Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
Abstact
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.
Authors
- 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