TY - JOUR
T1 - Evolutionary characterization of lung adenocarcinoma morphology in TRACERx
AU - Swanton, Charles
AU - Jamal-Hanjani, Mariam
AU - McGranahan, Nicholas
AU - Karasaki, Takahiro
AU - Moore, David A.
AU - Veeriah, Selvaraju
AU - Naceur-Lombardelli, Cristina
AU - Toncheva, Antonia
AU - Magno, Neil
AU - Ward, Sophia
AU - Al Bakir, Maise
AU - Watkins, Thomas B. K.
AU - Grigoriadis, Kristiana
AU - Huebner, Ariana
AU - Hill, Mark S.
AU - Frankell, Alexander M.
AU - Abbosh, Christopher
AU - Puttick, Clare
AU - Zhai, Haoran
AU - Gimeno-Valiente, Francisco
AU - Saghafinia, Sadegh
AU - Kanu, Nnennaya
AU - Dietzen, Michelle
AU - Pich, Oriol
AU - Lim, Emilia L.
AU - Martinez-Ruiz, Carlos
AU - Black, James R. M.
AU - Biswas, Dhruva
AU - Campbell, Brittany B.
AU - Lee, Claudia
AU - Colliver, Emma
AU - Enfield, Katey S. S.
AU - Hessey, Sonya
AU - Hiley, Crispin T.
AU - Zaccaria, Simone
AU - Litchfield, Kevin
AU - Birkbak, Nicolai J.
AU - Cadieux, Elizabeth Larose
AU - Demeulemeester, Jonas
AU - Van Loo, Peter
AU - Adusumilli, Prasad R.
AU - Tan, Kay See
AU - Cheema, Waseem
AU - Sanchez-Vega, Francisco
AU - Jones, David R.
AU - Rekhtman, Natasha
AU - Travis, William D.
AU - Hackshaw, Allan
AU - Marafioti, Teresa
AU - Salgado, Roberto
AU - Le Quesne, John
AU - Aerts, Hugo J. W. L.
AU - TRACERx Consortium
PY - 2023/4/12
Y1 - 2023/4/12
N2 - Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.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.
AB - Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.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.
KW - TUMOR-INFILTRATING LYMPHOCYTES
KW - AIR SPACES STAS
KW - LIMITED RESECTION
KW - INDEPENDENT PREDICTOR
KW - HISTOLOGIC SUBTYPE
KW - PROGNOSTIC IMPACT
KW - GRADING SYSTEM
KW - COPY NUMBER
KW - CANCER
KW - SPREAD
U2 - 10.1038/s41591-023-02230-w
DO - 10.1038/s41591-023-02230-w
M3 - Article
C2 - 37045996
SN - 1078-8956
VL - 29
SP - 833
EP - 845
JO - Nature Medicine
JF - Nature Medicine
IS - 4
ER -