Neuroblastoma arises in early fetal development and its evolutionary duration predicts outcome

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(4), P. 619 - 630

Published: March 27, 2023

Abstract Neuroblastoma, the most frequent solid tumor in infants, shows very diverse outcomes from spontaneous regression to fatal disease. When these different tumors originate and how they evolve are not known. Here we quantify somatic evolution of neuroblastoma by deep whole-genome sequencing, molecular clock analysis population-genetic modeling a comprehensive cohort covering all subtypes. We find that across entire clinical spectrum begin develop via aberrant mitoses as early first trimester pregnancy. Neuroblastomas with favorable prognosis expand clonally after short evolution, whereas aggressive neuroblastomas show prolonged during which acquire telomere maintenance mechanisms. The initial aneuploidization events condition subsequent exhibiting genomic instability. discovery ( n = 100), validate an independent 86), duration is accurate predictor outcome. Thus, insight into may prospectively guide treatment decisions.

Language: Английский

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Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(3), P. 654 - 671

Published: Jan. 4, 2023

Abstract Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome multiregional exome sequencing, transcriptomic, methylation profiling of 95 samples revealed the order genomic events evolution. Following biallelic inactivation NF1, loss CDKN2A or TP53 without polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways evolution are associated PRC2 genes H3K27 trimethylation (H3K27me3) status. Tumors H3K27me3 evolve through chromosomal losses followed by whole-genome doubling chromosome 8 amplification, show lower levels immune cell infiltration. Retention instability, but cell-rich phenotype. Specific SCNAs detected both cell-free DNA (cfDNA) act as a surrogate for infiltration, predict prognosis. Significance: MPNST is most common cause death morbidity individuals relatively predisposition syndrome. Our results suggest that cfDNA could serve biomarker early diagnosis stratify patients into prognostic treatment-related subgroups. This article highlighted In Issue feature, p. 517

Language: Английский

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Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112212 - 112212

Published: March 1, 2023

Human lung cancer is a constellation of tumors with various histological and molecular properties. To build preclinical platform that covers this broad disease spectrum, we obtained specimens from multiple sources, including sputum circulating tumor cells, generated living biobank consisting 43 lines patient-derived organoids. The organoids recapitulated the hallmarks original tumors. Phenotypic screening niche factor dependency revealed EGFR mutations in adenocarcinoma are associated independence Wnt ligands. Gene engineering alveolar reveals constitutive activation EGFR-RAS signaling provides independence. Loss identity gene NKX2-1 confers dependency, regardless signal mutation. Sensitivity to Wnt-targeting therapy can be stratified by expression status NKX2-1. Our results highlight potential phenotype-driven organoid for fabrication therapeutic strategies combat cancer.

Language: Английский

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Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(12), P. 2083 - 2099.e9

Published: Dec. 1, 2023

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs derive PDTOs an understudied subtype NEC, large cell carcinoma (LCNEC), arising multiple body sites. maintain the gene expression patterns, intra-tumoral heterogeneity, evolutionary processes parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker response LCNEC treatment BCL-2 inhibitors. Additionally, discover dependency on EGF NET PDTOs. Consistent these findings, find that, independent cohort, approximately 50% express EGFR. This study identifies actionable vulnerability subset NETs, emphasizing utility PDTO

Language: Английский

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Widespread somatic L1 retrotransposition in normal colorectal epithelium

Nature, Journal Year: 2023, Volume and Issue: 617(7961), P. 540 - 547

Published: May 10, 2023

Throughout an individual's lifetime, genomic alterations accumulate in somatic cells

Language: Английский

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