{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T08:01:12Z","timestamp":1771920072213,"version":"3.50.1"},"reference-count":123,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Somatic mutations with low variant allele frequencies offer a highly sensitive lens for detecting cancer relapse driven by diverse causes, including clonal evolution and therapy resistance. Advances in next-generation sequencing have enabled robust subclonal variant identification that typically fall below conventional detection limits, supporting a comprehensive understanding of individual molecular profiles that can lead to relapse. These low-level alterations frequently emerge before clinical or radiological relapse and can inform response-adaptive treatment decisions. This review integrates the current biological and technical insights into low-frequency mutations and evaluates their emerging roles in tumor relapse management and precision oncology.<\/jats:p>","DOI":"10.3389\/fonc.2026.1772616","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T05:19:36Z","timestamp":1771910376000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Emerging role of low-frequency somatic mutations in cancer relapse: from early detection to precision oncology"],"prefix":"10.3389","volume":"16","author":[{"given":"Eunsoo","family":"Kim","sequence":"first","affiliation":[{"name":"College of Medicine, Gyeongsang National University","place":["Jinju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gu Seob","family":"Roh","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Medicine, Metabolic Dysfunction liver disease Research Center, Institute of Medical Science, Gyeongsang National University","place":["Jinju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seong Gyu","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Medical Science, Gyeongsang National University","place":["Jinju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13030376","article-title":"Cancer stem cells\u2014Key players in tumor relapse","volume":"13","author":"Marzagalli","year":"2021","journal-title":"Cancers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/s40779-025-00595-2","article-title":"Tumor dormancy and relapse: understanding the molecular mechanisms of cancer recurrence","volume":"12","author":"Tufail","year":"2025","journal-title":"Military Med Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2016.02.023","article-title":"Genomic and epigenomic alterations in cancer","volume":"186","author":"Chakravarthi","year":"2016","journal-title":"Am J Pathol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.14694\/EdBook_AM.2015.35.e662","article-title":"Clonal evolution models of tumor heterogeneity","volume":"35","author":"Shlush","year":"2015","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nature10762","article-title":"Clonal evolution in cancer","volume":"481","author":"Greaves","year":"2012","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002827","article-title":"A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma","volume":"4","author":"Munshi","year":"2020","journal-title":"Blood Adv"},{"key":"B7","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/s41408-023-00833-7","article-title":"NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia","volume":"13","author":"Li","year":"2023","journal-title":"Blood Cancer J"},{"key":"B8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3390\/ph15010075","article-title":"Relevance of circulating tumor cells as predictive markers for cancer incidence and relapse","volume":"15","author":"Chelakkot","year":"2022","journal-title":"Pharmaceuticals"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13153759","article-title":"Detection of tumor recurrence via circulating tumor DNA profiling in patients with localized lung cancer: clinical considerations and challenges","volume":"13","author":"Ulrich","year":"2021","journal-title":"Cancers"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-020-03529-4","article-title":"Circulating tumor cells as Trojan Horse for understanding, preventing, and treating cancer: a critical appraisal","volume":"77","author":"Mentis","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/genes5041064","article-title":"Somatic mosaicism in the human genome","volume":"5","author":"Freed","year":"2014","journal-title":"Genes"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2022.1115408","article-title":"Editorial: Somatic mutations, genome mosaicism and aging","volume":"3","author":"Lodato","year":"2023","journal-title":"Front Aging"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e1007108","DOI":"10.1371\/journal.pgen.1007108","article-title":"Aging and the rise of somatic cancer-associated mutations in normal tissues","volume":"14","author":"Risques","year":"2018","journal-title":"PloS Genet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.cell.2020.06.024","article-title":"Pathogenic mechanisms of somatic mutation and genome mosaicism in aging","volume":"182","author":"Vijg","year":"2020","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2023.08.011","article-title":"Variant allele frequency: a decision-making tool in precision oncology","volume":"9","author":"Boscolo Bielo","year":"2023","journal-title":"Trends Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18020308","article-title":"Next-generation sequencing in oncology: genetic diagnosis, risk prediction and cancer classification","volume":"18","author":"Kamps","year":"2017","journal-title":"IJMS"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16040782","article-title":"Variant allele frequency analysis of circulating tumor DNA as a promising tool in assessing the effectiveness of treatment in non-small cell lung carcinoma patients","volume":"16","author":"Galant","year":"2024","journal-title":"Cancers"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1443","article-title":"Discovery and characterization of artifactual mutations in deep coverage targeted capture sequencing data due to oxidative DNA damage during sample preparation","volume":"41","author":"Costello","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-3425-4","article-title":"Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller","volume":"18","author":"Xu","year":"2017","journal-title":"BMC Genomics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1038\/s41467-017-01470-y","article-title":"Prevalence and detection of low-allele-fraction variants in clinical cancer samples","volume":"8","author":"Shin","year":"2017","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1111\/codi.16807","article-title":"Chemotherapy reduces long-term quality of life in recurrence-free colon cancer survivors (LATE study)\u2014a nationwide inverse probability of treatment-weighted registry-based cohort study and survey","volume":"26","author":"Malik","year":"2024","journal-title":"Colorectal Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2021.100505","article-title":"Risk for relapse and death after adjuvant chemotherapy associated with SNPs in patients with breast cancer - A retrospective study","volume":"30","author":"Oliva","year":"2022","journal-title":"Cancer Treat Res Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA A Cancer J Clin"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701830","article-title":"20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years","volume":"377","author":"Pan","year":"2017","journal-title":"N Engl J Med"},{"key":"B25","article-title":"Cancer facts & Figures\u00a02025","year":"2025","journal-title":"Am Cancer Soc"},{"key":"B26","doi-asserted-by":"publisher","first-page":"12306","DOI":"10.1038\/s41598-024-63143-3","article-title":"Prognostic factors and survival disparities in right-sided versus left-sided colon cancer","volume":"14","author":"Asghari-Jafarabadi","year":"2024","journal-title":"Sci Rep"},{"key":"B27","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s12957-025-03783-5","article-title":"Factors associated with postoperative recurrence in perforated colorectal cancer: unraveling the high recurrence rate of perforated colorectal cancer","volume":"23","author":"Takagi","year":"2025","journal-title":"World J Surg Onc"},{"key":"B28","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1186\/s12876-022-02319-5","article-title":"Oncologic outcome of colon cancer with perforation and obstruction","volume":"22","author":"Yang","year":"2022","journal-title":"BMC Gastroenterol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejso.2022.08.008","article-title":"Outcomes of patients with perforated colon cancer: A systematic review","volume":"49","author":"Zamaray","year":"2023","journal-title":"Eur J Surg Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"7686","DOI":"10.1038\/ncomms8686","article-title":"Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients","volume":"6","author":"Sausen","year":"2015","journal-title":"Nat Commun"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.11115","article-title":"Impact of resection margin status on recurrence and survival in pancreatic cancer surgery","volume":"106","author":"Tummers","year":"2019","journal-title":"Br J Surg"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i11.3157","article-title":"Update on the management of pancreatic cancer: Surgery is not enough","volume":"21","author":"Ansari","year":"2015","journal-title":"WJG"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20184504","article-title":"Chemoresistance in pancreatic cancer","volume":"20","author":"Zeng","year":"2019","journal-title":"IJMS"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14205114","article-title":"Hepatocellular carcinoma recurrence and mortality rate post liver transplantation: meta-analysis and systematic review of real-world evidence","volume":"14","author":"Bzeizi","year":"2022","journal-title":"Cancers"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16040696","article-title":"Hepatoblastoma relapse\u2014Findings from the german HB99 trial and the german liver tumor registry","volume":"16","author":"Maxwell","year":"2024","journal-title":"Cancers"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.1001\/jamaoncol.2021.4932","article-title":"Update of incidence, prevalence, survival, and initial treatment in patients with non\u2013small cell lung cancer in the US","volume":"7","author":"Ganti","year":"2021","journal-title":"JAMA Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.resinv.2012.08.007","article-title":"Prognostic factors before and after recurrence of resected non-small cell lung cancer","volume":"50","author":"Baba","year":"2012","journal-title":"Respir Invest"},{"key":"B38","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s00345-012-0824-2","article-title":"Prostate cancer epidemiology in the United States","volume":"30","author":"Brawley","year":"2012","journal-title":"World J Urol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djaf012","article-title":"Incidence and prognostic implications of prostate-specific antigen persistence and relapse after radical prostatectomy: population-based study","volume":"117","author":"Scilipoti","year":"2025","journal-title":"JNCI: J Natl Cancer Institute"},{"key":"B40","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41408-023-00853-3","article-title":"Global burden of hematologic Malignancies and evolution patterns over the past 30 years","volume":"13","author":"Zhang","year":"2023","journal-title":"Blood Cancer J"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-187856","article-title":"Projected global trends in hematological Malignancies: incidence, mortality, and disability-adjusted life years from 2020 to 2030","volume":"142","author":"An","year":"2023","journal-title":"Blood"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2013.09.011","article-title":"Outcome and prognostic factors for patients who relapse after allogeneic hematopoietic stem cell transplantation","volume":"19","author":"Thanarajasingam","year":"2013","journal-title":"Biol Blood Marrow Transplant"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i19.5934","article-title":"Factors associated with early recurrence after curative surgery for gastric cancer","volume":"21","author":"Kang","year":"2015","journal-title":"WJG"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1097\/01.sla.0000143245.28656.15","article-title":"Patterns of initial recurrence in completely resected gastric adenocarcinoma","volume":"240","author":"D\u2019Angelica","year":"2004","journal-title":"Ann Surg"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.5_suppl.521","article-title":"Global and regional burden of kidney cancer: Analysis and future predictions based on GBD data from 1990 to 2021","volume":"43","author":"Zhao","year":"2025","journal-title":"JCO"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfae036","article-title":"Global epidemiology of kidney cancer","volume":"39","author":"Cirillo","year":"2024","journal-title":"Nephrol Dialysis Transplant"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000002009","article-title":"Recurrence of renal cell cancer after renal transplantation in a multicenter french cohort","volume":"102","author":"Cognard","year":"2018","journal-title":"Transplantation"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-018-2309-4","article-title":"Prognostic factors and prognostic models for renal cell carcinoma: a literature review","volume":"36","author":"Klatte","year":"2018","journal-title":"World J Urol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3802\/jgo.2011.22.1.3","article-title":"Multivariate survival analysis of the patients with recurrent endometrial cancer","volume":"22","author":"Odagiri","year":"2011","journal-title":"J Gynecol Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.808037","article-title":"Risk factors and prognosis of early recurrence in stage I\u2013II endometrial cancer: A large-scale, multi-center, and retrospective study","volume":"9","author":"Dou","year":"2022","journal-title":"Front Med"},{"key":"B51","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1136\/ijgc-2019-000822","article-title":"Clinical outcome of recurrent endometrial cancer: analysis of post-relapse survival by pattern of recurrence and secondary treatment","volume":"30","author":"Legge","year":"2020","journal-title":"Int J Gynecological Cancer"},{"key":"B52","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1159\/000544932","article-title":"The epidemiological trends and prediction of brain and central nervous system cancer incidence and mortality, 1992-2021: Age-period-cohort analysis","volume":"60","author":"Li","year":"2026","journal-title":"Neuroepidemiology"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030925","article-title":"Central nervous system progression\/relapse in mature T- and NK-cell lymphomas","volume":"15","author":"Bhansali","year":"2023","journal-title":"Cancers"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13010047","article-title":"Recurrent glioblastoma: from molecular landscape to new treatment perspectives","volume":"13","author":"Birzu","year":"2020","journal-title":"Cancers"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-018-2644-2","article-title":"Patterns of breast cancer relapse in accordance to biological subtype","volume":"144","author":"Ignatov","year":"2018","journal-title":"J Cancer Res Clin Oncol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2019.07.008","article-title":"Differential relapse patterns for non-small cell lung cancer subtypes adenocarcinoma and squamous cell carcinoma: implications for radiation oncology","volume":"31","author":"McAleese","year":"2019","journal-title":"Clin Oncol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s13058-020-01345-z","article-title":"Inter-tumor genomic heterogeneity of breast cancers: comprehensive genomic profile of primary early breast cancers and relapses","volume":"22","author":"Fumagalli","year":"2020","journal-title":"Breast Cancer Research : BCR"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.5772\/61964","article-title":"Next-generation sequencing \u2014 An overview of the history, tools, and \u201cOmic\u201d Applications","author":"Kulski","year":"2016","journal-title":"Next Generation Sequencing - Advances Appl Challenges"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1002\/bies.200900181","article-title":"High-throughput DNA sequencing \u2013 concepts and limitations","volume":"32","author":"Kircher","year":"2010","journal-title":"BioEssays"},{"key":"B60","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.csbj.2019.11.002","article-title":"Long walk to genomics: History and current approaches to genome sequencing and assembly","volume":"18","author":"Giani","year":"2020","journal-title":"Comput Struct Biotechnol J"},{"key":"B61","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/gm483","article-title":"The human genome project: big science transforms biology and medicine","volume":"5","author":"Hood","year":"2013","journal-title":"Genome Med"},{"key":"B62","doi-asserted-by":"publisher","first-page":"997","DOI":"10.3390\/biology12070997","article-title":"Next-generation sequencing technology: current trends and advancements","volume":"12","author":"Satam","year":"2023","journal-title":"Biology"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0509-455","article-title":"How to map billions of short reads onto genomes","volume":"27","author":"Trapnell","year":"2009","journal-title":"Nat Biotechnol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2010.03.001","article-title":"Assembly algorithms for next-generation sequencing data","volume":"95","author":"Miller","year":"2010","journal-title":"Genomics"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1007\/s12687-020-00500-5","article-title":"Improving diagnostics of rare genetic diseases with NGS approaches","volume":"12","author":"Vink\u0161el","year":"2021","journal-title":"J Community Genet"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S99807","article-title":"Next-generation sequencing: advances and applications in cancer diagnosis","volume":"9","author":"Serrat\u00ec","year":"2016","journal-title":"OTT"},{"key":"B67","doi-asserted-by":"publisher","first-page":"e2200715","DOI":"10.1200\/PO.22.00715","article-title":"Comprehensive review on the clinical impact of next-generation sequencing tests for the management of advanced cancer","volume":"7","author":"Gibbs","year":"2023","journal-title":"JCO Precis Oncol"},{"key":"B68","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41525-020-00154-9","article-title":"Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease","volume":"5","author":"Marshall","year":"2020","journal-title":"NPJ Genomic Med"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.21037\/atm-21-1948","article-title":"A narrative review of tumor heterogeneity and challenges to tumor drug therapy","volume":"9","author":"Zhu","year":"2021","journal-title":"Ann Transl Med"},{"key":"B70","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1007\/s12672-025-01816-9","article-title":"Next-generation sequencing in cancer diagnosis and treatment: clinical applications and future directions","volume":"16","author":"Ghoreyshi","year":"2025","journal-title":"Discover Oncol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1007\/s12253-016-0124-z","article-title":"Clinical applications of next-generation sequencing in cancer diagnosis","volume":"23","author":"Sabour","year":"2017","journal-title":"Pathol Oncol Res"},{"key":"B72","doi-asserted-by":"publisher","first-page":"e70039","DOI":"10.1111\/1759-7714.70039","article-title":"Next-generation sequencing vs. Clinical-pathological assessment in diagnosis of multiple lung cancers: A systematic review and meta-analysis","volume":"16","author":"Wang","year":"2025","journal-title":"Thorac Cancer"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3390\/cimb44040106","article-title":"Comparison of next-generation sequencing and polymerase chain reaction for personalized treatment-related genomic status in patients with metastatic colorectal cancer","volume":"44","author":"Su","year":"2022","journal-title":"CIMB"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22047","article-title":"Comparison of targeted next-generation sequencing (NGS) and real-time PCR in the detection of EGFR, KRAS, and BRAF mutations on formalin-fixed, paraffin-embedded tumor material of non-small cell lung carcinoma\u2014Superiority of NGS","volume":"52","author":"Tuononen","year":"2013","journal-title":"Genes Chromosomes Cancer"},{"key":"B75","doi-asserted-by":"publisher","first-page":"6123","DOI":"10.1038\/s41467-021-26308-6","article-title":"Calibration-free NGS quantitation of mutations below 0.01% VAF","volume":"12","author":"Dai","year":"2021","journal-title":"Nat Commun"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.e14545","article-title":"Analytical and clinical validation of a personalized, tumor-informed circulating tumor DNA assay for minimal residual disease detection","volume":"42","author":"Yang","year":"2024","journal-title":"JCO"},{"key":"B77","doi-asserted-by":"publisher","first-page":"11640","DOI":"10.1038\/s41598-021-91142-1","article-title":"Confirming putative variants at \u2264 5% allele frequency using allele enrichment and Sanger sequencing","volume":"11","author":"Yan","year":"2021","journal-title":"Sci Rep"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.170","article-title":"Detecting ultralow-frequency mutations by Duplex Sequencing","volume":"9","author":"Kennedy","year":"2014","journal-title":"Nat Protoc"},{"key":"B79","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s12920-020-0671-8","article-title":"Error-corrected sequencing strategies enable comprehensive detection of leukemic mutations relevant for diagnosis and minimal residual disease monitoring","volume":"13","author":"Crowgey","year":"2020","journal-title":"BMC Med Genomics"},{"key":"B80","doi-asserted-by":"publisher","first-page":"484","DOI":"10.4143\/crt.2023.712","article-title":"Revolutionizing non\u2013small cell lung cancer diagnosis: ultra-high-sensitive ctDNA analysis for detecting hotspot mutations with long-term stored plasma","volume":"56","author":"Lee","year":"2024","journal-title":"Cancer Res Treat"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1200\/PO.17.00318","article-title":"Use of low-frequency driver mutations detected by cell-free circulating tumor DNA to guide targeted therapy in non\u2013small-cell lung cancer: A multicenter case series","volume":"2","author":"Jacobs","year":"2018","journal-title":"JCO Precis Oncol"},{"key":"B82","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1186\/s13073-016-0370-4","article-title":"Technological considerations for genome-guided diagnosis and management of cancer","volume":"8","author":"Lennon","year":"2016","journal-title":"Genome Med"},{"key":"B83","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/s41698-025-00991-w","article-title":"Tissue-based genomic profiling of 300,000 tumors highlights the detection of variants with low allele fraction","volume":"9","author":"Sisoudiya","year":"2025","journal-title":"NPJ Precis Onc"},{"key":"B84","doi-asserted-by":"publisher","first-page":"R124","DOI":"10.1186\/gb-2011-12-12-r124","article-title":"Detection of low prevalence somatic mutations in solid tumors with ultra-deep targeted sequencing","volume":"12","author":"Harismendy","year":"2011","journal-title":"Genome Biol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1038\/s41467-019-09026-y","article-title":"The use of technical replication for detection of low-level somatic mutations in next-generation sequencing","volume":"10","author":"Kim","year":"2019","journal-title":"Nat Commun"},{"key":"B86","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s40246-019-0220-8","article-title":"Next-generation sequencing in liquid biopsy: cancer screening and early detection","volume":"13","author":"Chen","year":"2019","journal-title":"Hum Genomics"},{"key":"B87","doi-asserted-by":"publisher","first-page":"e0194630","DOI":"10.1371\/journal.pone.0194630","article-title":"Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA","volume":"13","author":"Gale","year":"2018","journal-title":"PloS One"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2023.102595","article-title":"Strategies for improving detection of circulating tumor DNA using next generation sequencing","volume":"119","author":"T\u00e9bar-Mart\u00ednez","year":"2023","journal-title":"Cancer Treat Rev"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0058-3","article-title":"Early stage NSCLC \u2014 challenges to implementing ctDNA-based screening and MRD detection","volume":"15","author":"Abbosh","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlb.2023.100135","article-title":"Clinical significance of genomic sequencing of circulating tumour cells (CTCs) in cancer","volume":"3","author":"Auwal","year":"2024","journal-title":"J Liquid Biopsy"},{"key":"B91","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s12943-021-01392-w","article-title":"Using single-cell sequencing technology to detect circulating tumor cells in solid tumors","volume":"20","author":"Xu","year":"2021","journal-title":"Mol Cancer"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2013.07.007","article-title":"Analysing the mutational status of PIK3CA in circulating tumor cells from metastatic breast cancer patients","volume":"7","author":"Schneck","year":"2013","journal-title":"Mol Oncol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2018.08.004","article-title":"Accurate and sensitive analysis of minimal residual disease in acute myeloid leukemia using deep sequencing of single nucleotide variations","volume":"21","author":"Delsing Malmberg","year":"2019","journal-title":"J Mol Diagnostics"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-04-848028","article-title":"Next-generation sequencing\u2013based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse","volume":"132","author":"Kim","year":"2018","journal-title":"Blood"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019001156","article-title":"Targeted next-generation sequencing of circulating cell-free DNA vs bone marrow in patients with acute myeloid leukemia","volume":"4","author":"Short","year":"2020","journal-title":"Blood Adv"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.010","article-title":"The role of extracellular vesicles in cancer","volume":"186","author":"Kalluri","year":"2023","journal-title":"Cell"},{"key":"B97","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1016\/j.ccell.2024.06.003","article-title":"Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution","volume":"42","author":"Casanova-Salas","year":"2024","journal-title":"Cancer Cell"},{"key":"B98","doi-asserted-by":"publisher","first-page":"e70047","DOI":"10.1002\/jev2.70047","article-title":"Unravelling the significance of extracellular vesicle-associated DNA in cancer biology and its potential clinical applications","volume":"14","author":"Ghanam","year":"2025","journal-title":"J Extracellular Vesicles"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-20-888","article-title":"Genomic profiling of extracellular vesicle-derived DNA from bronchoalveolar lavage fluid of patients with lung adenocarcinoma","volume":"10","author":"Lee","year":"2021","journal-title":"Transl Lung Cancer Res"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-00981-w","article-title":"Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA","volume":"39","author":"Kurtz","year":"2021","journal-title":"Nat Biotechnol"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2023.283520","article-title":"Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia","volume":"109","author":"Dillon","year":"2023","journal-title":"Haematologica"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0528","article-title":"Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer","volume":"5","author":"Reinert","year":"2019","journal-title":"JAMA Oncol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213686","article-title":"Detection of measurable residual disease biomarkers in extracellular vesicles from liquid biopsies of multiple myeloma patients\u2014A proof of concept","volume":"23","author":"Bergantim","year":"2022","journal-title":"IJMS"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0187-3","article-title":"Liquid biopsy and minimal residual disease \u2014 latest advances and implications for cure","volume":"16","author":"Pantel","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3571","article-title":"Inferring the evolution and progression of small-cell lung cancer by single-cell sequencing of circulating tumor cells","volume":"25","author":"Su","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy458","article-title":"Nanoscale extracellular vesicle-derived DNA is superior to circulating cell-free DNA for mutation detection in early-stage non-small-cell lung cancer","volume":"29","author":"Wan","year":"2018","journal-title":"Ann Oncol"},{"key":"B107","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1093\/annonc\/mdz046","article-title":"Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium","volume":"30","author":"Li","year":"2019","journal-title":"Ann Oncol"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu239","article-title":"Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle","volume":"25","author":"De Mattos-Arruda","year":"2014","journal-title":"Ann Oncol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14092","article-title":"Monitoring of cancer patients via next-generation sequencing of patient-derived circulating tumor cells and tumor DNA","volume":"110","author":"Onidani","year":"2019","journal-title":"Cancer Sci"},{"key":"B110","doi-asserted-by":"publisher","first-page":"JCO","DOI":"10.1200\/JCO-25-01534","article-title":"Remission assessment by circulating tumor DNA in large B-cell lymphoma","volume":"43","author":"Roschewski","year":"2025","journal-title":"J Clin Oncol"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.e17600","article-title":"Circulating tumor DNA-based molecular residual disease detection for the monitoring of high-grade serous ovarian cancer","volume":"41","author":"Ying","year":"2023","journal-title":"JCO"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf6219","article-title":"Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer","volume":"8","author":"Tie","year":"2016","journal-title":"Sci Transl Med"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1111\/cas.70059","article-title":"Detection of KRAS mutations using extracellular vesicle DNA in colorectal cancer patients","volume":"116","author":"Kuriyama","year":"2025","journal-title":"Cancer Sci"},{"key":"B114","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1002\/med4.11","article-title":"Molecular residual disease: A new clue for individualized approach in non-small cell lung cancer","volume":"1","author":"Zhang","year":"2023","journal-title":"Med Adv"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1127","article-title":"Dynamics of tumor and immune responses during immune checkpoint blockade in non\u2013small cell lung cancer","volume":"79","author":"Anagnostou","year":"2019","journal-title":"Cancer Res"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2632","article-title":"Serial ultra-deep sequencing of circulating tumor DNA reveals the clonal evolution in non-small cell lung cancer patients treated with anti-PD1 immunotherapy","volume":"8","author":"Li","year":"2019","journal-title":"Cancer Med"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.02052","article-title":"Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma","volume":"37","author":"Christensen","year":"2019","journal-title":"J Clin Oncol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00555-1","article-title":"Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial","volume":"23","author":"Bidard","year":"2022","journal-title":"Lancet Oncol"},{"key":"B119","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s12935-021-01761-x","article-title":"Exosome-based detection of EGFR T790M in plasma and pleural fluid of prospectively enrolled non-small cell lung cancer patients after first-line tyrosine kinase inhibitor therapy","volume":"21","author":"Kim","year":"2021","journal-title":"Cancer Cell Int"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax7392","article-title":"Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer","volume":"11","author":"McDonald","year":"2019","journal-title":"Sci Transl Med"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-020-01874-2","article-title":"Clinical implications of intratumor heterogeneity: challenges and opportunities","volume":"98","author":"Ram\u00f3n y Cajal","year":"2020","journal-title":"J Mol Med"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.02.017","article-title":"Attack of the subclones: accurate detection of mutational heterogeneity in bulk DNA from tumors","volume":"140","author":"Rodgers","year":"2020","journal-title":"J Invest Dermatol"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00851","article-title":"Standardization of sequencing coverage depth in NGS: recommendation for detection of clonal and subclonal mutations in cancer diagnostics","volume":"9","author":"Petrackova","year":"2019","journal-title":"Front Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1772616\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T05:19:37Z","timestamp":1771910377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1772616\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,24]]},"references-count":123,"alternative-id":["10.3389\/fonc.2026.1772616"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1772616","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,24]]},"article-number":"1772616"}}