Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
Karasaki T., Moore DA., Veeriah S., Naceur-Lombardelli C., Toncheva A., Magno N., Ward S., Bakir MA., Watkins TBK., Grigoriadis K., Huebner A., Hill MS., Frankell AM., Abbosh C., Puttick C., Zhai H., Gimeno-Valiente F., Saghafinia S., Kanu N., Dietzen M., Pich O., Lim EL., Martínez-Ruiz C., Black JRM., Biswas D., Campbell BB., Lee C., Colliver E., Enfield KSS., Hessey S., Hiley CT., Zaccaria S., Litchfield K., Birkbak NJ., Cadieux EL., Demeulemeester J., Van Loo P., Adusumilli PS., Tan KS., Cheema W., Sanchez-Vega F., Jones DR., Rekhtman N., Travis WD., Hackshaw A., Marafioti T., Salgado R., Le Quesne J., Nicholson AG., TRACERx Consortium None., McGranahan N., Swanton C., Jamal-Hanjani M.
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.