Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Takahiro Karasaki, David A. Moore, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Antonia Toncheva, Neil Magno, Sophia Ward, Maise Al Bakir, Thomas B.K. Watkins, Kristiana Grigoriadis, Ariana Huebner, Mark S. Hill, Alexander M. Frankell, Christopher Abbosh, Clare Puttick, Haoran Zhai, Francisco Gimeno-Valiente, Sadegh Saghafinia, Nnennaya Kanu, Michelle DietzenOriol Pich, Emilia L. Lim, Carlos Martínez-Ruiz, James R.M. Black, Dhruva Biswas, Brittany B. Campbell, Claudia Lee, Emma Colliver, Katey S.S. Enfield, Sonya Hessey, Crispin T. Hiley, Simone Zaccaria, Kevin Litchfield, Nicolai J. Birkbak, Elizabeth Larose Cadieux, Jonas Demeulemeester, Peter Van Loo, Prasad S. Adusumilli, Kay See Tan, Waseem Cheema, Francisco Sanchez-Vega, David R. Jones, Natasha Rekhtman, William D. Travis, Allan Hackshaw, Teresa Marafioti, TRACERx Consortium

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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.

Original languageEnglish
JournalNature Medicine
Pages (from-to)833-845
Number of pages13
Publication statusPublished - Apr 2023


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