Abigail Ward , Dana Farengo-Clark , Danielle B. McKenna , Anton Safonov , Madeline Good , Anh Le , Lisa Kessler , Payal D. Shah , Angela R. Bradbury , Susan M. Domchek , Katherine L. Nathanson , Jacquelyn Powers , Kara N. Maxwell
{"title":"种系遗传检测中发现的 TP53 马赛克变体的临床管理","authors":"Abigail Ward , Dana Farengo-Clark , Danielle B. McKenna , Anton Safonov , Madeline Good , Anh Le , Lisa Kessler , Payal D. Shah , Angela R. Bradbury , Susan M. Domchek , Katherine L. Nathanson , Jacquelyn Powers , Kara N. Maxwell","doi":"10.1016/j.cancergen.2024.04.002","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Germline heterozygous <em>TP53</em> pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). <em>TP53</em> PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.</p></div><div><h3>Patients and methods</h3><p>Retrospective analysis of probands who presented to an academic cancer genetics program with a <em>TP53</em> PV result on germline genetic testing.</p></div><div><h3>Results</h3><p>Twenty-one of 125 unrelated probands (17 %) were found to harbor a <em>TP53</em> PV with VAF<30 % or a designation of “mosaic”. A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (<em>n</em> = 8) or without (<em>n</em> = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative.</p></div><div><h3>Conclusions</h3><p>Determining the etiology of low VAF <em>TP53</em> PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.</p></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":null,"pages":null},"PeriodicalIF":1.4000,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Clinical management of TP53 mosaic variants found on germline genetic testing\",\"authors\":\"Abigail Ward , Dana Farengo-Clark , Danielle B. McKenna , Anton Safonov , Madeline Good , Anh Le , Lisa Kessler , Payal D. Shah , Angela R. Bradbury , Susan M. Domchek , Katherine L. Nathanson , Jacquelyn Powers , Kara N. Maxwell\",\"doi\":\"10.1016/j.cancergen.2024.04.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Germline heterozygous <em>TP53</em> pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). <em>TP53</em> PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.</p></div><div><h3>Patients and methods</h3><p>Retrospective analysis of probands who presented to an academic cancer genetics program with a <em>TP53</em> PV result on germline genetic testing.</p></div><div><h3>Results</h3><p>Twenty-one of 125 unrelated probands (17 %) were found to harbor a <em>TP53</em> PV with VAF<30 % or a designation of “mosaic”. A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (<em>n</em> = 8) or without (<em>n</em> = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative.</p></div><div><h3>Conclusions</h3><p>Determining the etiology of low VAF <em>TP53</em> PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.</p></div>\",\"PeriodicalId\":49225,\"journal\":{\"name\":\"Cancer Genetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.4000,\"publicationDate\":\"2024-04-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2210776224000140\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Genetics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2210776224000140","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Clinical management of TP53 mosaic variants found on germline genetic testing
Background
Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.
Patients and methods
Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing.
Results
Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of “mosaic”. A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative.
Conclusions
Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.
期刊介绍:
The aim of Cancer Genetics is to publish high quality scientific papers on the cellular, genetic and molecular aspects of cancer, including cancer predisposition and clinical diagnostic applications. Specific areas of interest include descriptions of new chromosomal, molecular or epigenetic alterations in benign and malignant diseases; novel laboratory approaches for identification and characterization of chromosomal rearrangements or genomic alterations in cancer cells; correlation of genetic changes with pathology and clinical presentation; and the molecular genetics of cancer predisposition. To reach a basic science and clinical multidisciplinary audience, we welcome original full-length articles, reviews, meeting summaries, brief reports, and letters to the editor.