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The study identifies six fundamental types of polygenic illnesses, with five non-cancerous, and contrasts tumor and non-tumor genetic architectures. It distinguishes “Drivers” and “Passengers,” highlights missing alterations in tumors (“Goners”) as potential therapeutic targets, and argues that the largest count of entities likely resides in hyper-rare disorders (\u003C1/108). For non-tumor diseases, pathway-centered taxonomies may be preferable, while cancer nomenclature may require incorporating Drivers and relevant epigenetic changes.","Perspective  \nEstimating the Number of Polygenic Diseases Among Six Mutually Exclusive Entities of Non-Tumors and Cancer  \nC. I. Edvard Smith 1,2,3, *, Jan A. Burger 4 and Rula Zain 1,2,5  \nCitation: Smith, C.I.E.; Burger, J.A.; Zain, R. Estimating the Number of Polygenic Diseases Among Six Mutually Exclusive Entities of Non-Tumors and Cancer. Int. J. Mol. Sci. 2024, 25, 11968. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms252211968](10.3390/ijms252211968)  \nAcademic Editors: Shira Rockowitz and Piotr Sliz  \nReceived: 18 September 2024  \nRevised: 4 November 2024  \nAccepted: 5 November 2024  \nPublished: 7 November 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, Alfred Nobels Allé 8 Floor 8, SE-141 52 Huddinge, Sweden; [rula.zain@ki.se](rula.zain@ki.se)  \n2 Karolinska ATMP Center, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden  \n3 Department of Infectious Diseases, Karolinska University Hospital, SE-141 86 Huddinge, Sweden  \n4 Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [jaburger@mdanderson.org](jaburger@mdanderson.org)  \n5 Centre for Rare Diseases, Department of Clinical Genetics, Karolinska University Hospital, SE-171 76 Stockholm, Sweden  \n* Correspondence: [edvard.smith@ki.se](edvard.smith@ki.se)  \nAbstract: In the era of precision medicine with increasing amounts of sequenced cancer and noncancer genomes of different ancestries, we here enumerate the resulting polygenic disease entities. Based on the cell number status, we first identified six fundamental types of polygenic illnesses, five of which are non-cancerous. Like complex, non-tumor disorders, neoplasms normally carry alterations in multiple genes, including in ‘Drivers’ and ‘Passengers’. However, tumors also lack certain genetic alterations/epigenetic changes, recently named ‘Goners’, which are toxic for the neoplasm and potentially constitute therapeutic targets. Drivers are considered essential for malignant transformation, whereas environmental influences vary considerably among both types of polygenic diseases. For each form, hyper-rare disorders, defined as affecting \u003C1/108 individuals, likely represent the largest number of disease entities. Loss of redundant tumor-suppressor genes exemplifies such a profoundly rare mutational event. For non-tumor, polygenic diseases, pathway-centered taxonomies seem preferable. This classification is not readily feasible in cancer, but the inclusion of Drivers and possibly also of epigenetic changes to the existing nomenclature might serve as initial steps in this direction. Based on the detailed genetic alterations, the number of polygenic diseases is essentially countless, but different forms of nosologies may be used to restrict the number.  \nKeywords: autoimmunity; leukemia; GWAS; SNP; BTK; COVID-19  \n1. Introduction  \nComplex traits were first mathematically interpreted by Ronald Aylmer Fisher in a landmark paper in which the effects of dominance and assortative mating on correlation values were clarified [1], and during the same period, Theodor Heinrich Boveri used groundbreaking experimental approaches to search for the origin of tumors [2] . A hundred years later, next-generation sequencing has enabled a deeper understanding of complex traits from the constantly increasing number of genome-wide association studies (GWASs) . This has important implications for polygenic inheritance and risk calculations [3] . GWAS investigations have not only increased the number of recognized polymorphisms in noncancerous disease but have al","cbCaioKnLkiGfUFZ","https://ap.wps.com/l/cbCaioKnLkiGfUFZ","pdf",1219931,23,"English","en",105,"# Abstract\n# Introduction\n## Background on complex traits and GWAS","[{\"question\":\"What is the main objective of estimating polygenic disease entities in this work?\",\"answer\":\"To enumerate the polygenic disease entities that arise from increasingly available sequenced cancer and noncancer genomes across different ancestries, and to clarify how these entities should be defined.\"},{\"question\":\"How many fundamental types of polygenic illnesses are proposed, and how many are non-cancerous?\",\"answer\":\"Six fundamental types are identified, and five of them are non-cancerous.\"},{\"question\":\"Why does the authors’ framework emphasize hyper-rare disorders?\",\"answer\":\"Hyper-rare disorders, defined as affecting fewer than 1/108 individuals, likely represent the largest number of disease entities, even though they involve very few affected individuals.\"}]","Estimating the Number of Polygenic Diseases Among Six Mutually Exclusive Entities of Non-Tumors and Cancer - Perspective | PDF",1789984331,58,{"code":4,"msg":82,"data":83},"ok",{"site_id":75,"language":74,"slug":84,"title":65,"keywords":85,"description":66,"schema_data":86,"social_meta":140,"head_meta":142,"extra_data":144,"updated_unix":145},"estimating-the-number-of-polygenic-diseases-among-six-mutually-exclusive-entities-of-non-tumors-and-cancer-perspective","",{"@graph":87,"@context":139},[88,102,122],{"@type":89,"itemListElement":90},"BreadcrumbList",[91,95,97,100],{"item":92,"name":93,"@type":94,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":96,"name":9,"@type":94,"position":14},"https://docshare.wps.com/document/",{"item":98,"name":40,"@type":94,"position":99},"https://docshare.wps.com/document/research-report/",3,{"item":101,"name":65,"@type":94,"position":19},"https://docshare.wps.com/document/estimating-the-number-of-polygenic-diseases-among-six-mutually-exclusive-entities-of-non-tumors-and-cancer-perspective/329493/",{"url":101,"name":65,"@type":103,"image":104,"author":109,"headline":65,"publisher":111,"fileFormat":114,"inLanguage":74,"description":66,"dateModified":115,"datePublished":116,"encodingFormat":114,"isAccessibleForFree":117,"interactionStatistic":118},"DigitalDocument",{"url":105,"@type":106,"width":107,"height":108},"https://docshare.wps.com/thumbnails/estimating-the-number-of-polygenic-diseases-among-six-mutually-exclusive-entities-of-non-tumors-and-cancer-perspective/329493.png","ImageObject",300,407,{"name":63,"@type":110},"Person",{"url":92,"name":112,"@type":113},"DocShare","Organization","application/pdf","2026-11-04","2026-09-21",true,{"@type":119,"interactionType":120,"userInteractionCount":39},"InteractionCounter",{"@type":121},"ViewAction",{"@type":123,"mainEntity":124},"FAQPage",[125,131,135],{"name":126,"@type":127,"acceptedAnswer":128},"What is the main objective of estimating polygenic disease entities in this work?","Question",{"text":129,"@type":130},"To enumerate the polygenic disease entities that arise from increasingly available sequenced cancer and noncancer genomes across different ancestries, and to clarify how these entities should be defined.","Answer",{"name":132,"@type":127,"acceptedAnswer":133},"How many fundamental types of polygenic illnesses are proposed, and how many are non-cancerous?",{"text":134,"@type":130},"Six fundamental types are identified, and five of them are non-cancerous.",{"name":136,"@type":127,"acceptedAnswer":137},"Why does the authors’ framework emphasize hyper-rare disorders?",{"text":138,"@type":130},"Hyper-rare disorders, defined as affecting fewer than 1/108 individuals, likely represent the largest number of disease entities, even though they involve very few affected individuals.","https://schema.org",{"og:url":101,"og:type":141,"og:title":65,"og:site_name":112,"og:description":66},"article",{"robots":143,"canonical":101},"index,follow",{"doc_id":61,"site_id":75},1791435800]