Evolutionary characterization of lung adenocarcinoma morphology in TRACERx Journal Article
| Authors: | 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. L.; 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.; TRACERx Consortium; McGranahan, N.; Swanton, C.; Jamal-Hanjani, M. |
| Article Title: | Evolutionary characterization of lung adenocarcinoma morphology in TRACERx |
| 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. © The Author(s) under exclusive license to Springer Nature America, Inc. 2023. |
| Keywords: | genetics; adenocarcinoma; neoplasm recurrence, local; nuclear protein; lung neoplasms; transcription factor; pathology; transcription factors; nuclear proteins; lung tumor; lung adenocarcinoma; disease progression; tumor recurrence; disease exacerbation; dna helicases; dna helicase; adenocarcinoma of lung; humans; human; smarca4 protein, human |
| Journal Title: | Nature Medicine |
| Volume: | 29 |
| Issue: | 4 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-04-01 |
| Start Page: | 833 |
| End Page: | 845 |
| Language: | English |
| DOI: | 10.1038/s41591-023-02230-w |
| PUBMED: | 37045996 |
| PROVIDER: | scopus |
| PMCID: | PMC7614478 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
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