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| Item Type: | Article |
|---|---|
| Title: | Evolutionary characterization of lung adenocarcinoma morphology in TRACERx |
| Creators: |
Karasaki, T.  ORCID: https://orcid.org/0000-0001-6863-2360, Moore, D.A. ORCID: https://orcid.org/0000-0002-6296-1312, Veeriah, S., Naceur-Lombardelli, C., Toncheva, A., Magno, N., Ward, S. ORCID: https://orcid.org/0000-0002-6777-5279, Bakir, M.A. ORCID: https://orcid.org/0000-0002-0846-8332, Watkins, T.B.K., Grigoriadis, K. ORCID: https://orcid.org/0000-0002-8435-0176, Huebner, A. ORCID: https://orcid.org/0000-0001-8009-4999, Hill, M.S. ORCID: https://orcid.org/0000-0003-0718-8934, Frankell, A.M. ORCID: https://orcid.org/0000-0002-0341-7878, Abbosh, C. ORCID: https://orcid.org/0000-0002-8983-1382, Puttick, C., Zhai, H., Gimeno-Valiente, F., Saghafinia, S., Kanu, N., Dietzen, M. ORCID: https://orcid.org/0000-0002-6853-7563, Pich, O. ORCID: https://orcid.org/0000-0002-1956-1882, Lim, E.., Martínez-Ruiz, C. ORCID: https://orcid.org/0000-0002-4817-0565, Black, J.R.M., Biswas, D. ORCID: https://orcid.org/0000-0001-9141-5188, Campbell, B.B., Lee, C. ORCID: https://orcid.org/0000-0003-1715-2265, Colliver, E. ORCID: https://orcid.org/0000-0002-1497-0740, Enfield, K.S.S. ORCID: https://orcid.org/0000-0002-4551-6073, Hessey, S. ORCID: https://orcid.org/0000-0001-9856-424X, Hiley, C.T., Zaccaria, S. ORCID: https://orcid.org/0000-0002-5265-7392, Litchfield, K., Birkbak, N.J. ORCID: https://orcid.org/0000-0003-1613-9587, Cadieux, E.L., Demeulemeester, J. ORCID: https://orcid.org/0000-0002-2660-2478, Van Loo, P. ORCID: https://orcid.org/0000-0003-0292-1949, Adusumilli, P.S. ORCID: https://orcid.org/0000-0002-1699-2046, Tan, K.S., Cheema, W. ORCID: https://orcid.org/0000-0002-8000-7493, Sanchez-Vega, F. ORCID: https://orcid.org/0000-0002-2990-4893, Jones, D.R. ORCID: https://orcid.org/0000-0002-3318-0146, Rekhtman, N., Travis, W.D., Hackshaw, A. ORCID: https://orcid.org/0000-0002-5570-5070, Marafioti, T., Salgado, R. ORCID: https://orcid.org/0000-0002-1110-3801, Le Quesne, J. ORCID: https://orcid.org/0000-0003-3552-7446, Nicholson, A.G., McGranahan, N. ORCID: https://orcid.org/0000-0001-9537-4045, Swanton, C. ORCID: https://orcid.org/0000-0002-4299-3018 and Jamal-Hanjani, M. ORCID: https://orcid.org/0000-0003-1212-1259
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| 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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