Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Karasaki, T; Moore, DA; Veeriah, S; Naceur-Lombardelli, C; Toncheva, A; Magno, N; Ward, S; Bakir, MA; Watkins, TBK; Grigoriadis, K; Huebner, A; Hill, MS; Frankell, AM; Abbosh, C; Puttick, C; Zhai, H; Gimeno-Valiente, F; Saghafinia, S; Kanu, N; Dietzen, M; Pich, O; Lim, EL; Martinez-Ruiz, C; Black, JRM; Biswas, D; Campbell, BB; Lee, C; Colliver, E; Enfield, KSS; Hessey, S; Hiley, CT; Zaccaria, S; Litchfield, K; Birkbak, NJ; Cadieux, EL; Demeulemeester, J; Van Loo, P; Adusumilli, PS; Tan, KS; Cheema, W; Sanchez-Vega, F; Jones, DR; Rekhtman, N; Travis, WD; Hackshaw, A; Marafioti, T; Salgado, R; Le Quesne, J; Nicholson, AG; TRACERx Consortium; McGranahan, N; Swanton, C; Jamal-Hanjani, M

Author(s): Karasaki, T; Moore, DA; Veeriah, S; Naceur-Lombardelli, C; Toncheva, A; Magno, N; Ward, S; Bakir, MA; Watkins, TBK; Grigoriadis, K; Huebner, A; Hill, MS; Frankell, AM; Abbosh, C; Puttick, C; Zhai, H; Gimeno-Valiente, F; Saghafinia, S; Kanu, N; Dietzen, M; Pich, O; Lim, EL; Martinez-Ruiz, C; Black, JRM; Biswas, D; Campbell, BB; Lee, C; Colliver, E; Enfield, KSS; Hessey, S; Hiley, CT; Zaccaria, S; Litchfield, K; Birkbak, NJ; Cadieux, EL; Demeulemeester, J; Van Loo, P; Adusumilli, PS; Tan, KS; Cheema, W; Sanchez-Vega, F; Jones, DR; Rekhtman, N; Travis, WD; Hackshaw, A; Marafioti, T; Salgado, R; Le Quesne, J; Nicholson, AG; TRACERx Consortium; McGranahan, N; Swanton, C; Jamal-Hanjani, M;
Details: Publication Year 2023-04,Volume 29,Issue #4,Page 833-845
Journal Title: Nature Medicine
Publication Type: Research article
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.
Publisher: Springer Nature
Keywords: Humans; *Lung Neoplasms/genetics/pathology; *Adenocarcinoma/genetics/pathology; Neoplasm Recurrence, Local/pathology; *Adenocarcinoma of Lung/genetics; Disease Progression; DNA Helicases; Nuclear Proteins; Transcription Factors
Department(s): Laboratory Research
PubMed ID: 37045996
Publisher's Version: https://doi.org/10.1038/s41591-023-02230-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-07-27 08:03:02

Last Modified: 2024-07-09 06:23:50