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Article ; Online: SnapShot: Tumor evolution.

Huebner, Ariana / Dietzen, Michelle / McGranahan, Nicholas

2021 Volume 184, Issue 6, Page(s) 1650–1650.e1

Abstract: Understanding how tumors grow and evolve over time is crucial to help shed light on the underlying reasons why treatments fail and tumors metastasize. This SnapShot provides a brief introduction into the main concepts of tumor evolution. To view this ... ...

Abstract	Understanding how tumors grow and evolve over time is crucial to help shed light on the underlying reasons why treatments fail and tumors metastasize. This SnapShot provides a brief introduction into the main concepts of tumor evolution. To view this SnapShot, open or download the PDF.
MeSH term(s)	Humans ; Mutation/genetics ; Neoplasm Metastasis ; Neoplasms/genetics ; Neoplasms/pathology
Language	English
Publishing date	2021-03-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2021.02.024
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Article ; Online: CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction.

Grigoriadis, Kristiana / Huebner, Ariana / Bunkum, Abigail / Colliver, Emma / Frankell, Alexander M / Hill, Mark S / Thol, Kerstin / Birkbak, Nicolai J / Swanton, Charles / Zaccaria, Simone / McGranahan, Nicholas

Nature protocols

2023 Volume 19, Issue 1, Page(s) 159–183

Abstract: Intratumor heterogeneity provides the fuel for the evolution and selection of subclonal tumor cell populations. However, accurate inference of tumor subclonal architecture and reconstruction of tumor evolutionary histories from bulk DNA sequencing data ... ...

Abstract	Intratumor heterogeneity provides the fuel for the evolution and selection of subclonal tumor cell populations. However, accurate inference of tumor subclonal architecture and reconstruction of tumor evolutionary histories from bulk DNA sequencing data remains challenging. Frequently, sequencing and alignment artifacts are not fully filtered out from cancer somatic mutations, and errors in the identification of copy number alterations or complex evolutionary events (e.g., mutation losses) affect the estimated cellular prevalence of mutations. Together, such errors propagate into the analysis of mutation clustering and phylogenetic reconstruction. In this Protocol, we present a new computational framework, CONIPHER (COrrecting Noise In PHylogenetic Evaluation and Reconstruction), that accurately infers subclonal structure and phylogenetic relationships from multisample tumor sequencing, accounting for both copy number alterations and mutation errors. CONIPHER has been used to reconstruct subclonal architecture and tumor phylogeny from multisample tumors with high-depth whole-exome sequencing from the TRACERx421 dataset, as well as matched primary-metastatic cases. CONIPHER outperforms similar methods on simulated datasets, and in particular scales to a large number of tumor samples and clones, while completing in under 1.5 h on average. CONIPHER enables automated phylogenetic analysis that can be effectively applied to large sequencing datasets generated with different technologies. CONIPHER can be run with a basic knowledge of bioinformatics and R and bash scripting languages.
MeSH term(s)	Humans ; Phylogeny ; Algorithms ; Neoplasms/genetics ; Neoplasms/pathology ; Computational Biology/methods ; Sequence Analysis, DNA ; Mutation
Language	English
Publishing date	2023-11-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2244966-8
ISSN	1750-2799 ; 1754-2189
ISSN (online)	1750-2799
ISSN	1754-2189
DOI	10.1038/s41596-023-00913-9
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Article ; Online: ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA.

Huebner, Ariana / Black, James R M / Sarno, Francesca / Pazo, Roberto / Juez, Ignacio / Medina, Laura / Garcia-Carbonero, Rocio / Guillén, Carmen / Feliú, Jaime / Alonso, Carolina / Arenillas, Carlota / Moreno-Cárdenas, Ana Belén / Verdaguer, Helena / Macarulla, Teresa / Hidalgo, Manuel / McGranahan, Nicholas / Toledo, Rodrigo A

Genome medicine

2023 Volume 15, Issue 1, Page(s) 27

Abstract: Background: Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, ... ...

Abstract	Background: Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods: To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results: SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions: This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.
MeSH term(s)	Humans ; Circulating Tumor DNA/genetics ; Adenocarcinoma/genetics ; Pancreatic Neoplasms/genetics ; Prospective Studies ; Cell-Free Nucleic Acids ; Karyotype ; Mutation ; Biomarkers, Tumor/genetics
Chemical Substances	Circulating Tumor DNA ; Cell-Free Nucleic Acids ; Biomarkers, Tumor
Language	English
Publishing date	2023-04-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-023-01171-w
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Article: Phenotyping of lymphoproliferative tumours generated in xenografts of non-small cell lung cancer.

Pearce, David R / Akarca, Ayse U / De Maeyer, Roel P H / Kostina, Emily / Huebner, Ariana / Sivakumar, Monica / Karasaki, Takahiro / Shah, Kavina / Janes, Sam M / McGranahan, Nicholas / Reddy, Venkat / Akbar, Arne N / Moore, David A / Marafioti, Teresa / Swanton, Charles / Hynds, Robert E

Frontiers in oncology

2023 Volume 13, Page(s) 1156743

Abstract: Background: Patient-derived xenograft (PDX) models involve the engraftment of tumour tissue in immunocompromised mice and represent an important pre-clinical oncology research method. A limitation of non-small cell lung cancer (NSCLC) PDX model ... ...

Abstract	Background: Patient-derived xenograft (PDX) models involve the engraftment of tumour tissue in immunocompromised mice and represent an important pre-clinical oncology research method. A limitation of non-small cell lung cancer (NSCLC) PDX model derivation in NOD- Methods: The immunophenotype of lymphoproliferations arising in the lung TRACERx PDX pipeline were characterised. To present the histology data herein, we developed a Python-based tool for generating patient-level pathology overview figures from whole-slide image files; PATHOverview is available on GitHub (https://github.com/EpiCENTR-Lab/PATHOverview). Results: Lymphoproliferations occurred in 17.8% of lung adenocarcinoma and 10% of lung squamous cell carcinoma transplantations, despite none of these patients having a prior or subsequent clinical history of lymphoproliferative disease. Lymphoproliferations were predominantly human CD20+ B cells and had the immunophenotype expected for post-transplantation diffuse large B cell lymphoma with plasma cell features. All lymphoproliferations expressed Epstein-Barr-encoded RNAs (EBER). Analysis of immunoglobulin light chain gene rearrangements in three tumours where multiple tumour regions had resulted in lymphoproliferations suggested that each had independent clonal origins. Discussion: Overall, these data suggest that B cell clones with lymphoproliferative potential are present within primary NSCLC tumours, and that these are under continuous immune surveillance. Since these cells can be expanded following transplantation into NSG mice, our data highlight the value of quality control measures to identify lymphoproliferations within xenograft pipelines and support the incorporation of strategies to minimise lymphoproliferations during the early stages of xenograft establishment pipelines.
Language	English
Publishing date	2023-06-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1156743
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Article ; Online: Blood culture sampling rate in hospitalised children as a quality indicator for diagnostic stewardship.

Araujo da Silva, André Ricardo / Jaszkowski, Elena / Schober, Tilmann / von Both, Ulrich / Meyer-Buehn, Melanie / Hübner, Ariana / Hübner, Johannes

Infection

2020 Volume 48, Issue 4, Page(s) 569–575

Abstract: Purpose: Recommendations regarding the optimal number of blood cultures in children are not available. The aim of this article is to describe the correlation between blood culture (BC) rates and laboratory-confirmed bloodstream infection (LCBSI) rates, ... ...

Abstract	Purpose: Recommendations regarding the optimal number of blood cultures in children are not available. The aim of this article is to describe the correlation between blood culture (BC) rates and laboratory-confirmed bloodstream infection (LCBSI) rates, on different paediatric wards of a tertiary-care centre in Germany. Methods: We conducted a retrospective cohort study in a paediatric university hospital, from 1st January to 31st December 2018. All blood cultures collected from neonatal (NICU) and paediatric intensive-care units (PICU), haematology/oncology, and general paediatric wards were included. There were no exclusion criteria. BC taken/1000 patients-days (BC rates/BCR) and LCBSI/1000 patient-days at risk (LCBSI rates) were calculated for each unit. Results: A total of 6040 patients were admitted to the hospital with 3114 of them into wards studied. Of the 3072 BCs collected, 200 (6.5%) were positive. Collection of BCs was performed in 51/77 (66.2%) of admitted patients on NICU, in 151/399 (37.8%) of PICU patients, in 163/755 (21.6%) of haematology/oncology patients, and in 281/1883 (14.9%) of children on general paediatric wards. Gram-positive bacteria were the most commonly detected organisms in blood cultures from all wards with exception of NICU. The BCR in NICU, PICU, haematology/oncology wards, and general wards were 61.6, 196.2, 358.4, and 52.3, respectively. Excluding commensal pathogens and possible contaminations, the LCBSI rates in the same units were 2.4, 5.6, 4.4, and 1.0, respectively. Conclusion: We found different BCR values according the ward studied, being higher in patients with high risk of bloodstream infection such as haematology/oncology patients.
MeSH term(s)	Adolescent ; Blood Culture/statistics & numerical data ; Child ; Child, Hospitalized ; Child, Preschool ; Cohort Studies ; Germany ; Hospitalization ; Humans ; Infant ; Infant, Newborn ; Quality Indicators, Health Care/statistics & numerical data ; Retrospective Studies ; Sampling Studies ; Sepsis/diagnosis
Language	English
Publishing date	2020-05-19
Publishing country	Germany
Document type	Journal Article
ZDB-ID	185104-4
ISSN	1439-0973 ; 0300-8126 ; 0173-2129
ISSN (online)	1439-0973
ISSN	0300-8126 ; 0173-2129
DOI	10.1007/s15010-020-01439-y
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Article: Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.

bioRxiv : the preprint server for biology

2023

Abstract: Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system ... ...

Abstract	Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system x
Language	English
Publishing date	2023-12-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.16.572007
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Article ; Online: Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution.

López, Saioa / Lim, Emilia L / Horswell, Stuart / Haase, Kerstin / Huebner, Ariana / Dietzen, Michelle / Mourikis, Thanos P / Watkins, Thomas B K / Rowan, Andrew / Dewhurst, Sally M / Birkbak, Nicolai J / Wilson, Gareth A / Van Loo, Peter / Jamal-Hanjani, Mariam / Swanton, Charles / McGranahan, Nicholas

Nature genetics

2020 Volume 52, Issue 3, Page(s) 283–293

Abstract: Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been ... ...

Abstract	Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.
MeSH term(s)	Adenocarcinoma of Lung/genetics ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Squamous Cell/genetics ; Cohort Studies ; Computer Simulation ; DNA Copy Number Variations ; Evolution, Molecular ; Gene Duplication ; Genome, Human/genetics ; Humans ; Longitudinal Studies ; Loss of Heterozygosity ; Lung Neoplasms/genetics ; Mutation ; Prospective Studies ; Tumor Suppressor Proteins/genetics
Chemical Substances	Tumor Suppressor Proteins
Language	English
Publishing date	2020-03-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-020-0584-7
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Article ; Online: Body composition and lung cancer-associated cachexia in TRACERx.

Al-Sawaf, Othman / Weiss, Jakob / Skrzypski, Marcin / Lam, Jie Min / Karasaki, Takahiro / Zambrana, Francisco / Kidd, Andrew C / Frankell, Alexander M / Watkins, Thomas B K / Martínez-Ruiz, Carlos / Puttick, Clare / Black, James R M / Huebner, Ariana / Bakir, Maise Al / Sokač, Mateo / Collins, Susie / Veeriah, Selvaraju / Magno, Neil / Naceur-Lombardelli, Cristina /

Nature medicine

2023 Volume 29, Issue 4, Page(s) 846–858

Abstract: Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body ... ...

Abstract	Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
MeSH term(s)	Male ; Humans ; Cachexia/complications ; Lung Neoplasms/pathology ; Carcinoma, Non-Small-Cell Lung/pathology ; Proteomics ; Neoplasm Recurrence, Local/pathology ; Body Composition ; Body Weight ; Muscle, Skeletal/metabolism ; Antigens, Neoplasm/metabolism ; Neoplasm Proteins
Chemical Substances	MAGEA6 protein, human ; Antigens, Neoplasm ; Neoplasm Proteins
Language	English
Publishing date	2023-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02232-8
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Article ; Online: Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.

Abbosh, Christopher / Frankell, Alexander M / Harrison, Thomas / Kisistok, Judit / Garnett, Aaron / Johnson, Laura / Veeriah, Selvaraju / Moreau, Mike / Chesh, Adrian / Chaunzwa, Tafadzwa L / Weiss, Jakob / Schroeder, Morgan R / Ward, Sophia / Grigoriadis, Kristiana / Shahpurwalla, Aamir / Litchfield, Kevin / Puttick, Clare / Biswas, Dhruva / Karasaki, Takahiro /

Black, James R M / Martínez-Ruiz, Carlos / Bakir, Maise Al / Pich, Oriol / Watkins, Thomas B K / Lim, Emilia L / Huebner, Ariana / Moore, David A / Godin-Heymann, Nadia / L'Hernault, Anne / Bye, Hannah / Odell, Aaron / Roberts, Paula / Gomes, Fabio / Patel, Akshay J / Manzano, Elizabeth / Hiley, Crispin T / Carey, Nicolas / Riley, Joan / Cook, Daniel E / Hodgson, Darren / Stetson, Daniel / Barrett, J Carl / Kortlever, Roderik M / Evan, Gerard I / Hackshaw, Allan / Daber, Robert D / Shaw, Jacqui A / Aerts, Hugo J W L / Licon, Abel / Stahl, Josh / Jamal-Hanjani, Mariam / Birkbak, Nicolai J / McGranahan, Nicholas / Swanton, Charles

Nature

2023 Volume 616, Issue 7957, Page(s) 553–562

Abstract: Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent ... ...

Abstract	Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy
MeSH term(s)	Humans ; Biomarkers, Tumor/blood ; Biomarkers, Tumor/genetics ; Carcinoma, Non-Small-Cell Lung/blood ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Circulating Tumor DNA/blood ; Circulating Tumor DNA/genetics ; Cohort Studies ; Lung Neoplasms/blood ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Mutation ; Neoplasm Metastasis/diagnosis ; Neoplasm Metastasis/genetics ; Neoplasm Metastasis/pathology ; Neoplasm Recurrence, Local/diagnosis ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Phylogeny ; Small Cell Lung Carcinoma/pathology ; Liquid Biopsy
Chemical Substances	Biomarkers, Tumor ; Circulating Tumor DNA
Language	English
Publishing date	2023-04-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-023-05776-4
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Article ; Online: Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.

Karasaki, Takahiro / Moore, David A / Veeriah, Selvaraju / Naceur-Lombardelli, Cristina / Toncheva, Antonia / Magno, Neil / Ward, Sophia / Bakir, Maise Al / Watkins, Thomas B K / Grigoriadis, Kristiana / Huebner, Ariana / Hill, Mark S / Frankell, Alexander M / Abbosh, Christopher / Puttick, Clare / Zhai, Haoran / Gimeno-Valiente, Francisco / Saghafinia, Sadegh / Kanu, Nnennaya /

Dietzen, Michelle / Pich, Oriol / Lim, Emilia L / Martínez-Ruiz, Carlos / Black, James R M / Biswas, Dhruva / Campbell, Brittany B / Lee, Claudia / Colliver, Emma / Enfield, Katey S S / Hessey, Sonya / Hiley, Crispin T / Zaccaria, Simone / Litchfield, Kevin / Birkbak, Nicolai J / Cadieux, Elizabeth Larose / Demeulemeester, Jonas / Van Loo, Peter / Adusumilli, Prasad S / Tan, Kay See / Cheema, Waseem / Sanchez-Vega, Francisco / Jones, David R / Rekhtman, Natasha / Travis, William D / Hackshaw, Allan / Marafioti, Teresa / Salgado, Roberto / Le Quesne, John / Nicholson, Andrew G / McGranahan, Nicholas / Swanton, Charles / Jamal-Hanjani, Mariam

Nature medicine

2023 Volume 29, Issue 4, Page(s) 833–845

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 ... ...

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.
MeSH term(s)	Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Neoplasm Recurrence, Local/pathology ; Adenocarcinoma of Lung/genetics ; Disease Progression ; DNA Helicases ; Nuclear Proteins ; Transcription Factors
Chemical Substances	SMARCA4 protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; Nuclear Proteins ; Transcription Factors
Language	English
Publishing date	2023-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02230-w
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