Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi-Cancer Early Detection.
| Title: | Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi-Cancer Early Detection. |
|---|---|
| Authors: | Nguyen THH; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Vu GH; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen TT; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen TA; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Tran VU; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Vu LT; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen GTH; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen ND; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Tran TH; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen VTC; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen TD; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen TH; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Vo DH; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Van TTV; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Do TT; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Le MP; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Huynh LAK; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen DS; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Tang HS; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Nguyen HN; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Phan MD; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Giang H; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Tu LN; Medical Genetics Institute, Ho Chi Minh, Vietnam.; Tran LS; Medical Genetics Institute, Ho Chi Minh, Vietnam. |
| Source: | Cancer medicine [Cancer Med] 2025 Jan; Vol. 14 (1), pp. e70575. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: John Wiley & Sons Ltd Country of Publication: United States NLM ID: 101595310 Publication Model: Print Cited Medium: Internet ISSN: 2045-7634 (Electronic) Linking ISSN: 20457634 NLM ISO Abbreviation: Cancer Med Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Malden, MA] : John Wiley & Sons Ltd., c2012- |
| MeSH Terms: | Early Detection of Cancer*/methods ; Biomarkers, Tumor*/genetics ; DNA Methylation* ; Mutation*; Circulating Tumor DNA/genetics ; Circulating Tumor DNA/blood ; Neoplasms/genetics ; Neoplasms/diagnosis ; Humans ; Female ; Male ; Retrospective Studies ; Middle Aged ; Aged ; Adult |
| Abstract: | Background: Multi-cancer early detection (MCED) through a single blood test significantly advances cancer diagnosis. However, most MCED tests rely on a single type of biomarkers, leading to limited sensitivity, particularly for early-stage cancers. We previously developed SPOT-MAS, a multimodal ctDNA-based assay analyzing methylation and fragmentomic profiles to detect five common cancers. Despite its potential, SPOT-MAS exhibited moderate sensitivities for early-stage cancers. This study investigated whether integrating hotspot mutations into SPOT-MAS could enhance its detection rates.; Method: A targeted amplicon sequencing approach was developed to profile 700 hotspot mutations in cell-free DNA and integrated into the SPOT-MAS assay, creating a single-blood draw workflow. This workflow, namely SPOT-MAS Plus was retrospectively validated in a cohort of 255 non-metastatic cancer patients (breast, colorectal, gastric, liver, and lung) and 304 healthy individuals.; Results: Hotspot mutations were detected in 131 of 255 (51.4%) cancer patients, with the highest rates in liver cancer (96.5%), followed by colorectal (59.3%) and lung cancer (53.7%). Lower detection rates were found for cancers with low tumor mutational burden, such as breast (31.3%) and gastric (41.9%) cancers. In contrast, SPOT-MAS demonstrated higher sensitivities for these cancers (51.6% for breast and 62.9% for gastric). The combination of hotspot mutations with SPOT-MAS predictions improved early-stage cancer detection, achieving an overall sensitivity of 78.5% at a specificity of 97.7%. Enhanced sensitivities were observed for colorectal (81.36%) and lung cancer (82.9%).; Conclusion: The integration of genetic and epigenetic alterations into a multimodal assay significantly enhances the early detection of various cancers. Further validation in larger cohorts is necessary to support broader clinical applications.; (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.) |
| References: | Cell Rep. 2018 Oct 23;25(4):1066-1080.e8. (PMID: 30355485); Expert Rev Mol Diagn. 2021 Jan;21(1):63-75. (PMID: 33270495); NPJ Breast Cancer. 2024 Jun 19;10(1):50. (PMID: 38898045); Lancet. 2023 Oct 7;402(10409):1251-1260. (PMID: 37805216); Nucleic Acids Res. 2012 Aug;40(15):e115. (PMID: 22730293); Cancer Cell. 2022 Feb 14;40(2):109-113. (PMID: 35120599); Elife. 2023 Oct 11;12:. (PMID: 37819044); Br J Cancer. 2013 Aug 20;109(4):1004-12. (PMID: 23900220); Clin Chim Acta. 2001 Nov;313(1-2):139-42. (PMID: 11694251); Nature. 2017 Apr 26;545(7655):446-451. (PMID: 28445469); J Transl Med. 2022 May 13;20(1):211. (PMID: 35562750); Nat Med. 2019 Dec;25(12):1928-1937. (PMID: 31768066); Br J Cancer. 2023 Dec;129(12):1893-1902. (PMID: 37789101); Ann Oncol. 2018 Jun 1;29(6):1351-1353. (PMID: 29668834); Ann Oncol. 2021 Sep;32(9):1167-1177. (PMID: 34176681); PLoS One. 2007 Dec 19;2(12):e1314. (PMID: 18091988); Cancer Invest. 2022 Apr;40(4):354-365. (PMID: 34894952); Curr Top Microbiol Immunol. 2006;301:259-81. (PMID: 16570852); Oncotarget. 2017 Mar 14;8(11):18166-18176. (PMID: 28199989); Bioinformatics. 2014 Aug 1;30(15):2114-20. (PMID: 24695404); Hum Genomics. 2019 Aug 1;13(1):34. (PMID: 31370908); Biochimie. 2012 Nov;94(11):2219-30. (PMID: 22609632); Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1107-12. (PMID: 25583476); Sci Transl Med. 2014 Feb 19;6(224):224ra24. (PMID: 24553385); Clin Chim Acta. 2014 Jun 10;433:284-9. (PMID: 24685572); Science. 2020 Jul 3;369(6499):. (PMID: 32345712); Mol Oncol. 2023 Apr;17(4):598-610. (PMID: 36495126); Trends Cancer. 2016 Jul;2(7):350-364. (PMID: 27819059); Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943); Br J Cancer. 2023 Feb;128(4):505-518. (PMID: 36357703); Cancer Cell. 2023 Jun 12;41(6):1091-1102.e4. (PMID: 37146605) |
| Grant Information: | Gene Solutions (K-Discovery) |
| Contributed Indexing: | Keywords: MCED; cfDNA; genetic and epigenetic alterations; hotspot mutations |
| Substance Nomenclature: | 0 (Biomarkers, Tumor); 0 (Circulating Tumor DNA) |
| Entry Date(s): | Date Created: 20250103 Date Completed: 20250103 Latest Revision: 20250105 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11695824 |
| DOI: | 10.1002/cam4.70575 |
| PMID: | 39748775 |
| Database: | MEDLINE |
Journal Article