Genome Medicine最新文献

{"title":"Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach","authors":"Carolina Jaramillo Oquendo, Htoo A. Wai, Wil I. Rich, David J. Bunyan, N. Simon Thomas, David Hunt, Jenny Lord, Andrew G. L. Douglas, Diana Baralle","doi":"10.1186/s13073-024-01381-w","DOIUrl":"https://doi.org/10.1186/s13073-024-01381-w","url":null,"abstract":"RNA sequencing (RNA-seq) is increasingly being used as a complementary tool to DNA sequencing in diagnostics where DNA analysis has been uninformative. RNA-seq enables the identification of aberrant splicing and aberrant gene expression, improving the interpretation of variants of unknown significance (VUSs), and provides the opportunity to scan the transcriptome for aberrant splicing and expression in relevant genes that may be the cause of a patient’s phenotype. This work aims to investigate the feasibility of generating new diagnostic candidates in patients without a previously reported VUS using an RNA-seq-centric approach. We systematically assessed the transcriptomic profiles of 86 patients with suspected Mendelian disorders, 38 of whom had no candidate sequence variant, using RNA from blood samples. Each VUS was visually inspected to search for splicing abnormalities. Once aberrant splicing was identified in cases with VUS, multiple open-source alternative splicing tools were used to investigate if they would identify what was observed in IGV. Expression outliers were detected using OUTRIDER. Diagnoses in cases without a VUS were explored using two separate strategies. RNA-seq allowed us to assess 71% of VUSs, detecting aberrant splicing in 14/48 patients with a VUS. We identified four new diagnoses by detecting novel aberrant splicing events in patients with no candidate sequence variants from prior DNA testing (n = 32) or where the candidate VUS did not affect splicing (n = 23). An additional diagnosis was made through the detection of skewed X-inactivation. This work demonstrates the utility of an RNA-centric approach in identifying novel diagnoses in patients without candidate VUSs. It underscores the utility of blood-based RNA analysis in improving diagnostic yields and highlights optimal approaches for such analyses.\u0000","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"5 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222582","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":"Long-term persistence of diverse clones shapes the transmission landscape of invasive Listeria monocytogenes.","authors":"Odion O Ikhimiukor, Lisa Mingle, Samantha E Wirth, Damaris V Mendez-Vallellanes, Hannah Hoyt, Kimberlee A Musser, William J Wolfgang, Cheryl P Andam","doi":"10.1186/s13073-024-01379-4","DOIUrl":"10.1186/s13073-024-01379-4","url":null,"abstract":"<p><strong>Background: </strong>The foodborne bacterium Listeria monocytogenes (Lm) causes a range of diseases, from mild gastroenteritis to invasive infections that have high fatality rate in vulnerable individuals. Understanding the population genomic structure of invasive Lm is critical to informing public health interventions and infection control policies that will be most effective especially in local and regional communities.</p><p><strong>Methods: </strong>We sequenced the whole draft genomes of 936 Lm isolates from human clinical samples obtained in a two-decade active surveillance program across 58 counties in New York State, USA. Samples came mostly from blood and cerebrospinal fluid. We characterized the phylogenetic relationships, population structure, antimicrobial resistance genes, virulence genes, and mobile genetic elements.</p><p><strong>Results: </strong>The population is genetically heterogenous, consisting of lineages I-IV, 89 clonal complexes, 200 sequence types, and six known serogroups. In addition to intrinsic antimicrobial resistance genes (fosX, lin, norB, and sul), other resistance genes tetM, tetS, ermG, msrD, and mefA were sparsely distributed in the population. Within each lineage, we identified clusters of isolates with ≤ 20 single nucleotide polymorphisms in the core genome alignment. These clusters may represent isolates that share a most recent common ancestor, e.g., they are derived from the same contamination source or demonstrate evidence of transmission or outbreak. We identified 38 epidemiologically linked clusters of isolates, confirming eight previously reported disease outbreaks and the discovery of cryptic outbreaks and undetected chains of transmission, even in the rarely reported Lm lineage III (ST3171). The presence of animal-associated lineages III and IV may suggest a possible spillover of animal-restricted strains to humans. Many transmissible clones persisted over several years and traversed distant sites across the state.</p><p><strong>Conclusions: </strong>Our findings revealed the bacterial determinants of invasive listeriosis, driven mainly by the diversity of locally circulating lineages, intrinsic and mobile antimicrobial resistance and virulence genes, and persistence across geographical and temporal scales. Our findings will inform public health efforts to reduce the burden of invasive listeriosis, including the design of food safety measures, source traceback, and outbreak detection.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"109"},"PeriodicalIF":10.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132529","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":"Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors.","authors":"Yingjie Zhu, Xin Pei, Ardijana Novaj, Jeremy Setton, Daniel Bronder, Fatemeh Derakhshan, Pier Selenica, Niamh McDermott, Mehmet Orman, Sarina Plum, Shyamal Subramanyan, Sara H Braverman, Biko McMillan, Sonali Sinha, Jennifer Ma, Andrea Gazzo, Atif Khan, Samuel Bakhoum, Simon N Powell, Jorge S Reis-Filho, Nadeem Riaz","doi":"10.1186/s13073-024-01371-y","DOIUrl":"10.1186/s13073-024-01371-y","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear.</p><p><strong>Methods: </strong>We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher's exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations.</p><p><strong>Results: </strong>We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation.</p><p><strong>Conclusions: </strong>This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"108"},"PeriodicalIF":10.4,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092722","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":"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":"16 1","pages":"104"},"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":"16 1","pages":"107"},"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":"16 1","pages":"106"},"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":"16 1","pages":"105"},"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":"16 1","pages":"102"},"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":"16 1","pages":"103"},"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":"16 1","pages":"101"},"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}