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

    Nature medicine, 04/2023, Letnik: 29, Številka: 4
    Journal Article

    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.