.1073/pnas.2303224120. Epub 2023 Sep 11.

Abstract

Cancer genomes are almost invariably complex with genomic alterations cooperating during each step of carcinogenesis. In cancers that lack a single dominant oncogene mutation, cooperation between the inactivation of multiple tumor suppressor genes can drive tumor initiation and growth. Here, we shed light on how the sequential acquisition of genomic alterations generates oncogene-negative lung tumors. We couple tumor barcoding with combinatorial and multiplexed somatic genome editing to characterize the fitness landscapes of three tumor suppressor genes NF1, RASA1, and PTEN, the inactivation of which jointly drives oncogene-negative lung adenocarcinoma initiation and growth. The fitness landscape was surprisingly accessible, with each additional mutation leading to growth advantage. Furthermore, the fitness landscapes remained fully accessible across backgrounds with the inactivation of additional tumor suppressor genes. These results suggest that while predicting cancer evolution will be challenging, acquiring the multiple alterations that drive the growth of oncogene-negative tumors can be facilitated by the lack of constraints on mutational order.

Keywords: cancer evolution; fitness landscapes; mouse models; quantitative.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Cell Transformation, Neoplastic
  • Humans
  • Lung Neoplasms* / genetics
  • Mutation
  • Oncogenes / genetics
  • p120 GTPase Activating Protein

Substances

  • RASA1 protein, human
  • p120 GTPase Activating Protein