Biology subjects

Wu, F.

Publications and source records attributed to Wu, F..

At least 109 records · Page 6Linked to original sources

bioRxiv2023

A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) with a high mortality rate, and few effective therapeutic strategies are available. CCL5/CCR5 is an appealing immunotherapeutic target for TNBC. However, its signaling mechanism is poorly understood and its direct antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a more selective and potent antagonist than the known CCR5 antagonist maraviroc. Without photodynamic therapy, verteporfin demonstrated significant inhibition on TNBC tumor growth through immune regulation, remarkable suppression of lung metastasis by cell-intrinsic mechanism, and a significant extension of overall survival in vivo. Mechanistically, CCR5 was found to be essential for expression of the key hippo effector YAP1. It promoted YAP1 transcription via HIF-1 and exerted further control over the migration of CD8+ T, NK, and MDSC immune cells through chemokines CXCL16 and CXCL8 which were identified from RNA-seq. Moreover, the CCR5-YAP1 axis played a vital role in promoting metastasis by modulating {beta}-catenin and core epithelial-mesenchymal transition transcription factors ZEB1 and ZEB2. It is noteworthy that the regulatory relationship between CCR5 and YAP1 was observed across various BC subtypes, TNBC patients, and showed potential relevance in fifteen additional cancer types. Overall, this study introduced an easy-to-use HTS assay that streamlines the discovery of CCL5/CCR5 axis antagonists. Verteporfin was identified as a specific molecular probe of this axis with great potentials as a therapeutic agent for treating sixteen malignant diseases characterized by heightened CCR5 and YAP1 levels.

cancer biology↗

bioRxiv2023

Last in first out: SIV proviruses seeded later in infection are harbored in short-lived CD4+ T cells

HIV can persist in a latent form as integrated DNA (provirus) in resting CD4+ T cells of infected individuals and as such is unaffected by antiretroviral therapy (ART). Despite being a major obstacle for eradication efforts, the genetic variation and timing of formation of this latent reservoir remains poorly understood. Previous studies on when virus is deposited in the latent reservoir have come to contradictory conclusions. To reexamine the genetic variation of HIV in CD4+ T cells during ART, we determined the divergence in envelope sequences collected from 10 SIV infected rhesus macaques. We found that the macaques displayed a biphasic decline of the viral divergence over time, where the first phase lasted for an average of 11.6 weeks (range 4-28 weeks). Motivated by recent observations that the HIV-infected CD4+ T cell population is composed of short- and long-lived subsets, we developed a model to study the divergence dynamics. We found that SIV in short-lived cells was on average more diverged, while long-lived cells harbored less diverged virus. This suggests that the long-lived cells harbor virus deposited starting earlier in infection and continuing throughout infection, while short-lived cells predominantly harbor more recent virus. As these cell populations decayed, the overall proviral divergence decline matched that observed in the empirical data. This model explains previous seemingly contradictory results on the timing of virus deposition into the latent reservoir, and should provide guidance for future eradication efforts. Significance statementHIV can persist in a latent reservoir unaffected by antiretroviral drugs. The genetic variation of this latent virus population is a major obstacle for eradication efforts, but also a clue to when HIV variants are deposited in the reservoirs. Unfortunately, previous studies assessing when the virus was deposited in latent reservoirs have come to contradictory conclusions. Here, we propose SIV proviral DNA exists in both short- and long-lived CD4+ T cells, and that these two cell subsets harbor different genetically diverged virus populations. Our model explains the contradictory findings and shows that when CD4+ T cells decay under effective drug treatment, which prevents virus replication, the resulting virus divergence decreases and recapitulates observed data. This knowledge should help in improving future eradication efforts.

microbiology↗

bioRxiv2023

Mapping Cell-to-cell Interactions from Spatially Resolved Transcriptomics Data

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently, through the introduction of spatially resolved transcriptomics technologies (SRTs), especially those that achieve single cell resolution. However, significant challenges remain to analyze such highly complex data properly. Here, we introduce a Bayesian multi-instance learning framework, spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight spacias power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates, and most importantly the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of spacia for all three commercialized single cell resolution ST technologies: MERSCOPE/Vizgen, CosMx/Nanostring, and Xenium/10X. Spacia unveiled how endothelial cells, fibroblasts and B cells in the tumor microenvironment contribute to Epithelial-Mesenchymal Transition and lineage plasticity in prostate cancer cells. We deployed spacia in a set of pan-cancer datasets and showed that B cells also participate in PDL1/PD1 signaling in tumors. We demonstrated that a CD8+ T cell/PDL1 effectiveness signature derived from spacia analyses is associated with patient survival and response to immune checkpoint inhibitor treatments in 3,354 patients. We revealed differential spatial interaction patterns between {gamma}{delta} T cells and liver hepatocytes in healthy and cancerous contexts. Overall, spacia represents a notable step in advancing quantitative theories of cellular communications.

bioinformatics↗

bioRxiv2023

B Cells Promote T Cell Immunosenescence and Mammalian Aging Parameters

A dysregulated adaptive immune system is a key feature of aging, and is associated with age-related chronic diseases and mortality. Most notably, aging is linked to a loss in the diversity of the T cell repertoire and expansion of activated inflammatory age-related T cell subsets, though the main drivers of these processes are largely unknown. Here, we find that T cell aging is directly influenced by B cells. Using multiple models of B cell manipulation and single-cell omics, we find B cells to be a major cell type that is largely responsible for the age-related reduction of naive T cells, their associated differentiation towards pathogenic immunosenescent T cell subsets, and for the clonal restriction of their T cell receptor (TCR). Accordingly, we find that these pathogenic shifts can be therapeutically targeted via CD20 monoclonal antibody treatment. Mechanistically, we uncover a new role for insulin receptor signaling in influencing age-related B cell pathogenicity that in turn induces T cell dysfunction and a decline in healthspan parameters. These results establish B cells as a pivotal force contributing to age-associated adaptive immune dysfunction and healthspan outcomes, and suggest new modalities to manage aging and related multi-morbidity. One Sentence SummaryInsulin receptor signaling facilitates the induction of age associated B cell inflammatory changes, which drive phenotypic aging of the T cell compartment and adverse outcomes to mammalian healthspan parameters.

immunology↗

bioRxiv2023

Viperin immunity evolved across the tree of life through serial innovations on a conserved scaffold

Evolutionary arms races between cells and viruses drive the rapid diversification of antiviral genes in diverse life forms. Recent discoveries have revealed the existence of shared immune genes between prokaryotes and eukaryotes, showing molecular and mechanistic similarities in their response to viruses. However, the underlying evolutionary dynamics that explain the conservation and adaptation of these antiviral genes remain mostly unexplored. Here, we show that viperins constitute a highly conserved family of immune genes across diverse prokaryotes and eukaryotes, and uncover mechanisms by which they diversified in eukaryotes. Our findings indicate that viperins are enriched in Asgard archaea and widely distributed in all major eukaryotic clades, suggesting their presence in the Last Eukaryotic Common Ancestor (LECA). We show that viperins maintain their immune function by producing antiviral nucleotide analogs. We demonstrate that eukaryotic viperins diversified through serial innovations on the viperin gene, such as the emergence and selection of substrate specificity towards pyrimidine nucleotides, and through partnerships with genes maintained through genetic linkage, notably with nucleotide kinases. These findings unveil biochemical and genomic transitions underlying the adaptation of immune genes shared by prokaryotes and eukaryotes. Our study paves the way for the understanding of the conservation of immunity across domains of life.

evolutionary biology↗

bioRxiv2023

Enhancer-driven regulatory network of forebrain human development provides insights into autism

Cell differentiation is orchestrated by transcription factors (TFs) binding to enhancers, shaping gene regulatory networks that drive neuronal lineage specification. Deciphering these enhancer-driven networks in human forebrain development is essential for understanding the genetic basis of neurodevelopmental disorders. Through integrative epigenomic and transcriptomic analyses of human forebrain organoids derived from 10 individuals with autism spectrum disorder (ASD) and their neurotypical fathers, we constructed a comprehensive enhancer-driven gene regulatory network (GRN) of early neurodevelopment. This GRN revealed hierarchical regulatory transitions guiding neuronal differentiation and was experimentally validated via CRISPR interference (CRISPRi) and loss-of-function analyses. A subnetwork linked ASD-associated transcriptomic alterations to dysregulated TF activity, implicating FOXG1, BHLHE22, EOMES, and NEUROD2 as key regulators of excitatory neuron specification in macrocephalic ASD. These findings suggest that ASD disrupts enhancer-driven regulatory frameworks, altering neuronal cell fate decisions in the developing fetal brain.

genomics↗

bioRxiv2023

Progressive plasticity during colorectal cancer metastasis

Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.

cancer biology↗

bioRxiv2023

Characterization of enhancer activity in early human neurodevelopment using Massively parallel reporter assay (MPRA) and forebrain organoids

AO_SCPLOWBSTRACTC_SCPLOWRegulation of gene expression through enhancers is one of the major processes shaping the structure and function of the human brain during development. High-throughput assays have predicted thousands of enhancers involved in neurodevelopment, and confirming their activity through orthogonal functional assays is crucial. Here, we utilized Massively Parallel Reporter Assays (MPRAs) in stem cells and forebrain organoids to evaluate the activity of [~]7,000 gene-linked enhancers previously identified in human fetal tissues and brain organoids. We used a Gaussian mixture model to evaluate the contribution of background noise in the measured activity signal to confirm the activity of [~]35% of the tested enhancers, with most showing temporal-specific activity, suggesting their evolving role in neurodevelopment. The temporal specificity was further supported by the correlation of activity with gene expression. Our findings provide a valuable gene regulatory resource to the scientific community. AO_SCPLOWUTHORC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWSUMMARYC_SCPLOWEnhancers are non-coding elements that play a crucial role in the regulation of gene expression during brain development. Despite the availability of various techniques available to identify enhancers, their functional activity is relatively less understood, leaving a gap in our understanding of how enhancer behavior might regulate complex transitions of neurodevelopment. To address this, we utilized forebrain organoids, a 3D model system which closely mimics the complex cellular environment of the developing human brain, and employed Massively Parallel Reporter Assay (MPRA) to validate enhancer activity at various stages of forebrain differentiation, from induced pluripotent stem cells (iPSCs) to neuronal progenitors and cortical neurons. Our study provides a comprehensive catalog of over 2,300 enhancers, showcasing their temporal activity profiles during early neuronal development and offering valuable insights into their likely biological functions. This research advances our understanding of enhancer dynamics in brain development and offers new avenues for further investigations in this field.

genomics↗

bioRxiv2023

APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer

APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor {Delta}Np63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinib-resistant cells reduces the expression of the {Delta}Np63 target genes IL1/{beta} and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target {Delta}Np63 in gefitinib-resistant lung cancers may have therapeutic benefit.

cancer biology↗

bioRxiv2023

Lymphoid tissues contribute to viral clonotypes present in plasma at early post-ATI in SIV-infected rhesus macaques

The rebound-competent viral reservoir (RCVR), comprised of virus that is able to persist during antiretroviral therapy (ART) and mediate reactivation of systemic viral replication and rebound viremia after antiretroviral therapy interruption (ATI), remains the biggest obstacle to the eradication of HIV infection. A better understanding of the cellular and tissue origins and the dynamics of viral populations that initiate rebound upon ATI could help develop targeted therapeutic strategies for reducing the RCVR. In this study, barcoded SIVmac239M was used to infect rhesus macaques to enable monitoring of viral barcode clonotypes contributing to virus detectable in plasma after ATI. Blood, lymphoid tissues (LTs, spleen, mesenteric and inguinal lymph nodes), and non-lymphoid tissues (NLTs, colon, ileum, lung, liver, and brain) were analyzed using viral barcode sequencing, intact proviral DNA assay, single-cell RNA sequencing, and combined CODEX/RNAscope/in situ hybridization. Four of seven animals had viral barcodes detectable by deep sequencing of plasma at necropsy although plasma viral RNA remained < 22 copies/mL. Among the tissues studied, mesenteric and inguinal lymph nodes, and spleen contained viral barcodes detected in plasma, and trended to have higher cell-associated viral loads, higher intact provirus levels, and greater diversity of viral barcodes. CD4+ T cells were the main cell type harboring viral RNA (vRNA) after ATI. Further, T cell zones in LTs showed higher vRNA levels than B cell zones for most animals. These findings are consistent with LTs contributing to virus present in plasma early after ATI. One Sentence SummaryThe reemerging of SIV clonotypes at early post-ATI are likely from the secondary lymphoid tissues.

immunology↗

bioRxiv2023

Tomato CYP94C1 terminates jasmonate signaling during fruit ripening by inactivating bioactive jasmonoyl-L-isoleucine

Ripe fruits are more susceptible to necrotrophic pathogens than unripe fruits. Although this phenomenon is widespread across different fruit species and results in substantial economic losses, the underlying mechanism is still poorly understood. Previous studies revealed that ethylene (ET) is a key signal controlling climacteric fruit ripening and that jasmonate (JA) regulates plant resistance to necrotrophs. We investigated the function of tomato cytochrome P450 94 (CYP94) family genes in JA signaling and report here that ET-mediated ripening suppresses JA-mediated defense by promoting the deactivation of bioactive JA-Ile. ETHYLENE-INSENSITIVE 3 (EIN3)/EIN3-LIKE (EIL) transcription factors directly activated CYP94C1 to convert JA-Ile to its inactive form 12-COOH-JA-Ile, thereby terminating JA signaling during fruit ripening. Mutation of CYP94C1 led to increased resistance of ripe fruits to the necrotrophic pathogen Botrytis cinerea without affecting the ripening process. Additionally, the master transcription factor MYC2 directly activated two other CYP94 members CYP94B1 and CYP94B2 to convert JA-Ile to its less active form 12-OH-JA-Ile, thereby attenuating JA signaling in wounded leaves. Simultaneous mutation of CYP94B1 and CYP94B2 increased the resistance of leaves to B. cinerea. Thus, differences in the expression and enzymatic activities of CYP94 family gene members precisely control JA-mediated defense responses in tomato.

plant biology↗

bioRxiv2023

RaptorX-Single: single-sequence protein structure prediction by integrating protein language models

Protein structure prediction has been greatly improved by deep learning in the past few years. However, the most successful methods rely on multiple sequence alignment (MSA) of the sequence homologs of the protein under prediction. In nature a protein folds in the absence of its sequence homologs and thus, a MSA-free structure prediction method is desired. Here we develop a single sequence-based protein structure prediction method RaptorX-Single by integrating several protein language models and a structure generation module and then study its advantage over MSA-based prediction methods. Our experimental results indicate that in addition to running much faster than MSA-based methods such as AlphaFold2, RaptorX-Single outperforms AlphaFold2 and other MSA-free methods in predicting the structure of antibodies, proteins of very few sequence homologs and single mutation effects. RaptorX-Single also compares favorably to MSA-based AlphaFold2 when the protein under prediction has a large number of sequence homologs.

bioinformatics↗

bioRxiv2023

Assisting and Accelerating NMR Assignment with Restrainted Structure Prediction

NMR experiments can detect in situ structures and dynamic interactions, but the NMR assignment process requires expertise and is time-consuming, thereby limiting its applicability. Deep learning algorithms have been employed to aid in experimental data analysis. In this work, we developed a RASP model which can enhance structure prediction with restraints. Based on the Evoformer and structure module architecture of AlphaFold, this model can predict structure based on sequence and a flexible number of input restraints. Moreover, it can evaluate the consistency between the predicted structure and the imposed restraints. Based on this model, we constructed an iterative NMR NOESY peak assignment pipeline named FAAST, to accelerate assignment process of NOESY restraints and obtaining high quality structure ensemble. The RASP model and FAAST pipeline not only allow for the leveraging of experimental restraints to improve model prediction, but can also facilitate and expedite experimental data analysis with their integrated capabilities.

bioinformatics↗

bioRxiv2023

Shin in the eye: Au-CS@FNDs as contact lens additives for blocking UV irradiation, bacterial keratitis, and corneal neovascularizationtherapies

Ophthalmic disease treatment remains a significant problem globally, resulting in poor vision and blindness. UV irradiation and bacterial infection may cause severe damage to the corneal, leading to vision loss within a few days. Corneal neovascular abnormally growth that bock lights reach to eyes, causes low vision. Thus it requires urgent and efficient clinical treatment. Contact lenses play an essential role in treating ophthalmic issues. In this work, we synthesized the chitosan-stabilized Au nanoparticles with a simple method. The Au nanoparticles were further physically adsorbed with negatively charged fluorescent nanodiamonds, yielding Au-CS@FNDs. These Au-CS@FNDs particles were proven with excellent UV adsorption, antibacterial properties, and photothermal conversation ability. Furthermore, we embedded Au-CS@FNDs particles into contact lenses to prevent corneal damage from UV light and bacterial infection. Moreover, the Au-CS@FNDs embedded contact lenses were used to inhibit the neovascularization in the Human Vascular Endothelial Cells via the photodynamic effect of Au nanoparticles. To the best of our knowledge, it is the first time that gold and diamond nanoparticles were used as additives in contact lenses, aiming at clinically corneal neovascular. Our results suggest that the controllable photothermal effect of Au-CS@FNDs embedded contact lenses may provide a unique way to intervene the neovascular-induced vision loss. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/536356v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1b94b65org.highwire.dtl.DTLVardef@4f598org.highwire.dtl.DTLVardef@198058forg.highwire.dtl.DTLVardef@1950cd3_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Evaluating performance and applications of sample-wise cell deconvolution methods on human brain transcriptomic data

Sample-wise deconvolution methods have been developed to estimate cell-type proportions and gene expressions in bulk-tissue samples. However, the performance of these methods and their biological applications has not been evaluated, particularly on human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk-tissue RNAseq, single-cell/nuclei (sc/sn) RNAseq, and immunohistochemistry. A total of 1,130,767 nuclei/cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expression. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk-tissue or single-cell eQTLs alone. Differential gene expression associated with multiple phenotypes were also examined using the deconvoluted data. Our findings, which were replicated in bulk-tissue RNAseq and sc/snRNAseq data, provided new insights into the biological applications of deconvoluted data.

genomics↗

bioRxiv2023

High Resolution Salmonella Subtyping by the MLSTnext Method

The food industry needs a straightforward, efficient, widely applicable and cost-efficient method to not only detect, but also determine serovar and potential sources of multiple strains in food and environment. While Whole Genome Sequencing (WGS) can generate complete genomic profile of food pathogens, it is a laborious, time-consuming, and expensive method that necessitates pure isolates. As a result, it is unsuitable for samples with complex background, limiting its widespread application by food industry. However, traditional multilocus sequence typing (MLST) approaches do not provide sufficient single nucleotide polymorphism (SNP) information to effectively track- and-trace sources of contamination. In contrast, ChapterDx MLSTnext-NGS (next-generation sequencing) Salmonella assay amplifies and sequences 47 polymorphic loci, evenly spanning the Salmonella enterica genome. As demonstrated in this study, the ChapterDx MLSTnext-NGS Salmonella can identify serovar with high resolution, distinguishing between various strains of the same serovar and resolve co-presence of different strains in a single sample. Additionally, this assay can analyze up to thousand samples in a single sequencing run within 22 hours, making it a highly efficient and scalable method for the food industry. Moreover, the cost per sample of the ChapterDx MLSTnext-NGS Salmonella assay is comparable to that of quantitative Polymerase Chain Reaction (qPCR), making it an affordable option. The assay uses ChapterDx amplification technology, allowing for the amplification of all 47 loci in a single-tube, single-step PCR reaction. This makes it one of the simplest NGS applications available. In summary, ChapterDx MLSTnext-NGS Salmonella assay can be implemented in many diagnostic laboratories to address increasingly complex food safety issues.

microbiology↗

bioRxiv2023

Acetylation-dependent coupling between G6PD activity and apoptotic signaling

Lysine acetylation has been discovered in thousands of non-histone human proteins, including most metabolic enzymes. Deciphering the functions of acetylation is key to understanding how metabolic cues mediate metabolic enzyme regulation and cellular signaling. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is acetylated on multiple lysine residues. Using site-specifically acetylated G6PD, we show that acetylation can activate (AcK89) and inhibit (AcK403) G6PD. Acetylation-dependent inactivation is explained by structural studies showing distortion of the dimeric structure and active site of G6PD. We provide evidence for acetylation-dependent K95/97 ubiquitylation of G6PD and Y503 phosphorylation, as well as interaction with p53 and induction of early apoptotic events. Notably, we found that the acetylation of a single lysine residue coordinates diverse acetylation-dependent processes. Our data provide an example of the complex roles of acetylation as a posttranslational modification that orchestrates the regulation of enzymatic activity, posttranslational modifications, and apoptotic signaling

biochemistry↗

bioRxiv2023

Somatic mutation but not aneuploidy differentiates lung cancer in never-smokers and smokers.

Lung cancer in never-smokers disproportionately affects older women. To understand the mutational landscape of this cohort, we performed detailed genome characterization of 73 lung adenocarcinomas from participants of the Womens Health Initiative (WHI). We find enrichment of EGFR mutations in never-/light-smokers and KRAS mutations in heavy smokers as expected, but we also show that the specific variants of these genes differ by smoking status, with important therapeutic implications. Mutational signature analysis revealed signatures of clock, APOBEC, and DNA repair deficiency in never-/light-smokers; however, the mutational load of these signatures did not differ significantly from those found in smokers. Last, tumors from both smokers and never-/light-smokers shared copy number subtypes, with no significant differences in aneuploidy. Thus, the genomic landscape of lung cancer in never-/light-smokers and smokers is predominantly differentiated by somatic mutations and not copy number alterations.

genomics↗