Genome Medicine最新文献

{"title":"Genome Tunisia Project: paving the way for precision medicine in North Africa.","authors":"Yosr Hamdi, Mediha Trabelsi, Kais Ghedira, Maroua Boujemaa, Ikhlas Ben Ayed, Cherine Charfeddine, Amal Souissi, Imen Rejeb, Wafa Kammoun Rebai, Chaima Hkimi, Fadoua Neifar, Nouha Jandoubi, Rahma Mkaouar, Melek Chaouch, Ayda Bennour, Selim Kamoun, Hend Chaker Masmoudi, Nabil Abid, Maha Mezghani Khemakhem, Saber Masmoudi, Ali Saad, Lamia BenJemaa, Alia BenKahla, Samir Boubaker, Ridha Mrad, Hassen Kamoun, Sonia Abdelhak, Moez Gribaa, Neila Belguith, Najla Kharrat, Dorra Hmida, Ahmed Rebai","doi":"10.1186/s13073-024-01365-w","DOIUrl":"10.1186/s13073-024-01365-w","url":null,"abstract":"<p><strong>Background: </strong>Key discoveries and innovations in the field of human genetics have led to the foundation of molecular and personalized medicine. Here, we present the Genome Tunisia Project, a two-phased initiative (2022-2035) which aims to deliver the reference sequence of the Tunisian Genome and to support the implementation of personalized medicine in Tunisia, a North African country that represents a central hub of population admixture and human migration between African, European, and Asian populations. The main goal of this initiative is to develop a healthcare system capable of incorporating omics data for use in routine medical practice, enabling medical doctors to better prevent, diagnose, and treat patients.</p><p><strong>Methods: </strong>A multidisciplinary partnership involving Tunisian experts from different institutions has come to discern all requirements that would be of high priority to fulfill the project's goals. One of the most urgent priorities is to determine the reference sequence of the Tunisian Genome. In addition, extensive situation analysis and revision of the education programs, community awareness, appropriate infrastructure including sequencing platforms and biobanking, as well as ethical and regulatory frameworks, have been undertaken towards building sufficient capacity to integrate personalized medicine into the Tunisian healthcare system.</p><p><strong>Results: </strong>In the framework of this project, an ecosystem with all engaged stakeholders has been implemented including healthcare providers, clinicians, researchers, pharmacists, bioinformaticians, industry, policymakers, and advocacy groups. This initiative will also help to reinforce research and innovation capacities in the field of genomics and to strengthen discoverability in the health sector.</p><p><strong>Conclusions: </strong>Genome Tunisia is the first initiative in North Africa that seeks to demonstrate the major impact that can be achieved by Human Genome Projects in low- and middle-income countries to strengthen research and to improve disease management and treatment outcomes, thereby reducing the social and economic burden on healthcare systems. Sharing this experience within the African scientific community is a chance to turn a major challenge into an opportunity for dissemination and outreach. Additional efforts are now being made to advance personalized medicine in patient care by educating consumers and providers, accelerating research and innovation, and supporting necessary changes in policy and regulation.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072574","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":"The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models.","authors":"Andrea Herencia-Ropero, Alba Llop-Guevara, Anna D Staniszewska, Joanna Domènech-Vivó, Eduardo García-Galea, Alejandro Moles-Fernández, Flaminia Pedretti, Heura Domènech, Olga Rodríguez, Marta Guzmán, Enrique J Arenas, Helena Verdaguer, Fernando J Calero-Nieto, Sara Talbot, Luis Tobalina, Elisabetta Leo, Alan Lau, Paolo Nuciforo, Rodrigo Dienstmann, Teresa Macarulla, Joaquín Arribas, Orland Díez, Sara Gutiérrez-Enríquez, Josep V Forment, Mark J O'Connor, Mark Albertella, Judith Balmaña, Violeta Serra","doi":"10.1186/s13073-024-01370-z","DOIUrl":"10.1186/s13073-024-01370-z","url":null,"abstract":"<p><strong>Background: </strong>Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance.</p><p><strong>Methods: </strong>Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi.</p><p><strong>Results: </strong>AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively.</p><p><strong>Conclusions: </strong>Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072553","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":"Ancestry-aligned polygenic scores combined with conventional risk factors improve prediction of cardiometabolic outcomes in African populations.","authors":"Michelle Kamp, Oliver Pain, Cathryn M Lewis, Michèle Ramsay","doi":"10.1186/s13073-024-01377-6","DOIUrl":"10.1186/s13073-024-01377-6","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cardiovascular diseases (CVD) are a major health concern in Africa. Improved identification and treatment of high-risk individuals can reduce adverse health outcomes. Current CVD risk calculators are largely unvalidated in African populations and overlook genetic factors. Polygenic scores (PGS) can enhance risk prediction by measuring genetic susceptibility to CVD, but their effectiveness in genetically diverse populations is limited by a European-ancestry bias. To address this, we developed models integrating genetic data and conventional risk factors to assess the risk of developing cardiometabolic outcomes in African populations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We used summary statistics from a genome-wide association meta-analysis (n = 14,126) in African populations to derive novel genome-wide PGS for 14 cardiometabolic traits in an independent African target sample (Africa Wits-INDEPTH Partnership for Genomic Research (AWI-Gen), n = 10,603). Regression analyses assessed relationships between each PGS and corresponding cardiometabolic trait, and seven CVD outcomes (CVD, heart attack, stroke, diabetes mellitus, dyslipidaemia, hypertension, and obesity). The predictive utility of the genetic data was evaluated using elastic net models containing multiple PGS (MultiPGS) and reference-projected principal components of ancestry (PPCs). An integrated risk prediction model incorporating genetic and conventional risk factors was developed. Nested cross-validation was used when deriving elastic net models to enhance generalisability.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our African-specific PGS displayed significant but variable within- and cross- trait prediction (max.R&lt;sup&gt;2&lt;/sup&gt; = 6.8%, p = 1.86 × 10&lt;sup&gt;-173&lt;/sup&gt;). Significantly associated PGS with dyslipidaemia included the PGS for total cholesterol (logOR = 0.210, SE = 0.022, p = 2.18 × 10&lt;sup&gt;-21&lt;/sup&gt;) and low-density lipoprotein (logOR =  - 0.141, SE = 0.022, p = 1.30 × 10&lt;sup&gt;-20&lt;/sup&gt;); with hypertension, the systolic blood pressure PGS (logOR = 0.150, SE = 0.045, p = 8.34 × 10&lt;sup&gt;-4&lt;/sup&gt;); and multiple PGS associated with obesity: body mass index (max. logOR = 0.131, SE = 0.031, p = 2.22 × 10&lt;sup&gt;-5&lt;/sup&gt;), hip circumference (logOR = 0.122, SE = 0.029, p = 2.28 × 10&lt;sup&gt;-5&lt;/sup&gt;), waist circumference (logOR = 0.013, SE = 0.098, p = 8.13 × 10&lt;sup&gt;-4&lt;/sup&gt;) and weight (logOR = 0.103, SE = 0.029, p = 4.89 × 10&lt;sup&gt;-5&lt;/sup&gt;). Elastic net models incorporating MultiPGS and PPCs significantly improved prediction over MultiPGS alone. Models including genetic data and conventional risk factors were more predictive than conventional risk models alone (dyslipidaemia: R&lt;sup&gt;2&lt;/sup&gt; increase = 2.6%, p = 4.45 × 10&lt;sup&gt;-12&lt;/sup&gt;; hypertension: R&lt;sup&gt;2&lt;/sup&gt; increase = 2.6%, p = 2.37 × 10&lt;sup&gt;-13&lt;/sup&gt;; obesity: R&lt;sup&gt;2&lt;/sup&gt; increase = 5.5%, 1.33 × 10&lt;sup&gt;-34&lt;/sup&gt;).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;In African populations, CVD and associated cardiometabolic trait predict","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072573","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":"Gut microbiome structure and function in asymptomatic diverticulosis.","authors":"Xinwei Hua, Jessica McGoldrick, Nour Nakrour, Kyle Staller, Daniel Chulyong Chung, Ramnik Joseph Xavier, Hamed Khalili","doi":"10.1186/s13073-024-01374-9","DOIUrl":"10.1186/s13073-024-01374-9","url":null,"abstract":"<p><strong>Background: </strong>Colonic diverticulosis, the most common lesion found in routine colonoscopy, affects more than 50% of individuals aged ≥ 60 years. Emerging evidence suggest that dysbiosis of gut microbiota may play an important role in the pathophysiology of diverticular disease. However, specific changes in microbial species and metabolic functions in asymptomatic diverticulosis remain unknown.</p><p><strong>Methods: </strong>In a cohort of US adults undergoing screening colonoscopy, we analyzed the gut microbiota using shotgun metagenomic sequencing. Demographic factors, lifestyle, and medication use were assessed using a baseline questionnaire administered prior to colonoscopy. Taxonomic structures and metabolic pathway abundances were determined using MetaPhlAn3 and HUMAnN3. We used multivariate association with linear models to identify microbial species and metabolic pathways that were significantly different between asymptomatic diverticulosis and controls, while adjusting for confounders selected a priori including age at colonoscopy, sex, body mass index (BMI), and dietary pattern.</p><p><strong>Results: </strong>Among 684 individuals undergoing a screening colonoscopy, 284 (42%) had diverticulosis. Gut microbiome composition explained 1.9% variation in the disease status of asymptomatic diverticulosis. We observed no significant differences in the overall diversity of gut microbiome between asymptomatic diverticulosis and controls. However, microbial species Bifidobacterium pseudocatenulatum and Prevotella copri were significantly enriched in controls (q value = 0.19 and 0.14, respectively), whereas Roseburia intestinalis, Dorea sp. CAG:317, and Clostridium sp. CAG: 299 were more abundant in those with diverticulosis (q values = 0.17, 0.24, and 0.10, respectively). We observed that the relationship between BMI and diverticulosis appeared to be limited to carriers of Bifidobacterium pseudocatenulatum and Roseburia intestinalis (P_interaction = 0.09).</p><p><strong>Conclusions: </strong>Our study provides the first large-scale evidence supporting taxonomic and functional shifts of the gut microbiome in individuals with asymptomatic diverticulosis. The suggestive interaction between gut microbiota and BMI on prevalent diverticulosis deserves future investigations.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046585","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":"Identification of tumor rejection antigens and the immunologic landscape of medulloblastoma.","authors":"Changlin Yang, Vrunda Trivedi, Kyle Dyson, Tongjun Gu, Kate M Candelario, Oleg Yegorov, Duane A Mitchell","doi":"10.1186/s13073-024-01363-y","DOIUrl":"10.1186/s13073-024-01363-y","url":null,"abstract":"<p><strong>Background: </strong>The current standard of care treatments for medulloblastoma are insufficient as these do not take tumor heterogeneity into account. Newer, safer, patient-specific treatment approaches are required to treat high-risk medulloblastoma patients who are not cured by the standard therapies. Immunotherapy is a promising treatment modality that could be key to improving survival and avoiding morbidity. For an effective immune response, appropriate tumor antigens must be targeted. While medulloblastoma patients with subgroup-specific genetic substitutions have been previously reported, the immunogenicity of these genetic alterations remains unknown. The aim of this study is to identify potential tumor rejection antigens for the development of antigen-directed cellular therapies for medulloblastoma.</p><p><strong>Methods: </strong>We developed a cancer immunogenomics pipeline and performed a comprehensive analysis of medulloblastoma subgroup-specific transcription profiles (n = 170, 18 WNT, 46 SHH, 41 Group 3, and 65 Group 4 patient tumors) available through International Cancer Genome Consortium (ICGC) and European Genome-Phenome Archive (EGA). We performed in silico antigen prediction across a broad array of antigen classes including neoantigens, tumor-associated antigens (TAAs), and fusion proteins. Furthermore, we evaluated the antigen processing and presentation pathway in tumor cells and the immune infiltrating cell landscape using the latest computational deconvolution methods.</p><p><strong>Results: </strong>Medulloblastoma patients were found to express multiple private and shared immunogenic antigens. The proportion of predicted TAAs was higher than neoantigens and gene fusions for all molecular subgroups, except for sonic hedgehog (SHH), which had a higher neoantigen burden. Importantly, cancer-testis antigens, as well as previously unappreciated neurodevelopmental antigens, were found to be expressed by most patients across all medulloblastoma subgroups. Despite being immunologically cold, medulloblastoma subgroups were found to have distinct immune cell gene signatures.</p><p><strong>Conclusions: </strong>Using a custom antigen prediction pipeline, we identified potential tumor rejection antigens with important implications for the development of immunotherapy for medulloblastoma.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004062","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":"Evolutionary dependency of cancer mutations in gene pairs inferred by nonsynonymous-synonymous mutation ratios.","authors":"Dong-Jin Han, Sunmin Kim, Seo-Young Lee, Youngbeen Moon, Su Jung Kang, Jinseon Yoo, Hye Young Jeong, Hae Jin Cho, Jeong Yang Jeon, Byeong Chang Sim, Jaehoon Kim, Seungho Lee, Ruibin Xi, Tae-Min Kim","doi":"10.1186/s13073-024-01376-7","DOIUrl":"10.1186/s13073-024-01376-7","url":null,"abstract":"<p><strong>Background: </strong>Determining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other.</p><p><strong>Methods: </strong>We employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity.</p><p><strong>Results: </strong>We propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively.</p><p><strong>Conclusions: </strong>We propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004061","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":"Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.","authors":"Jonathan E Knikman, Qinglian Zhai, Carin A T C Lunenburg, Linda M Henricks, Stefan Böhringer, Maaike van der Lee, Femke M de Man, Steven M Offer, Shikshya Shrestha, Geert-Jan Creemers, Arnold Baars, Vincent O Dezentjé, Alexander L T Imholz, Frank J F Jeurissen, Johanna E A Portielje, Rob L H Jansen, Paul Hamberg, Helga J Droogendijk, Miriam Koopman, Peter Nieboer, Marlène H W van de Poel, Caroline M P W Mandigers, Ron H N van Schaik, Hans Gelderblom, Ron H J Mathijssen, Jan H M Schellens, Annemieke Cats, Henk-Jan Guchelaar, Jesse J Swen","doi":"10.1186/s13073-024-01354-z","DOIUrl":"10.1186/s13073-024-01354-z","url":null,"abstract":"<p><strong>Background: </strong>The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity.</p><p><strong>Methods: </strong>Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS.</p><p><strong>Results: </strong>Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 - 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41-11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10^-8), however, five variants were suggestive of association (P < 5 × 10^-6) with severe toxicity.</p><p><strong>Conclusions: </strong>Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987774","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":"Laterality, heterotaxy, and isolated congenital heart defects : The genetic basis of the segmental nature of the heart.","authors":"Carolina Putotto, Flaminia Pugnaloni, Marta Unolt, Giulio Calcagni, Paolo Versacci, Bruno Marino","doi":"10.1186/s13073-024-01375-8","DOIUrl":"10.1186/s13073-024-01375-8","url":null,"abstract":"<p><p>To date, the role of NODAL in normal and abnormal L-R asymmetry has been well established. In a recent paper, mutations of this gene have been reported in heterotaxy but also in transposition with D- or L-ventricular loop. The effects of NODAL and other laterality genes can be recognized separately in all three cardiac segments: for topology and septation of the atria, for ventricular looping, and for spiralization and alignment of the great arteries.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975500","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":"Association of genetic ancestry with molecular tumor profiles in colorectal cancer.","authors":"Brooke Rhead, David M Hein, Yannick Pouliot, Justin Guinney, Francisco M De La Vega, Nina N Sanford","doi":"10.1186/s13073-024-01373-w","DOIUrl":"10.1186/s13073-024-01373-w","url":null,"abstract":"<p><strong>Background: </strong>There are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.</p><p><strong>Methods: </strong>Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily late-stage CRC patients. Genetic ancestry proportions for five continental groups-Africa (AFR), American indigenous (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS)-were estimated using ancestry informative markers. To address data gaps, race and ethnicity categories were imputed, resulting in assignments for 952 Hispanic/Latino, 420 non-Hispanic (NH) Asian, 1061 NH Black, and 5763 NH White individuals. We assessed association of genetic ancestry proportions and imputed race and ethnicity categories with somatic mutations in relevant CRC genes and in 2608 expression profiles, as well as 1957 consensus molecular subtypes (CMS).</p><p><strong>Results: </strong>Increased AFR ancestry was associated with higher odds of somatic mutations in APC, KRAS, and PIK3CA and lower odds of BRAF mutations. Additionally, increased EAS ancestry was associated with lower odds of mutations in KRAS, EUR with higher odds in BRAF, and the Hispanic/Latino category with lower odds in BRAF. Greater AFR ancestry and the NH Black category were associated with higher rates of CMS3, while a higher proportion of Hispanic/Latino patients exhibited indeterminate CMS classifications.</p><p><strong>Conclusions: </strong>Molecular differences in CRC tumor mutation frequencies and gene expression that may underlie observed differences by race and ethnicity were identified. The association of AFR ancestry with increased KRAS mutations aligns with higher CMS3 subtype rates in NH Black patients. The increase of indeterminate CMS in Hispanic/Latino patients suggests that subtype classification methods could benefit from enhanced patient diversity.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":null,"pages":null},"PeriodicalIF":10.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11321170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141977642","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 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":null,"pages":null},"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}