Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Item Type:	Article
Title:	Evolutionary characterization of lung adenocarcinoma morphology in TRACERx
Creators Name:	Karasaki, T. and Moore, D.A. and Veeriah, S. and Naceur-Lombardelli, C. and Toncheva, A. and Magno, N. and Ward, S. and Bakir, M.A. and Watkins, T.B.K. and Grigoriadis, K. and Huebner, A. and Hill, M.S. and Frankell, A.M. and Abbosh, C. and Puttick, C. and Zhai, H. and Gimeno-Valiente, F. and Saghafinia, S. and Kanu, N. and Dietzen, M. and Pich, O. and Lim, E.. and Martínez-Ruiz, C. and Black, J.R.M. and Biswas, D. and Campbell, B.B. and Lee, C. and Colliver, E. and Enfield, K.S.S. and Hessey, S. and Hiley, C.T. and Zaccaria, S. and Litchfield, K. and Birkbak, N.J. and Cadieux, E.L. and Demeulemeester, J. and Van Loo, P. and Adusumilli, P.S. and Tan, K.S. and Cheema, W. and Sanchez-Vega, F. and Jones, D.R. and Rekhtman, N. and Travis, W.D. and Hackshaw, A. and Marafioti, T. and Salgado, R. and Le Quesne, J. and Nicholson, A.G. and McGranahan, N. and Swanton, C. and Jamal-Hanjani, M.
Abstract:	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.
Keywords:	Adenocarcinoma, Adenocarcinoma of Lung, DNA Helicases, Disease Progression, Local Neoplasm Recurrence, Lung Neoplasms, Nuclear Proteins, Transcription Factors
Source:	Nature Medicine
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Volume:	29
Number:	4
Page Range:	833-845
Date:	April 2023
Additional Information:	Tom L. Kaufmann (19184) is a member of the TRACERx Consortium. - Copyright © 2023. The Author(s) under exclusive license to Springer Nature America, Inc.
Official Publication:	https://doi.org/10.1038/s41591-023-02230-w
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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