The evolution of two transmissible cancers in Tasmanian devils DOI
Maximilian R. Stammnitz, Kevin Gori, Young Mi Kwon

et al.

Science, Journal Year: 2023, Volume and Issue: 380(6642), P. 283 - 293

Published: April 20, 2023

Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumor 1 (DFT1) and 2 (DFT2). We investigated the genetic diversity evolution of these clones by analyzing 78 DFT1 41 DFT2 genomes relative to a newly assembled, chromosome-level reference. Time-resolved phylogenetic trees reveal that first emerged in 1986 (1982 1989) 2011 (2009 2012). Subclone analysis documents transmission heterogeneous cell populations. has faster mutation rates than across all variant classes, including substitutions, indels, rearrangements, transposable element insertions, copy number alterations, we identify hypermutated lineage with defective DNA mismatch repair. Several loci show plausible evidence positive selection or DFT2, loss chromosome Y inactivation MGA , but none are common both cancers. This study reveals parallel long-term cancers inhabiting niche devils.

Language: Английский

AlphaFold, Artificial Intelligence (AI), and Allostery DOI Creative Commons
Ruth Nussinov, Mingzhen Zhang, Yonglan Liu

et al.

The Journal of Physical Chemistry B, Journal Year: 2022, Volume and Issue: 126(34), P. 6372 - 6383

Published: Aug. 17, 2022

AlphaFold has burst into our lives. A powerful algorithm that underscores the strength of biological sequence data and artificial intelligence (AI). appended projects research directions. The database it been creating promises an untold number applications with vast potential impacts are still difficult to surmise. AI approaches can revolutionize personalized treatments usher in better-informed clinical trials. They promise make giant leaps toward reshaping revamping drug discovery strategies, selecting prioritizing combinations targets. Here, we briefly overview structural biology, including molecular dynamics simulations prediction microbiota-human protein-protein interactions. We highlight advancements accomplished by deep-learning-powered protein structure their impact on life sciences. At same time, does not resolve decades-long folding challenge, nor identify pathways. models provides do capture conformational mechanisms like frustration allostery, which rooted ensembles, controlled dynamic distributions. Allostery signaling properties populations. also generate ensembles intrinsically disordered proteins regions, instead describing them low probabilities. Since generates single ranked structures, rather than cannot elucidate allosteric activating driver hotspot mutations resistance. However, capturing key features, deep learning techniques use predicted conformation as basis for generating a diverse ensemble.

Language: Английский

Citations

109
Pan-cancer landscape of T-cell exhaustion heterogeneity within the tumor microenvironment revealed a progressive roadmap of hierarchical dysfunction associated with prognosis and therapeutic efficacy DOI Creative Commons
Zicheng Zhang, Lu Chen, Jun Chen

et al.

EBioMedicine, Journal Year: 2022, Volume and Issue: 83, P. 104207 - 104207

Published: Aug. 10, 2022

Language: Английский

Citations

90
Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking DOI
Zhenqiu Huang, Shixiang Sun, Moonsook Lee

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(4), P. 492 - 498

Published: April 1, 2022

Language: Английский

Citations

82
Review: RNA-based diagnostic markers discovery and therapeutic targets development in cancer DOI
Hongbo Wang, Qinghai Meng, Jinjun Qian

et al.

Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 234, P. 108123 - 108123

Published: Feb. 1, 2022

Language: Английский

Citations

82
Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource DOI Creative Commons
Lisa Dreßler, Michele Bortolomeazzi,

Mohamed Reda Keddar

et al.

Genome biology, Journal Year: 2022, Volume and Issue: 23(1)

Published: Jan. 26, 2022

Abstract Background Genetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear hampers our understanding tissue homeostasis development. Results Here, we collect a literature-based repertoire 3355 well-known or predicted drivers non-cancer evolution in 122 types 12 tissues. Mapping genes 7953 pan-cancer samples reveals that, despite large size, known compendium is still incomplete biased towards frequently occurring coding mutations. High overlap exists evolution, although significant differences emerge their recurrence. We confirm expand unique properties identify core evolutionarily conserved essential whose germline variation strongly counter-selected. Somatic alteration even one sufficient to clonal expansion but not malignant transformation. Conclusions Our study offers comprehensive overview current genetic events initiating revealing gaps biases that need be addressed. The drivers, literature support, are accessible Network Cancer Genes Healthy Drivers resource at http://www.network-cancer-genes.org/ .

Language: Английский

Citations

77
The co-evolution of the genome and epigenome in colorectal cancer DOI Creative Commons
Timon Heide, Jacob Househam, George D. Cresswell

et al.

Nature, Journal Year: 2022, Volume and Issue: 611(7937), P. 733 - 743

Published: Oct. 26, 2022

Abstract Colorectal malignancies are a leading cause of cancer-related death 1 and have undergone extensive genomic study 2,3 . However, DNA mutations alone do not fully explain malignant transformation 4–7 Here we investigate the co-evolution genome epigenome colorectal tumours at single-clone resolution using spatial multi-omic profiling individual glands. We collected 1,370 samples from 30 primary cancers 8 concomitant adenomas generated 1,207 chromatin accessibility profiles, 527 whole genomes 297 transcriptomes. found positive selection for in modifier genes recurrent somatic alterations, including regulatory regions cancer driver that were otherwise devoid genetic mutations. Genome-wide alterations transcription factor binding involved CTCF, downregulation interferon increased SOX HOX families, suggesting involvement developmental during tumourigenesis. Somatic heritable distinguished cancers. Mutational signature analysis showed turn influences accumulation This provides map epigenetic tumour heterogeneity, with fundamental implications understanding biology.

Language: Английский

Citations

76
Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors DOI Creative Commons
Jessica Lee, Smruthy Sivakumar, Alexa B. Schrock

et al.

npj Precision Oncology, Journal Year: 2022, Volume and Issue: 6(1)

Published: Dec. 9, 2022

Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape KRAS-altered cancers. We performed a pan-cancer analysis samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% had alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, prevalence was similar biopsies. Co-alteration landscapes largely across mutations but distinct wild-type, though differences observed some tumor types for mutational burden, PD-L1 expression, microsatellite instability, other signatures. Prognosis KRAS-mutant versus cohorts lung, pancreatic, colorectal cancer assessed real-world clinicogenomic database. As specific combination therapeutic strategies are being developed, profiling to understand co-alterations biomarkers that may modulate response targeted immunotherapies will be imperative.

Language: Английский

Citations

76
Diseases 2.0: a weekly updated database of disease–gene associations from text mining and data integration DOI Creative Commons
Dhouha Grissa, Alexander Junge, Tudor I. Oprea

et al.

Database, Journal Year: 2022, Volume and Issue: 2022

Published: Jan. 1, 2022

Abstract The scientific knowledge about which genes are involved in diseases grows rapidly, makes it difficult to keep up with new publications and genetics datasets. DISEASES database aims provide a comprehensive overview by systematically integrating assigning confidence scores evidence for disease–gene associations from curated databases, genome-wide association studies (GWAS) automatic text mining of the biomedical literature. Here, we present major update this resource, greatly increases number all these sources. This is especially true text-mined associations, have increased at least 9-fold cutoffs. We show that dramatic increase primarily due adding full-text articles corpus, secondarily improvements both disease gene dictionaries used named entity recognition, only very small extent growth PubMed abstracts. now also use GWAS database, Target Illumination Analytics, considerably GWAS-derived associations. itself integrated into several other databases resources, including GeneCards/MalaCards, Pharos/Target Central Resource Database Cytoscape stringApp. All data updated on weekly basis available via web interface https://diseases.jensenlab.org, where can be downloaded under open licenses. URL: https://diseases.jensenlab.org

Language: Английский

Citations

75
Genetic immune escape landscape in primary and metastatic cancer DOI Creative Commons
Francisco Martínez-Jiménez, Peter Priestley, Charles Shale

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(5), P. 820 - 831

Published: May 1, 2023

Studies have characterized the immune escape landscape across primary tumors. However, whether late-stage metastatic tumors present differences in genetic (GIE) prevalence and dynamics remains unclear. We performed a pan-cancer characterization of GIE six pathways 6,319 uniformly processed tumor samples. To address complexity HLA-I locus germline tumors, we developed LILAC, an open-source integrative framework. One four harbors alterations, with high mechanistic frequency variability cancer types. is generally consistent between reveal that alterations are selected for evolution focal loss heterozygosity tends to eliminate HLA allele, presenting largest neoepitope repertoire. Finally, mutational burden showed tendency toward as evasion mechanism, whereas, hypermutated other strategies prevail.

Language: Английский

Citations

74
Estrogen Receptor Signaling in Breast Cancer DOI Open Access
Paulina Miziak, Marzena Baran, Ewa Błaszczak

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(19), P. 4689 - 4689

Published: Sept. 23, 2023

Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) other hormone-sensitive cancers. In this review, we explore the mechanism ER-dependent downstream BC role estrogens as growth factors necessary for invasion dissemination. The significance clinical implications ER BC, including potential endocrine therapies that target estrogens’ synthesis signal transmission, such aromatase inhibitors or selective estrogen modulators, discussed. As consequence, challenges associated with resistance to these resulting from acquired mutations strategies overcome them are point new treatment strategies’ development.

Language: Английский

Citations

61