Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

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Item Type:	Article
Title:	Evolutionary characterization of lung adenocarcinoma morphology in TRACERx
Creators Name:	Karasaki, T., Moore, D.A., Veeriah, S., Naceur-Lombardelli, C., Toncheva, A., Magno, N., Ward, S., Bakir, M.A., Watkins, T.B.K., Grigoriadis, K., Huebner, A., Hill, M.S., Frankell, A.M., Abbosh, C., Puttick, C., Zhai, H., Gimeno-Valiente, F., Saghafinia, S., Kanu, N., Dietzen, M., Pich, O., Lim, E.., Martínez-Ruiz, C., Black, J.R.M., Biswas, D., Campbell, B.B., Lee, C., Colliver, E., Enfield, K.S.S., Hessey, S., Hiley, C.T., Zaccaria, S., Litchfield, K., Birkbak, N.J., Cadieux, E.L., Demeulemeester, J., Van Loo, P., Adusumilli, P.S., Tan, K.S., Cheema, W., Sanchez-Vega, F., Jones, D.R., Rekhtman, N., Travis, W.D., Hackshaw, A., Marafioti, T., Salgado, R., Le Quesne, J., Nicholson, A.G., McGranahan, N., 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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