Genome Medicine最新文献

{"title":"Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma.","authors":"Si-Yu Jing, Dan Liu, Na Feng, Hui Dong, He-Qi Wang, Xi Yan, Xu-Feng Chen, Min-Cheng Qu, Ping Lin, Bin Yi, Feiling Feng, Lei Chen, Hong-Yang Wang, Hong Li, Yu-Fei He","doi":"10.1186/s13073-024-01367-8","DOIUrl":"10.1186/s13073-024-01367-8","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear.</p><p><strong>Methods: </strong>We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays.</p><p><strong>Results: </strong>We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells.</p><p><strong>Conclusions: </strong>We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"98"},"PeriodicalIF":10.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975501","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}

{"title":"ENU-based dominant genetic screen identifies contractile and neuronal gene mutations in congenital heart disease","authors":"Xiaoxi Luo, Lifeng Liu, Haowei Rong, Xiangyang Liu, Ling Yang, Nan Li, Hongjun Shi","doi":"10.1186/s13073-024-01372-x","DOIUrl":"https://doi.org/10.1186/s13073-024-01372-x","url":null,"abstract":"Congenital heart disease (CHD) is the most prevalent congenital anomaly, but its underlying causes are still not fully understood. It is believed that multiple rare genetic mutations may contribute to the development of CHD. In this study, we aimed to identify novel genetic risk factors for CHD using an ENU-based dominant genetic screen in mice. We analyzed fetuses with malformed hearts and compared them to control littermates by whole exome or whole genome sequencing (WES/WGS). The differences in mutation rates between observed and expected values were tested using the Poisson and Binomial distribution. Additionally, we compared WES data from human CHD probands obtained from the Pediatric Cardiac Genomics Consortium with control subjects from the 1000 Genomes Project using Fisher’s exact test to evaluate the burden of rare inherited damaging mutations in patients. By screening 10,285 fetuses, we identified 1109 cases with various heart defects, with ventricular septal defects and bicuspid aortic valves being the most common types. WES/WGS analysis of 598 cases and 532 control littermates revealed a higher number of ENU-induced damaging mutations in cases compared to controls. GO term and KEGG pathway enrichment analysis showed that pathways related to cardiac contraction and neuronal development and functions were enriched in cases. Further analysis of 1457 human CHD probands and 2675 control subjects also revealed an enrichment of genes associated with muscle and nervous system development in patients. By combining the mice and human data, we identified a list of 101 candidate digenic genesets, from which each geneset was co-mutated in at least one mouse and two human probands with CHD but not in control mouse and control human subjects. Our findings suggest that gene mutations affecting early hemodynamic perturbations in the developing heart may play a significant role as a genetic risk factor for CHD. Further validation of the candidate gene set identified in this study could enhance our understanding of the complex genetics underlying CHD and potentially lead to the development of new diagnostic and therapeutic approaches.","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"69 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141940261","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}

{"title":"The genetics and epidemiology of N- and O-immunoglobulin A glycomics.","authors":"Alessia Visconti, Niccolò Rossi, Albert Bondt, Agnes Hipgrave Ederveen, Gaurav Thareja, Carolien A M Koeleman, Nisha Stephan, Anna Halama, Hannah J Lomax-Browne, Matthew C Pickering, Xu-Jie Zhou, Manfred Wuhrer, Karsten Suhre, Mario Falchi","doi":"10.1186/s13073-024-01369-6","DOIUrl":"10.1186/s13073-024-01369-6","url":null,"abstract":"<p><strong>Background: </strong>Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation.</p><p><strong>Methods: </strong>We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species.</p><p><strong>Results: </strong>We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries.</p><p><strong>Conclusions: </strong>Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"96"},"PeriodicalIF":10.4,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11312925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912383","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}

{"title":"Microglial heterogeneity in the ischemic stroke mouse brain of both sexes.","authors":"Ángela Del Águila, Ran Zhang, Xinyuan Yu, Lihong Dang, Feng Xu, Jin Zhang, Vaibhav Jain, Jilin Tian, Xiao-Ping Zhong, Huaxin Sheng, Wei Yang","doi":"10.1186/s13073-024-01368-7","DOIUrl":"10.1186/s13073-024-01368-7","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke elicits a complex and sustained immune response in the brain. Immunomodulatory treatments have long held promise for improving stroke outcomes, yet none have succeeded in the clinical setting. This lack of success is largely due to our incomplete understanding of how immune cells respond to stroke. The objective of the current study was to dissect the effect of permanent stroke on microglia, the resident immune cells within the brain parenchyma.</p><p><strong>Methods: </strong>A permanent middle cerebral artery occlusion (pMCAO) model was used to induce ischemic stroke in young male and female mice. Microglia were sorted from fluorescence reporter mice after pMCAO or sham surgery and then subjected to single-cell RNA sequencing analysis. Various methods, including flow cytometry, RNA in situ hybridization, immunohistochemistry, whole-brain imaging, and bone marrow transplantation, were also employed to dissect the microglial response to stroke. Stroke outcomes were evaluated by infarct size and behavioral tests.</p><p><strong>Results: </strong>First, we showed the morphologic and spatial changes in microglia after stroke. We then performed single-cell RNA sequencing analysis on microglia isolated from sham and stroke mice of both sexes. The data indicate no major sexual dimorphism in the microglial response to permanent stroke. Notably, we identified seven potential stroke-associated microglial clusters, including four major clusters characterized by a disease-associated microglia-like signature, a highly proliferative state, a macrophage-like profile, and an interferon (IFN) response signature, respectively. Importantly, we provided evidence that the macrophage-like cluster may represent the long-sought stroke-induced microglia subpopulation with increased CD45 expression. Lastly, given that the IFN-responsive subset constitutes the most prominent microglial population in the stroke brain, we used fludarabine to pharmacologically target STAT1 signaling and found that fludarabine treatment improved long-term stroke outcome.</p><p><strong>Conclusions: </strong>Our findings shed new light on microglia heterogeneity in stroke pathology and underscore the potential of targeting specific microglial populations for effective stroke therapies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"95"},"PeriodicalIF":10.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878640","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}

{"title":"Meta-analysis identifies common gut microbiota associated with multiple sclerosis.","authors":"Qingqi Lin, Yair Dorsett, Ali Mirza, Helen Tremlett, Laura Piccio, Erin E Longbrake, Siobhan Ni Choileain, David A Hafler, Laura M Cox, Howard L Weiner, Takashi Yamamura, Kun Chen, Yufeng Wu, Yanjiao Zhou","doi":"10.1186/s13073-024-01364-x","DOIUrl":"10.1186/s13073-024-01364-x","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies.</p><p><strong>Methods: </strong>To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also by combining all data together. The blocked Wilcoxon rank-sum test and linear mixed-effects regression were used to identify differences in microbial composition and diversity between MS and healthy controls. Network analysis was conducted to identify bacterial correlations. A leave-one-out sensitivity analysis was performed to ensure the robustness of the findings.</p><p><strong>Results: </strong>The microbiome community structure was significantly different between studies. Re-analysis of data from individual studies revealed a lower relative abundance of Prevotella in MS across studies, compared to controls. Meta-analysis found that although alpha and beta diversity did not differ between MS and controls, a higher abundance of Actinomyces and a lower abundance of Faecalibacterium were reproducibly associated with MS. Additionally, network analysis revealed that the recognized negative Bacteroides-Prevotella correlation in controls was disrupted in patients with MS.</p><p><strong>Conclusions: </strong>Our meta-analysis identified common gut microbiota associated with MS across geographically and technically diverse studies.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"94"},"PeriodicalIF":10.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859530","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}

{"title":"Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response.","authors":"Elizabeth Theusch, Flora Y Ting, Yuanyuan Qin, Kristen Stevens, Devesh Naidoo, Sarah M King, Neil V Yang, Joseph Orr, Brenda Y Han, Jason G Cyster, Yii-Der I Chen, Jerome I Rotter, Ronald M Krauss, Marisa W Medina","doi":"10.1186/s13073-024-01366-9","DOIUrl":"10.1186/s13073-024-01366-9","url":null,"abstract":"<p><strong>Background: </strong>Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.</p><p><strong>Methods: </strong>To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335).</p><p><strong>Results: </strong>The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335^R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43 ± 18% and -23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335^R1092W allele(s) exhibited a significantly blunted LDL statin response.</p><p><strong>Conclusions: </strong>Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"93"},"PeriodicalIF":10.4,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765873","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}

{"title":"Prostate cancers with distinct transcriptional programs in Black and White men.","authors":"Minhyung Kim, Patrick Tamukong, Gloria Cecilia Galvan, Qian Yang, Amanda De Hoedt, Michael R Freeman, Sungyong You, Stephen Freedland","doi":"10.1186/s13073-024-01361-0","DOIUrl":"10.1186/s13073-024-01361-0","url":null,"abstract":"<p><strong>Background: </strong>Black men are at a higher risk of prostate cancer (PC) diagnosis and present with more high-grade PC than White men in an equal access setting. This study aimed to identify differential transcriptional regulation between Black and White men with PC.</p><p><strong>Methods: </strong>We performed microarray of radical prostatectomy tissue blocks from 305 Black and 238 White men treated at the Durham Veterans Affairs Medical Center. Differential expression, gene set enrichment analysis, master regulator analysis, and network modeling were conducted to compare gene expression by race. Findings were validated using external datasets that are available in the Gene Expression Omnibus (GEO) database. The first was a multi-institutional cohort of 1152 prostate cancer patients (596 Black, 556 White) with microarray data (GEO ID: GSE169038). The second was an Emory cohort of 106 patients (22 Black, 48 White, 36 men of unknown race) with RNA-seq data (GEO ID: GSE54460). Additionally, we analyzed androgen receptor (AR) chromatin binding profiles using paired AR ChIP-Seq datasets from Black and White men (GEO IDs: GSE18440 and GSE18441).</p><p><strong>Results: </strong>We identified 871 differentially expressed genes between Black and White men. White men had higher activity of MYC-related pathways, while Black men showed increased activity of inflammation, steroid hormone responses, and cancer progression-related pathways. We further identified the top 10 transcription factors (TFs) in Black patients, which formed a transcriptional regulatory network centered on the AR. The activities of this network and the pathways were significantly different in Black vs. White men across multiple cohorts and PC molecular subtypes.</p><p><strong>Conclusions: </strong>These findings suggest PC in Black and White men have distinct tumor transcriptional profiles. Furthermore, a highly interactive TF network centered on AR drives differential gene expression in Black men. Additional study is needed to understand the degree to which these differences in transcriptional regulatory elements contribute to PC health disparities.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"92"},"PeriodicalIF":10.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751457","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}

{"title":"PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression.","authors":"Yi Fei Lee, Cheryl Zi Jin Phua, Ju Yuan, Bin Zhang, May Yin Lee, Srinivasaraghavan Kannan, Yui Hei Jasper Chiu, Casslynn Wei Qian Koh, Choon Kong Yap, Edwin Kok Hao Lim, Jianbin Chen, Yuhua Lim, Jane Jia Hui Lee, Anders Jacobsen Skanderup, Zhenxun Wang, Weiwei Zhai, Nguan Soon Tan, Chandra S Verma, Yvonne Tay, Daniel Shao Weng Tan, Wai Leong Tam","doi":"10.1186/s13073-024-01328-1","DOIUrl":"10.1186/s13073-024-01328-1","url":null,"abstract":"<p><strong>Background: </strong>The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4.</p><p><strong>Methods: </strong>In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations.</p><p><strong>Results: </strong>PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss.</p><p><strong>Conclusions: </strong>PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"91"},"PeriodicalIF":10.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733942","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}

{"title":"Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy.","authors":"Sandra Brosda, Lauren G Aoude, Vanessa F Bonazzi, Kalpana Patel, James M Lonie, Clemence J Belle, Felicity Newell, Lambros T Koufariotis, Venkateswar Addala, Marjan M Naeini, John V Pearson, Lutz Krause, Nicola Waddell, Andrew P Barbour","doi":"10.1186/s13073-024-01362-z","DOIUrl":"10.1186/s13073-024-01362-z","url":null,"abstract":"<p><strong>Background: </strong>Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance.</p><p><strong>Methods: </strong>Whole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define 'shared' (between both samples) and 'private' (present in one sample) mutations.</p><p><strong>Results: </strong>Mutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones.</p><p><strong>Conclusions: </strong>This study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"90"},"PeriodicalIF":10.4,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633074","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}

{"title":"SARS-CoV-2 population dynamics in immunocompetent individuals in a closed transmission chain shows genomic diversity over the course of infection.","authors":"Hannah Goldswain, Rebekah Penrice-Randal, I'ah Donovan-Banfield, Craig W Duffy, Xiaofeng Dong, Nadine Randle, Yan Ryan, Aleksandra M Rzeszutek, Jack Pilgrim, Emma Keyser, Simon A Weller, Emma J Hutley, Catherine Hartley, Tessa Prince, Alistair C Darby, Niall Aye Maung, Henry Nwume, Julian A Hiscox, Stevan R Emmett","doi":"10.1186/s13073-024-01360-1","DOIUrl":"10.1186/s13073-024-01360-1","url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2 remains rapidly evolving, and many biologically important genomic substitutions/indels have characterised novel SARS-CoV-2 lineages, which have emerged during successive global waves of the pandemic. Worldwide genomic sequencing has been able to monitor these waves, track transmission clusters, and examine viral evolution in real time to help inform healthcare policy. One school of thought is that an apparent greater than average divergence in an emerging lineage from contemporary variants may require persistent infection, for example in an immunocompromised host. Due to the nature of the COVID-19 pandemic and sampling, there were few studies that examined the evolutionary trajectory of SARS-CoV-2 in healthy individuals.</p><p><strong>Methods: </strong>We investigated viral evolutionary trends and participant symptomatology within a cluster of 16 SARS-CoV-2 infected, immunocompetent individuals with no co-morbidities in a closed transmission chain. Longitudinal nasopharyngeal swab sampling allowed characterisation of SARS-CoV-2 intra-host variation over time at both the dominant and minor genomic variant levels through Nimagen-Illumina sequencing.</p><p><strong>Results: </strong>A change in viral lineage assignment was observed in individual infections; however, there was only one indel and no evidence of recombination over the period of an acute infection. Minor and dominant genomic modifications varied between participants, with some minor genomic modifications increasing in abundance to become the dominant viral sequence during infection.</p><p><strong>Conclusions: </strong>Data from this cohort of SARS-CoV-2-infected participants demonstrated that long-term persistent infection in an immunocompromised host was not necessarily a prerequisite for generating a greater than average frequency of amino acid substitutions. Amino acid substitutions at both the dominant and minor genomic sequence level were observed in immunocompetent individuals during infection showing that viral lineage changes can occur generating viral diversity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"89"},"PeriodicalIF":10.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626497","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}