[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-326724-105":59,"doc-detail-326724-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","clinical-application-of-tumour-in-normal-contamination-assessment-from-whole-genome-sequencing","Clinical application of tumour-in-normal contamination assessment from whole genome sequencing","","Clinical application of tumour-in-normal contamination assessment from whole genome sequencing focuses on how unexpected tumour-cell contamination in matched normal samples lowers variant-detection sensitivity and distorts downstream somatic analyses. Using whole-genome sequencing resources, the study develops a tool to quantify contamination and validates it computationally and with minimal residual disease testing. A systematic review of 771 patients shows contamination across cancer indications and DNA sources, highlights high prevalence in specific saliva and CD3+ T-cell contexts, and identifies hotspot mutations impacted by standard calling pipelines.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/clinical-application-of-tumour-in-normal-contamination-assessment-from-whole-genome-sequencing/326724/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/clinical-application-of-tumour-in-normal-contamination-assessment-from-whole-genome-sequencing/326724.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-10","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why does contamination in matched normal samples affect tumour-normal analyses?","Question",{"text":112,"@type":113},"Contamination introduces tumour-derived variants into the normal sample, causing standard pipelines to subtract genuine somatic mutations. This reduces sensitivity and increases false negatives.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What is the role of TIN contamination level in existing tumour-in-normal approaches?",{"text":117,"@type":113},"Prior methods require an estimate of the TIN contamination level and generally support only low contamination values. Only limited options exist for assessing contamination in matched pairs.",{"name":119,"@type":110,"acceptedAnswer":120},"How does this study validate and characterize contamination across cancers?",{"text":121,"@type":113},"It develops a computational tool using whole-genome data, validates it in silico and against minimal residual disease testing, and performs a systematic review of 771 patients to quantify contamination prevalence by cancer indications and DNA sources.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},326724,1790189323,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36,"preview_page_count":4},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","Article [https://doi.org/10.1038/s41467-023-44158-2](https://doi.org/10.1038/s41467-023-44158-2)  \nClinical application of tumour-in-normal contamination assessment from whole genome sequencing  \nReceived: 14 March 2022  \n\n| Accepted: 1 December 2023 |\n| --- |\n| |\n| Check for updates |\n\nJonathan Mitchell1,8, Salvatore Milite 2,3,8, Jack Bartram 4, Susan Walker1, Nadezda Volkova1, Olena Yavorska1, Magdalena Zarowiecki1, Jane Chalker5, Rebecca Thomas4, Luca Vago 6, Alona Sosinsky1,9  &  \nGiulio Caravagna 3,7,9   \nThe unexpected contamination of normal samples with tumour cells reduces variant detection sensitivity, compromising downstream analyses in canonical tumour-normal analyses. Leveraging whole-genome sequencing data available at Genomics England, we develop a tool for normal sample contamination assessment, which we validate in silico and against minimal residual disease testing. From a systematic review of 771 patients with haematological malignancies and sarcomas, we find contamination across a range of cancer clinical indications and DNA sources, with highest prevalence in saliva samples from acute myeloid leukaemia patients, and sorted CD3+ T-cells from myeloproliferative neoplasms. Further exploration reveals 108 hotspot mutations in genes associated with haematological cancers at risk of being subtracted by standard variant calling pipelines. Our work highlights the importance of contamination assessment for accurate somatic variants detection in research and clinical settings, especially with large-scale sequencing projects being utilised to deliver accurate data from which to make clinical decisions for patient care.  \nIn popular experimental designs for cancer bulk DNA sequencing—whole-exome sequencing (WES) or whole-genome sequencing (WGS)  \n—individual tumour samples are matched with a reference “normal”sample from the same patient, usually obtained from peripheral blood, saliva, or a skin biopsy1,2. Analysis is performed by first detecting variants with respect to the human reference genome in both normal and tumour samples, followed by subtraction of the patient-specific variants from the tumour to select variants that are private to the tumour sample3. However, this experimental design is only effective if the matched normal sample is free of contaminating tumour cells, an  \nassumption not often emphasised (Fig. 1a, b)4,5. When DNA derived from the normal sample is contaminated by tumour DNA, standard bioinformatics pipelines can mistakenly subtract genuine somatic mutations from the set of mutations identified in the tumour sample due to evidence for a mutation being present in the normal sample, resulting in a reduction in sensitivity for true somatic mutations (i.e. higher number of false negatives). Based on the clonal evolution model6, the probability of false negative increases with the fraction of cells harbouring the mutation (due to a higher likelihood that the variant will be present in the sequencing data for the normal sample),  \n1Genomics England, London, UK. 2Computational Biology Research Centre, Human Technopole, Milan, Italy. 3Cancer Data Science Laboratory, Department of Mathematics, Informatics and Geosciences, University of Trieste, Trieste, Italy. 4Department of Haematology, Great Ormond Street Hospital for Children, London, UK. 5Specialist Integrated Haematological Malignancy Diagnostic Service-Acquired Genomics, Great Ormond Street Hospital for Children, London, UK. 6Research Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS Hospital San Raffaele, Milan, Italy. 7Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK. 8These authors contributed equally: Jonathan Mitchell, Salvatore Milite. 9These authors jointly  \nsupervised this work: Alona Sosinsky, Giulio Caravagna. e-mail: [alona.sosinsky@genomicsengland.co.uk](alona.sosinsky@genomicsengland.co.uk); gcaravagna@units.it  \na  \nc  \nPipeline for matched tumour-normal  \nNormal   \nTumour   \nTINC-aware c","cbCaijRduwRhSNiX","https://ap.wps.com/l/cbCaijRduwRhSNiX","pdf",6296739,16,"English","# Overview\n## Matched tumour-normal design and contamination risk\n## Consequences for somatic variant detection\n## Limitations of existing tools\n## TINC method and validation","[{\"question\":\"Why does contamination in matched normal samples affect tumour-normal analyses?\",\"answer\":\"Contamination introduces tumour-derived variants into the normal sample, causing standard pipelines to subtract genuine somatic mutations. This reduces sensitivity and increases false negatives.\"},{\"question\":\"What is the role of TIN contamination level in existing tumour-in-normal approaches?\",\"answer\":\"Prior methods require an estimate of the TIN contamination level and generally support only low contamination values. Only limited options exist for assessing contamination in matched pairs.\"},{\"question\":\"How does this study validate and characterize contamination across cancers?\",\"answer\":\"It develops a computational tool using whole-genome data, validates it in silico and against minimal residual disease testing, and performs a systematic review of 771 patients to quantify contamination prevalence by cancer indications and DNA sources.\"}]","Clinical application of tumour-in-normal contamination assessment from whole genome sequencing | PDF",1789975197]