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Two large population-based adult cohorts were analyzed using case-control comparisons between PALB2 P/LP variant carriers and non-carriers. Logistic regression estimated odds ratios for cancer outcomes and Cox models assessed all-cause mortality, with penetrance derived by Kaplan–Meier methods. Carriers showed significantly increased odds of multiple cancer types and higher hazard of cancer and all-cause mortality; family history further elevated risk.",{"@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/genomic-ascertainment-of-palb2-related-cancer-predisposition/348982/",{"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/genomic-ascertainment-of-palb2-related-cancer-predisposition/348982.png","ImageObject",300,407,{"name":92,"@type":93},"Aria Callaghan","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-26","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the primary objective of the study on PALB2?","Question",{"text":112,"@type":113},"To quantify cancer incidence, mortality risk, and age-specific penetrance associated with heterozygous pathogenic or likely pathogenic PALB2 variants identified through genomic ascertainment, and to assess modification by family history.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were study participants and PALB2 variants identified?",{"text":117,"@type":113},"The study used case-control analyses in two population-based cohorts (UK Biobank and Geisinger MyCode). Individuals with heterozygous PALB2 P/LP variants were identified via exome sequencing and compared with non-carriers.",{"name":119,"@type":110,"acceptedAnswer":120},"What were the main findings for cancer risk and mortality?",{"text":121,"@type":113},"Across both cohorts, PALB2 heterozygotes had higher odds of any cancer and specific cancers including breast and pancreatic cancer, along with higher age-specific hazard of cancer and increased all-cause mortality. Family history further increased risk, and age-specific penetrance estimates were lower than familial ascertainment reports.","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},348982,1790151385,{"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":81,"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":145},962084926284,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","medRxiv preprint doi: [https://doi.org/10.64898/2026.04.03.26349984](https://doi.org/10.64898/2026.04.03.26349984); this version posted April 4, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \nGenomic ascertainment of PALB2-related cancer predisposition  \nPALB2-related cancer predisposition  \nDouglas R. Stewart 1, Jung Kim1, Jeremy S. Haley2, Jiang Li2, Michael R. Sargen 1, Hyokyoung Hong3, Marc Tischkowitz4, Lisa J. McReynolds 1, David J. Carey2  \n1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA; 2Department of Genomic Health, Geisinger, Danville, PA, USA; 3Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA; 4Department of Genomic Medicine, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK  \nCorrespondence to: Douglas R. Stewart, MD  \nAddress: 9609 Medical Center Drive Rm 6E450, Rockville, MD, 20850  \nTel: 240-276-7238; Fax: 240-276-7836.  \nEmail: [drstewart@mail.nih.gov](drstewart@mail.nih.gov)  \nAcknowledgments: This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Bethesda, MD and utilized the computational resources of the NIH High-Performance Computing Biowulf cluster. This research has been conducted using the UK Biobank Resources under application 54389. MT was supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312)  \n1  \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.  \nmedRxiv preprint doi: [https://doi.org/10.64898/2026.04.03.26349984](https://doi.org/10.64898/2026.04.03.26349984); this version posted April 4, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \nKey objective  \nTo quantify cancer incidence, mortality risk, and age-specific penetrance associated with heterozygous pathogenic or likely pathogenic PALB2 variants identified through genomic ascertainment, and to assess modification of these risks by family history of cancer.  \nKnowledge generated  \nAcross two large population-based cohorts, PALB2-heterozygotes had significantly increased odds of any cancer, breast cancer, and pancreatic cancer, and higher age-specific hazard of cancer and higher all-cause mortality compared with non-carriers. Family history further elevated cancer risk. Age-specific penetrance estimates were lower than those reported from familial ascertainment.  \nmedRxiv preprint doi: [https://doi.org/10.64898/2026.04.03.26349984](https://doi.org/10.64898/2026.04.03.26349984); this version posted April 4, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \nAbstract  \nPURPOSE  \nTo evaluate cancer risk, age-specific penetrance, and mortality associated with heterozygous pathogenic or likely pathogenic (P/LP) germline PALB2 variants identified through genomic ascertainment and to assess modification by family history of cancer.  \nPATIENTS AND METHODS  \nWe conducted a case-control study in two large population-based adult cohorts: the","cbCaivCUM5ys7HY4","https://ap.wps.com/l/cbCaivCUM5ys7HY4","pdf",2211701,31,"English","# Key objective\n# Knowledge generated\n# Abstract\n## Purpose\n## Patients and methods\n## Results\n## Conclusion","[{\"question\":\"What is the primary objective of the study on PALB2?\",\"answer\":\"To quantify cancer incidence, mortality risk, and age-specific penetrance associated with heterozygous pathogenic or likely pathogenic PALB2 variants identified through genomic ascertainment, and to assess modification by family history.\"},{\"question\":\"How were study participants and PALB2 variants identified?\",\"answer\":\"The study used case-control analyses in two population-based cohorts (UK Biobank and Geisinger MyCode). Individuals with heterozygous PALB2 P/LP variants were identified via exome sequencing and compared with non-carriers.\"},{\"question\":\"What were the main findings for cancer risk and mortality?\",\"answer\":\"Across both cohorts, PALB2 heterozygotes had higher odds of any cancer and specific cancers including breast and pancreatic cancer, along with higher age-specific hazard of cancer and increased all-cause mortality. Family history further increased risk, and age-specific penetrance estimates were lower than familial ascertainment reports.\"}]","Genomic ascertainment of PALB2-related cancer predisposition | PDF",1790081010,78]