Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma

Area of Science:

• Oncology
• Genomics
• Cancer Evolution

Background:

• Understanding cancer evolution is crucial for identifying key events and their sequence.
• Lung adenocarcinoma (LUAD) subtypes, including those in never-smokers (NS-LUAD) and smokers (S-LUAD), exhibit diverse evolutionary patterns.

Purpose of the Study:

• To chart and interpret the evolutionary trajectories of lung adenocarcinomas using whole-genome sequencing.
• To identify distinct evolutionary paths and the genomic alterations driving them, particularly in never-smokers.

Main Methods:

• Whole-genome sequencing of a large cohort of lung tumors, including a significant number from never-smokers.
• Ordering of frequent genomic alterations to reconstruct tumor evolutionary paths.

Main Results:

• Three distinct evolutionary paths were identified for lung adenocarcinomas.
• Two paths were predominantly observed in NS-LUAD, while one path was common in S-LUAD.
• A subset of NS-LUAD (1 in 6) followed the smoking-dominant trajectory, characterized by fewer somatic alterations, shorter latency, and enrichment for KRAS mutations.

Conclusions:

• KRAS mutations may enable accelerated tumor evolution in a subset of NS-LUAD, allowing acquisition of smoking-associated alterations with reduced genomic instability.
• These KRAS-mutant, smoking-like trajectory tumors are more prevalent in individuals of European ancestry compared to East Asian ancestry.
• Findings may inform clinical management strategies for lung adenocarcinoma, especially for tumors exhibiting smoking-like evolutionary patterns.