Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.


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.

  • Abbosh C
  • Adusumilli PS
  • Bakir MA
  • Birkbak NJ
  • Biswas D
  • Black JRM
  • Cadieux EL
  • Campbell BB
  • Cheema W
  • Colliver E
  • Demeulemeester J
  • Dietzen M
  • Enfield KSS
  • Frankell AM
  • Gimeno-Valiente F
  • Grigoriadis K
  • Hackshaw A
  • Hessey S
  • Hiley CT
  • Hill MS
  • Huebner A
  • Jamal-Hanjani M
  • Jones DR
  • Kanu N
  • Karasaki T
  • Le Quesne J
  • Lee C
  • Lim EL
  • Litchfield K
  • Magno N
  • Marafioti T
  • Martínez-Ruiz C
  • McGranahan N
  • Moore DA
  • Naceur-Lombardelli C
  • Nicholson AG
  • Pich O
  • Puttick C
  • Rekhtman N
  • Saghafinia S
  • Salgado R
  • Sanchez-Vega F
  • Swanton C
  • Tan KS
  • Toncheva A
  • Travis WD
  • Van Loo P
  • Veeriah S
  • Ward S
  • Watkins TBK
  • Zaccaria S
  • Zhai H
Pub Med ID
Appears In
Nat Med, 2023, 29 (4)