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Next-generation sequencing enables a genetic perspective, highlighting key susceptibility genes across oncogenic and caretaker mutations, pleiotropic loci spanning cancer types, and deleterious treatment-related mutations, with functional interpretation through signaling pathways and summarized genotype–tumor-pair associations.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/susceptibility-genes-associated-with-multiple-primary-cancers/375688/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/susceptibility-genes-associated-with-multiple-primary-cancers/375688.png","ImageObject",300,407,{"name":42,"@type":43},"Levi","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-03","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What 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Yuan Chen and Peng Zhang *  \nCitation: Lu, M.; Zhang, X.; Chu, Q.; Chen, Y.; Zhang, P. Susceptibility Genes Associated with Multiple Primary Cancers. Cancers 2023, 15, 5788. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers15245788  \nReceived: 22 October 2023  \nRevised: 29 November 2023  \nAccepted: 5 December 2023  \nPublished: 10 December 2023  \nCopyright: © 2023 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/)) .  \nDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; [m202176432@hust.edu.cn](m202176432@hust.edu.cn) (M.L.)  \n* Correspondence: [tjh_zhangpeng@hust.edu.cn](tjh_zhangpeng@hust.edu.cn)  \nSimple Summary: With advanced cancer treatments and screening techniques, a growing number of cancer survivors face the challenge of multiple primary cancers (MPCs), affecting approximately one in six patients. Distinguishing MPCs from recurrences or metastases is still challenging due to the limited clinicopathological criteria available. Next-generation sequencing (NGS) has facilitated the comprehension of MPCs from a genetic standpoint. In this review, we discuss three main inherit factors contributing to MPCs development: the mutations targeting oncogenes and caretaker genes directly involved in MPCs, the potential influence of pleiotropic loci spanning various cancer types, and the regulatory impact of deleterious mutations following treatment. These susceptibility genes will be discussed in relation to their background in signaling pathways. Additionally, the association network between genetic signatures and various tumor pairs will be summarized.  \nAbstract: With advancements in treatment and screening techniques, we have been witnessing an era where more cancer survivors harbor multiple primary cancers (MPCs), affecting approximately one in six patients. Identifying MPCs is crucial for tumor staging and subsequent treatment choices. However, the current clinicopathological criteria for clinical application are limited and insufficient, making it challenging to differentiate them from recurrences or metastases. The emergence of nextgeneration sequencing (NGS) technology has provided a genetic perspective for defining multiple primary cancers. Researchers have found that, when considering multiple tumor pairs, it is crucial not only to examine well-known essential mutations like MLH1/MSH2, EGFR, PTEN, BRCA1/2, CHEK2, and TP53 mutations but also to explore certain pleiotropic loci. Moreover, specific deleterious mutations may serve as regulatory factors in second cancer development following treatment. This review aims to discuss these susceptibility genes and provide an explanation of their functions based on the signaling pathway background. Additionally, the association network between genetic signatures and different tumor pairs will be summarized.  \nKeywords: multiple primary cancers; susceptibility genes; genetic predisposition; second cancer; next-generation sequencing  \n1. Introduction  \nCancer is a leading cause of death worldwide [1]. However, advancements in screening techniques and treatments have significantly improved cancer patient outcomes, with approximately 70% of individuals surviving for over five years [2] . The number of cancer survivors has been increasing at a rate of 2% per year since 1971 [3] . Alongside this trend, the incidence of second primary tumors has also risen. This condition, known as multiple primary cancers (MPCs), affects about one in six cancer patients [4] .  \nMPCs are defined","cbCailyKFsSoYKHI","https://ap.wps.com/l/cbCailyKFsSoYKHI","pdf",1213612,22,"English","# Introduction\n## Definition and clinical relevance of MPCs\n## Risk factors and epidemiology\n## Genetic predisposition and NGS perspective","[{\"question\":\"What makes multiple primary cancers (MPCs) difficult to identify clinically?\",\"answer\":\"Current clinicopathological criteria are limited, so MPCs can be challenging to differentiate from recurrences or metastases.\"},{\"question\":\"How does next-generation sequencing (NGS) contribute to understanding MPCs?\",\"answer\":\"NGS provides a genetic viewpoint for defining MPCs and analyzing susceptibility genes involved in their development.\"},{\"question\":\"Which gene categories are discussed as contributors to MPC development?\",\"answer\":\"The review focuses on mutations targeting oncogenes and caretaker genes, pleiotropic loci with influence across cancer types, and deleterious mutations that may regulate second-cancer development after treatment.\"}]","Susceptibility Genes Associated with Multiple Primary Cancers | PDF",1790215780,55]