Abstract A018: Micronuclei DNA enables early detection of gastrointestinal cancer
Authors: Haobo Sun, Xingyun Yao, Yuehua Han, Yurong Jiao, Xiangxing Kong, Chengcheng Liu, Qingqu Guo, Fei Meng, Honghao Liang, Xiuqin Fan, Jun Li, Xiaofei Gao
Journal: Cancer Research (2025)

Abstract Background: Gastrointestinal (GI) cancer accounts for over one-third of cancer-related deaths, yet early detection remains challenging. Micronuclei (MN) are cytoplasm-resident subcellular structures containing damaged chromosome segments, serving as a hallmark of genomic instability. Although elevated MN frequency in hematopoietic cells has been observed in patients with solid tumors, their role in disease progression remains elusive. We developed a technique (WO2021/228246 A1) that enables the purificationand characterization of MN DNA (MN-DNA) from erythrocytes in peripheral blood, unveiling the distinct genomic profiles in MN-DNA from GI cancer patients compared to healthy donors (HDs). Specific genomic regions within MN-DNA exhibited significant changes in read counts in GI cancer patients, which we termed as tumor-associated MN-DNA (taMN-DNA) features. This study evaluates the potential of taMN-DNA features for the early detection of GI cancer, including colorectal (CC), gastric (GC) and esophageal (EC) cancer, while exploring the impact of early-stage solid tumors on genomic instability in hematopoietic cells. Methods: Peripheral blood (1–2 mL) was collected from 1753 participants, including 987 HDs and 766 GI cancer patients (CC: 420, GC: 282, EC: 64). Participants were randomly divided into training, validation and independent test cohorts in a 7:2:1 ratio, maintaining similar cancer types, gender and age distribution. MN-DNA was extracted from erythrocytes, sequenced, and analyzed to identify taMN-DNA features. Machine learning algorithms were applied using these features for cancer detection. Results: In this study, over half the cancer cohort were diagnosed at early-stage: TNM stage 0-I accounted for 40.57%, stage II for 23.32%, stage III for 29.25% and stage IV for 6.87%. The pan-cancer detection model achieved an overall sensitivity of 88.2% across various cancer types, with a specificity of 95.4%. It accurately identified the tumor tissue of origin with an overall accuracy of 91.9% at 95.4% specificity, including sensitivities of 90.8% for CC, 91.7% for GC, and 100% for EC. Notably, for early-stage cancers (TNM stage 0-II), the model demonstrated exceptional performance, with sensitivities of 97.4% for CC, 94.7% for GC, and 100% for EC, at 95.4% specificity. Furthermore, our findings suggest that the significant increase of DNA damage in hematopoietic cells during tumor progression, contributing to the formation of taMN-DNA features. Conclusions: This pilot study demonstrates the potential of taMN-DNA features as a functional biomarker for early detection of GI cancer. The abundance of erythrocytes in peripheral blood provides a non-invasive, accessible source for MN-DNA enrichment. Our study also reveals a remote regulation of genomic instability in bone marrow hematopoietic cells by early-stage solid tumors, offering new insights into the development of effective GI cancer screening tests, precision diagnostics, and therapeutic strategies. Research sponsor: Timing Biotech. Citation Format: Haobo Sun, Xingyun Yao, Yuehua Han, Yurong Jiao, Xiangxing Kong, Chengcheng Liu, Qingqu Guo, Fei Meng, Honghao Liang, Xiuqin Fan, Jun Li, Xiaofei Gao. Micronuclei DNA enables early detection of gastrointestinal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A018.