[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-346140-105":59,"doc-detail-346140-en":129},{"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":122,"head_meta":124,"extra_data":126,"updated_unix":128},105,"en","integrating-germline-and-tumor-sequencing-to-improve-hereditary-cancer-diagnosis-and-care","Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care","","Integrating germline and tumor sequencing advances the identification and management of hereditary cancers driven by inherited pathogenic variants. The review explains how tumor features such as microsatellite instability, tumor mutational burden, and mutational signatures signal DNA repair or replication fidelity defects. It outlines how tumor profiling supports germline variant interpretation, detects somatic mosaicism, distinguishes hereditary from sporadic disease, and informs precision therapies including PARP inhibitors, immune checkpoint inhibitors, and targeted treatments for actionable oncogenic alterations.",{"@graph":69,"@context":121},[70,84,104],{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/integrating-germline-and-tumor-sequencing-to-improve-hereditary-cancer-diagnosis-and-care/346140/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/integrating-germline-and-tumor-sequencing-to-improve-hereditary-cancer-diagnosis-and-care/346140.png","ImageObject",300,407,{"name":92,"@type":93},"Valentina","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-22",true,{"@type":101,"interactionType":102,"userInteractionCount":14},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"Why is integrating germline and tumor sequencing important in hereditary cancer?","Question",{"text":111,"@type":112},"It improves diagnosis by combining inherited variant assessment with tumor molecular evidence that can indicate the underlying germline defect.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"Which tumor molecular features help identify hereditary tumors?",{"text":116,"@type":112},"Microsatellite instability, tumor mutational burden, and mutational signatures can reflect specific DNA repair or replication fidelity deficiencies.",{"name":118,"@type":109,"acceptedAnswer":119},"How can tumor sequencing guide treatment decisions?",{"text":120,"@type":112},"Tumor profiling reveals actionable targets and informs therapeutic strategies, including PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for mismatch repair or polymerase proofreading–deficient cancers.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},346140,1790095003,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},13056703020460,"https://ap-avatar.wpscdn.com/avatar/be000253dac470eee5d?_k=1778207105932848923","[www.nature.com/ejhg](www.nature.com/ejhg)  \nREVIEW ARTICLE OPEN   \nIntegrating germline and tumor sequencing to improve hereditary cancer diagnosis and care  \nRicharda M. de Voer 1,2,3,6 ✉ and Laura Valle 3,4,5,6 ✉  \n© The Author(s) 2026  \n|  |  |  |\n| --- | --- | --- |\n|  | A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occasionally oncogenes. In most hereditary cancer syndromes, Knudson’s two-hit hypothesis applies, where a second somatic event inactivates the remaining allele of a tumor suppressor or DNA repair gene, leading to tumorigenesis. Advancements in genome-wide sequencing have significantly enhanced our understanding of the mutational processes involved in hereditary cancers. In particular, the assessment of microsatellite instability (MSI), tumor mutational burden (TMB), and mutational signatures has emerged as a powerful tool for the identification of hereditary tumors. Tumors with high or ultra-high TMB often reflect underlying DNA repair deficiencies, while specific mutational signatures can pinpoint the defective pathway. These tumor mutational features are especially informative in syndromes involving mismatch repair (MMR), homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and polymerase proofreading. Moreover, tumor sequencing aids in the interpretation of germline variants, identifies somatic mosaicism, and helps differentiate hereditary from sporadic cancers. Additionally, tumor molecular features associated with DNA repair deficiencies offer insights into personalized therapies, such as the use of PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for MMRand polymerase proofreading-deficient cancers. Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer. |  |  |\n|  | European Journal of Human Genetics (2026) 34:1199–1209; [https://doi.org/10.1038/s41431-026-02046-5](https://doi.org/10.1038/s41431-026-02046-5) |  |\n|  |  |  |\n\nINTRODUCTION  \nHereditary cancer syndromes account for a substantial subset of malignancies and are caused by germline pathogenic variants in genes that regulate cell proliferation, genomic stability, and DNA repair. Identifying individuals with an inherited cancer predisposition is critical, as it informs cancer risk assessment, surveillance strategies, treatment selection, and cascade testing of at-risk relatives. Traditionally, the diagnosis of hereditary cancer has relied primarily on germline genetic testing guided by personal and family history, tumor histopathology, and, for selected tumor types, limited molecular assays [1] .  \nAdvances in next-generation sequencing have fundamentally transformed this landscape by enabling tumor genomic profiling alongside germline analysis [2] . Tumors arising in the context of inherited cancer predisposition often harbor characteristic molecular features, such as somatic second-hit events or distinct mutational patterns associated with defects in DNA repair or replication fidelity pathways [3] . These tumor-derived features can provide important evidence for the presence of an underlying germline pathogenic variant, support variant interpretation, reveal somatic mosaicism, and help distinguish hereditary cancers from sporadic or non-genetic disease processes. Moreover, tumor  \nmolecular profiles increasingly inform therapeutic decision-making, particularly with the advent of targeted therapies and immunotherapy [4] .  \nIn thi","cbCaionbcmdwLmmP","https://ap.wps.com/l/cbCaionbcmdwLmmP","pdf",2100739,11,"English","# Introduction\n# Key players in hereditary cancer: tumor suppressor genes, DNA repair genes and oncogenes\n## Tumor suppressor genes","[{\"question\":\"Why is integrating germline and tumor sequencing important in hereditary cancer?\",\"answer\":\"It improves diagnosis by combining inherited variant assessment with tumor molecular evidence that can indicate the underlying germline defect.\"},{\"question\":\"Which tumor molecular features help identify hereditary tumors?\",\"answer\":\"Microsatellite instability, tumor mutational burden, and mutational signatures can reflect specific DNA repair or replication fidelity deficiencies.\"},{\"question\":\"How can tumor sequencing guide treatment decisions?\",\"answer\":\"Tumor profiling reveals actionable targets and informs therapeutic strategies, including PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for mismatch repair or polymerase proofreading–deficient cancers.\"}]","Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care | PDF",1790060202,28]