Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade
lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform
and micropapillary tumors. How morphology reflects tumor evolution and disease progression
is poorly understood. Whole-exome sequencing data generated from 805 primary tumor
regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort,
together with RNA-sequencing data from 463 primary tumor regions, were integrated
with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly
high-grade patterns showed increased chromosomal complexity, with higher burden of
loss of heterozygosity and subclonal somatic copy number alterations. Individual regions
in predominantly high-grade pattern tumors exhibited higher proliferation and lower
clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence
of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade
tumors, while purely undifferentiated solid-pattern tumors had a higher frequency
of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern
tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal
evolution analysis revealed that tumors tend to evolve toward higher-grade patterns.
The presence of micropapillary pattern and 'tumor spread through air spaces' were
associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform
patterns, necrosis and preoperative circulating tumor DNA detection, which were associated
with extra-thoracic recurrence. These data provide insights into the relationship
between LUAD morphology, the underlying evolutionary genomic landscape, and clinical
and anatomical relapse risk.
