Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early Detection
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 multimo...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.70575 |
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| author | Thi Hue Hanh Nguyen Giang Hoang Vu Tu Thi Nguyen Tuan Anh Nguyen Vu Uyen Tran Luyen Thi Vu Giang Thi Huong Nguyen Nhat Duy Nguyen Trung Hieu Tran Van Thien Chi Nguyen Thanh Dat Nguyen Trong Hieu Nguyen Dac Ho Vo Thi Tuong Vi Van Thanh Thi Do Minh Phong Le Le Anh Khoa Huynh Duy Sinh Nguyen Hung Sang Tang Hoai‐Nghia Nguyen Minh‐Duy Phan Hoa Giang Lan N. Tu Le Son Tran |
| author_facet | Thi Hue Hanh Nguyen Giang Hoang Vu Tu Thi Nguyen Tuan Anh Nguyen Vu Uyen Tran Luyen Thi Vu Giang Thi Huong Nguyen Nhat Duy Nguyen Trung Hieu Tran Van Thien Chi Nguyen Thanh Dat Nguyen Trong Hieu Nguyen Dac Ho Vo Thi Tuong Vi Van Thanh Thi Do Minh Phong Le Le Anh Khoa Huynh Duy Sinh Nguyen Hung Sang Tang Hoai‐Nghia Nguyen Minh‐Duy Phan Hoa Giang Lan N. Tu Le Son Tran |
| author_sort | Thi Hue Hanh Nguyen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b9eb8d60212341b2b7c7cf9eb3cc1d5f |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-b9eb8d60212341b2b7c7cf9eb3cc1d5f2025-01-13T13:22:39ZengWileyCancer Medicine2045-76342025-01-01141n/an/a10.1002/cam4.70575Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early DetectionThi Hue Hanh Nguyen0Giang Hoang Vu1Tu Thi Nguyen2Tuan Anh Nguyen3Vu Uyen Tran4Luyen Thi Vu5Giang Thi Huong Nguyen6Nhat Duy Nguyen7Trung Hieu Tran8Van Thien Chi Nguyen9Thanh Dat Nguyen10Trong Hieu Nguyen11Dac Ho Vo12Thi Tuong Vi Van13Thanh Thi Do14Minh Phong Le15Le Anh Khoa Huynh16Duy Sinh Nguyen17Hung Sang Tang18Hoai‐Nghia Nguyen19Minh‐Duy Phan20Hoa Giang21Lan N. Tu22Le Son Tran23Medical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamMedical Genetics Institute Ho Chi Minh VietnamABSTRACT 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.https://doi.org/10.1002/cam4.70575cfDNAgenetic and epigenetic alterationshotspot mutationsMCED |
| spellingShingle | Thi Hue Hanh Nguyen Giang Hoang Vu Tu Thi Nguyen Tuan Anh Nguyen Vu Uyen Tran Luyen Thi Vu Giang Thi Huong Nguyen Nhat Duy Nguyen Trung Hieu Tran Van Thien Chi Nguyen Thanh Dat Nguyen Trong Hieu Nguyen Dac Ho Vo Thi Tuong Vi Van Thanh Thi Do Minh Phong Le Le Anh Khoa Huynh Duy Sinh Nguyen Hung Sang Tang Hoai‐Nghia Nguyen Minh‐Duy Phan Hoa Giang Lan N. Tu Le Son Tran Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early Detection Cancer Medicine cfDNA genetic and epigenetic alterations hotspot mutations MCED |
| title | Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early Detection |
| title_full | Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early Detection |
| title_fullStr | Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early Detection |
| title_full_unstemmed | Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early Detection |
| title_short | Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi‐Cancer Early Detection |
| title_sort | combination of hotspot mutations with methylation and fragmentomic profiles to enhance multi cancer early detection |
| topic | cfDNA genetic and epigenetic alterations hotspot mutations MCED |
| url | https://doi.org/10.1002/cam4.70575 |
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