Combination of Hotspot Mutations With Methylation and Fragmentomic Profiles to Enhance Multi-Cancer Early Detection.

Autor: 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.
Jazyk: angličtina
Zdroj: Cancer medicine [Cancer Med] 2025 Jan; Vol. 14 (1), pp. e70575.
DOI: 10.1002/cam4.70575
Abstrakt: 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.)
Databáze: MEDLINE
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