Pub Date : 2025-12-09DOI: 10.1038/s41588-025-02458-x
Hui Hua
{"title":"A twist to rose fragrance","authors":"Hui Hua","doi":"10.1038/s41588-025-02458-x","DOIUrl":"10.1038/s41588-025-02458-x","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2943-2943"},"PeriodicalIF":29.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1038/s41588-025-02411-y
Boyang Fu, Ali Pazokitoroudi, Zhuozheng Shi, Asha Kar, Albert Xue, Aakarsh Anand, Prateek Anand, Zhengtong Liu, Richard Border, Päivi Pajukanta, Noah Zaitlen, Sriram Sankararaman
The contribution of genetic interactions (epistasis) to human complex trait variation remains poorly understood due, in part, to the statistical and computational challenges involved in testing for interaction effects. Here we introduce FAME (FAst Marginal Epistasis test), a method that can test for marginal epistasis of a single-nucleotide polymorphism (SNP) on a quantitative trait (whether the effect of an SNP on the trait is modulated by genetic background). FAME is computationally efficient, enabling tests of marginal epistasis on biobank-scale data. Applying FAME to genome-wide association study (GWAS)-significant trait-SNP associations across 53 quantitative traits and ≈300 000 unrelated White British individuals in the UK Biobank (UKBB), we identified 16 significant marginal epistasis signals across 12 traits ( $$P < frac{5times {10}^{-8}}{53}$$ ). Leveraging the scalability of FAME, we further localized marginal epistasis signals across chromosomes and estimated the proportion of variance explained by marginal epistasis effects. Our study provides evidence for interactions between individual genetic variants and polygenic background influencing complex traits. FAME is a biobank-scale method that tests whether the effect of an SNP on a quantitative trait is modulated by an individual’s polygenic background. FAME can also be used to estimate of the proportion of variance explained by such marginal epistasis effects
{"title":"A biobank-scale test of marginal epistasis reveals genome-wide signals of polygenic interaction effects","authors":"Boyang Fu, Ali Pazokitoroudi, Zhuozheng Shi, Asha Kar, Albert Xue, Aakarsh Anand, Prateek Anand, Zhengtong Liu, Richard Border, Päivi Pajukanta, Noah Zaitlen, Sriram Sankararaman","doi":"10.1038/s41588-025-02411-y","DOIUrl":"10.1038/s41588-025-02411-y","url":null,"abstract":"The contribution of genetic interactions (epistasis) to human complex trait variation remains poorly understood due, in part, to the statistical and computational challenges involved in testing for interaction effects. Here we introduce FAME (FAst Marginal Epistasis test), a method that can test for marginal epistasis of a single-nucleotide polymorphism (SNP) on a quantitative trait (whether the effect of an SNP on the trait is modulated by genetic background). FAME is computationally efficient, enabling tests of marginal epistasis on biobank-scale data. Applying FAME to genome-wide association study (GWAS)-significant trait-SNP associations across 53 quantitative traits and ≈300 000 unrelated White British individuals in the UK Biobank (UKBB), we identified 16 significant marginal epistasis signals across 12 traits ( $$P < frac{5times {10}^{-8}}{53}$$ ). Leveraging the scalability of FAME, we further localized marginal epistasis signals across chromosomes and estimated the proportion of variance explained by marginal epistasis effects. Our study provides evidence for interactions between individual genetic variants and polygenic background influencing complex traits. FAME is a biobank-scale method that tests whether the effect of an SNP on a quantitative trait is modulated by an individual’s polygenic background. FAME can also be used to estimate of the proportion of variance explained by such marginal epistasis effects","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3175-3184"},"PeriodicalIF":29.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02411-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1038/s41588-025-02431-8
Carla Tangermann, Avantika Ghosh, Martin Ziegler, Francesco Facchinetti, Jannis Stappenbeck, Yagmur Oyku Carus Sahin, Marisa Riester, Luise Carmina Viardot, Tobias Zundel, Luc Friboulet, Antoine Hollebecque, José J. Naveja, Angela Wanninger, Maria Elena Hess, Tilman Brummer, Melanie Boerries, Sonja Loges, Yohann Loriot, Anna L. Illert, Sven Diederichs
Variants of uncertain significance represent the biggest challenge for genomics-based precision oncology. Activated fibroblast growth factor receptors (FGFRs) frequently drive tumorigenesis by different genetic aberrations. However, it remains unknown which of the many point mutations affecting FGFR1, FGFR2, FGFR3 or FGFR4 in cancer are druggable, that is, activating signaling while not mediating FGFR inhibitor resistance. Here we implemented a saturation mutational scanning platform to screen all 11,520 possible point mutations covering the kinase domains of FGFR1–4. Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable FGFR mutations analogous to a strong PS3/BS3 evidence level. The screens also identified loss-of-function mutations and an association of gain-of-function mutations with hydrophobic changes. The functional screens identified 97% of acquired resistance mutations in clinical trials. Our comprehensive catalog of every druggable mutation in the FGFR kinase domains is readily available for clinical decision support. Saturation mutagenesis screening examines 11,520 point mutations in the kinase domains of FGFR1, FGFR2, FGFR3 and FGFR4, identifying their activating and resistance properties to the FGFR inhibitors pemigatinib and futibatinib.
{"title":"Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations","authors":"Carla Tangermann, Avantika Ghosh, Martin Ziegler, Francesco Facchinetti, Jannis Stappenbeck, Yagmur Oyku Carus Sahin, Marisa Riester, Luise Carmina Viardot, Tobias Zundel, Luc Friboulet, Antoine Hollebecque, José J. Naveja, Angela Wanninger, Maria Elena Hess, Tilman Brummer, Melanie Boerries, Sonja Loges, Yohann Loriot, Anna L. Illert, Sven Diederichs","doi":"10.1038/s41588-025-02431-8","DOIUrl":"10.1038/s41588-025-02431-8","url":null,"abstract":"Variants of uncertain significance represent the biggest challenge for genomics-based precision oncology. Activated fibroblast growth factor receptors (FGFRs) frequently drive tumorigenesis by different genetic aberrations. However, it remains unknown which of the many point mutations affecting FGFR1, FGFR2, FGFR3 or FGFR4 in cancer are druggable, that is, activating signaling while not mediating FGFR inhibitor resistance. Here we implemented a saturation mutational scanning platform to screen all 11,520 possible point mutations covering the kinase domains of FGFR1–4. Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable FGFR mutations analogous to a strong PS3/BS3 evidence level. The screens also identified loss-of-function mutations and an association of gain-of-function mutations with hydrophobic changes. The functional screens identified 97% of acquired resistance mutations in clinical trials. Our comprehensive catalog of every druggable mutation in the FGFR kinase domains is readily available for clinical decision support. Saturation mutagenesis screening examines 11,520 point mutations in the kinase domains of FGFR1, FGFR2, FGFR3 and FGFR4, identifying their activating and resistance properties to the FGFR inhibitors pemigatinib and futibatinib.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"157-168"},"PeriodicalIF":29.0,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02431-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1038/s41588-025-02440-7
Stylianos E. Antonarakis
Small nuclear RNA (snRNA) genes represent a class of non-protein-coding genes involved in the processing of pre-mRNAs of intron-containing genes. The human genome contains approximately 2,000 snRNA genes; the majority are pseudogenes, and only a small fraction are functional. These snRNAs undergo extensive post-transcriptional modifications, and, together with proteins and other snRNAs, form small nuclear ribonucleoproteins, which are components of the spliceosome. This Review discusses high-impact variants in 12 snRNA genes that cause Mendelian disorders with either autosomal dominant or recessive inheritance patterns. The associated phenotypes include mainly neurodevelopmental delay, developmental abnormalities and retinitis pigmentosa. The presumed consequences of these variants are presented on the basis of previous functional characterization of the corresponding snRNAs. It is anticipated that the understanding of both Mendelian and complex traits due to snRNAs will increase the diagnostic potential, partially explain penetrance and provide more therapeutic options. This Review discusses the high-impact variants in 12 small nuclear RNA genes that cause Mendelian disorders with either autosomal dominant or recessive inheritance patterns, highlighting the biochemical consequences and therapeutic implications.
{"title":"Small nuclear RNA genes in Mendelian disorders","authors":"Stylianos E. Antonarakis","doi":"10.1038/s41588-025-02440-7","DOIUrl":"10.1038/s41588-025-02440-7","url":null,"abstract":"Small nuclear RNA (snRNA) genes represent a class of non-protein-coding genes involved in the processing of pre-mRNAs of intron-containing genes. The human genome contains approximately 2,000 snRNA genes; the majority are pseudogenes, and only a small fraction are functional. These snRNAs undergo extensive post-transcriptional modifications, and, together with proteins and other snRNAs, form small nuclear ribonucleoproteins, which are components of the spliceosome. This Review discusses high-impact variants in 12 snRNA genes that cause Mendelian disorders with either autosomal dominant or recessive inheritance patterns. The associated phenotypes include mainly neurodevelopmental delay, developmental abnormalities and retinitis pigmentosa. The presumed consequences of these variants are presented on the basis of previous functional characterization of the corresponding snRNAs. It is anticipated that the understanding of both Mendelian and complex traits due to snRNAs will increase the diagnostic potential, partially explain penetrance and provide more therapeutic options. This Review discusses the high-impact variants in 12 small nuclear RNA genes that cause Mendelian disorders with either autosomal dominant or recessive inheritance patterns, highlighting the biochemical consequences and therapeutic implications.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"58 1","pages":"28-38"},"PeriodicalIF":29.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1038/s41588-025-02423-8
Jonathan E. LoTempio Jr, Christopher R. Donohue, Jonathan D. Moreno, Ana Santos Rutschman, Joshua Sarnoff, Michael S. Sinha, Thomas Stoeger, Jorge L. Contreras
The bankruptcy of 23andMe was an inflection point for the direct-to-consumer genetics market. Although the privacy of consumer data has been highlighted by many as a concern, we discuss another key tension in this case: the corporate enclosure of scientific data that has considerable potential value for biomedical research and public health.
{"title":"Impact of the 23andMe bankruptcy on preserving the public benefit of scientific data","authors":"Jonathan E. LoTempio Jr, Christopher R. Donohue, Jonathan D. Moreno, Ana Santos Rutschman, Joshua Sarnoff, Michael S. Sinha, Thomas Stoeger, Jorge L. Contreras","doi":"10.1038/s41588-025-02423-8","DOIUrl":"10.1038/s41588-025-02423-8","url":null,"abstract":"The bankruptcy of 23andMe was an inflection point for the direct-to-consumer genetics market. Although the privacy of consumer data has been highlighted by many as a concern, we discuss another key tension in this case: the corporate enclosure of scientific data that has considerable potential value for biomedical research and public health.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2933-2936"},"PeriodicalIF":29.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1038/s41588-025-02430-9
Tao Sun, Qin Li, Jonathan M. Geisinger, Shi-Bin Hu, Boming Fan, Shichen Su, Waitang Tsui, Hongchao Guo, Jinbiao Ma, Jin Billy Li
Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5—termed as immunogenic dsRNAs—remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized. The authors show that only a small subset of cytosolic double-stranded RNAs (dsRNAs) requires ADAR1-mediated RNA editing to evade an MDA5-dependent immune response. These immunogenic dsRNAs are enriched in mRNAs and overlap with GWAS signals for common inflammatory diseases.
{"title":"ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity","authors":"Tao Sun, Qin Li, Jonathan M. Geisinger, Shi-Bin Hu, Boming Fan, Shichen Su, Waitang Tsui, Hongchao Guo, Jinbiao Ma, Jin Billy Li","doi":"10.1038/s41588-025-02430-9","DOIUrl":"10.1038/s41588-025-02430-9","url":null,"abstract":"Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5—termed as immunogenic dsRNAs—remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized. The authors show that only a small subset of cytosolic double-stranded RNAs (dsRNAs) requires ADAR1-mediated RNA editing to evade an MDA5-dependent immune response. These immunogenic dsRNAs are enriched in mRNAs and overlap with GWAS signals for common inflammatory diseases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3101-3111"},"PeriodicalIF":29.0,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02430-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1038/s41588-025-02464-z
David S. M. Lee, Kathleen M. Cardone, David Y. Zhang, Noah L. Tsao, Sarah Abramowitz, Pranav Sharma, John S. DePaolo, Mitchell Conery, Krishna G. Aragam, Kiran Biddinger, Ozan Dikilitas, Lily Hoffman-Andrews, Renae L. Judy, Atlas Khan, Iftikhar J. Kullo, Megan J. Puckelwartz, Nosheen Reza, Benjamin A. Satterfield, Pankhuri Singhal, Penn Medicine Biobank, Zoltan Arany, Thomas P. Cappola, Eric D. Carruth, Sharlene M. Day, Ron Do, Christopher M. Haggerty, Jacob Joseph, Elizabeth M. McNally, Girish Nadkarni, Anjali T. Owens, Daniel J. Rader, Marylyn D. Ritchie, Yan V. Sun, Benjamin F. Voight, Michael G. Levin, Scott M. Damrauer
{"title":"Author Correction: Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum","authors":"David S. M. Lee, Kathleen M. Cardone, David Y. Zhang, Noah L. Tsao, Sarah Abramowitz, Pranav Sharma, John S. DePaolo, Mitchell Conery, Krishna G. Aragam, Kiran Biddinger, Ozan Dikilitas, Lily Hoffman-Andrews, Renae L. Judy, Atlas Khan, Iftikhar J. Kullo, Megan J. Puckelwartz, Nosheen Reza, Benjamin A. Satterfield, Pankhuri Singhal, Penn Medicine Biobank, Zoltan Arany, Thomas P. Cappola, Eric D. Carruth, Sharlene M. Day, Ron Do, Christopher M. Haggerty, Jacob Joseph, Elizabeth M. McNally, Girish Nadkarni, Anjali T. Owens, Daniel J. Rader, Marylyn D. Ritchie, Yan V. Sun, Benjamin F. Voight, Michael G. Levin, Scott M. Damrauer","doi":"10.1038/s41588-025-02464-z","DOIUrl":"10.1038/s41588-025-02464-z","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3201-3201"},"PeriodicalIF":29.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02464-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145635672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1038/s41588-025-02418-5
Sukanya Panja, Padmaja Mantri, Kofi Ennu Johnson, Juan Sebastian Andrade-Martinez, Soo-Ryum Yang, Aditya Deshpande, Huasong Tian, Shaham Beg, Kentaro Ohara, Alessandro Leal, Joel Rosiene, Marlon Stoeckius, Peter Smibert, William D. Travis, Juan Miguel Mosquera, Paz Polak, Marcin Imieliński
DNA damage is preferentially repaired in expressed genes; thus, genome-wide correlations between somatic mutation patterns and normal cell transcription may reflect tumor cell origins. Accordingly, we found that aggregate lung adenocarcinoma (LUAD) and squamous cancer (LUSC) somatic mutation density associated most strongly with distal (alveolar) and proximal (basal) lung cell-type-specific gene expression, respectively, consistent with presumed LUAD and LUSC cell origins. Analyzing individual genomes, 21% of LUADs bore mutational footprints of proximal airway origins, with 38% classified as ambiguous. Distal origin LUADs, enriched for KRAS and STK11 drivers, occurred mainly in smokers; proximal origin LUADs, enriched for EGFR drivers, were more common in never-smokers. Ambiguous origin LUADs showed APOBEC signatures and SMARCA4 alterations. TP53 mutant LUADs with non-distal cell origins preferentially exhibited non-distal transcriptional identity. Our study reveals a complex interplay between lineage and identity in LUAD evolution and offers a scalable strategy to infer tumor origins in human cancers. This study shows how the links between somatic passenger mutations in tumors and normal cell transcriptomes can be used to infer cell-of-origin in lung adenocarcinoma.
{"title":"Passenger mutations link cellular origin and transcriptional identity in human lung adenocarcinomas","authors":"Sukanya Panja, Padmaja Mantri, Kofi Ennu Johnson, Juan Sebastian Andrade-Martinez, Soo-Ryum Yang, Aditya Deshpande, Huasong Tian, Shaham Beg, Kentaro Ohara, Alessandro Leal, Joel Rosiene, Marlon Stoeckius, Peter Smibert, William D. Travis, Juan Miguel Mosquera, Paz Polak, Marcin Imieliński","doi":"10.1038/s41588-025-02418-5","DOIUrl":"10.1038/s41588-025-02418-5","url":null,"abstract":"DNA damage is preferentially repaired in expressed genes; thus, genome-wide correlations between somatic mutation patterns and normal cell transcription may reflect tumor cell origins. Accordingly, we found that aggregate lung adenocarcinoma (LUAD) and squamous cancer (LUSC) somatic mutation density associated most strongly with distal (alveolar) and proximal (basal) lung cell-type-specific gene expression, respectively, consistent with presumed LUAD and LUSC cell origins. Analyzing individual genomes, 21% of LUADs bore mutational footprints of proximal airway origins, with 38% classified as ambiguous. Distal origin LUADs, enriched for KRAS and STK11 drivers, occurred mainly in smokers; proximal origin LUADs, enriched for EGFR drivers, were more common in never-smokers. Ambiguous origin LUADs showed APOBEC signatures and SMARCA4 alterations. TP53 mutant LUADs with non-distal cell origins preferentially exhibited non-distal transcriptional identity. Our study reveals a complex interplay between lineage and identity in LUAD evolution and offers a scalable strategy to infer tumor origins in human cancers. This study shows how the links between somatic passenger mutations in tumors and normal cell transcriptomes can be used to infer cell-of-origin in lung adenocarcinoma.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3066-3074"},"PeriodicalIF":29.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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