Evolutionary characterization of lung adenocarcinoma morphology in TRACERxMore about Open Access at the Crick
Authors listTakahiro Karasaki David A Moore Selvaraju Veeriah Cristina Naceur-Lombardelli Antonia Toncheva Neil Magno Sophie Ward Maise Al Bakir Tom Watkins Kristiana Grigoriadis Ariana Huebner Mark S Hill Alexander Frankell Christopher Abbosh Clare Puttick Haoran Zhai Francisco Gimeno-Valiente Sadegh Saghafinia Nnennaya Kanu Michelle Dietzen Oriol Pich Emilia Lim Carlos Martínez-Ruiz James RM Black Dhruva Biswas Brittany B Campbell Claudia Lee Emma Colliver Katey Enfield Sonya Hessey Crispin Hiley Simone Zaccaria Kevin Litchfield Nicolai 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 Roberto Salgado John Le Quesne Andrew G Nicholson TRACERx Consortium Nicholas McGranahan Charles Swanton Mariam Jamal-Hanjani
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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.
Journal Nature Medicine
Issue number 4