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September 10, 2025

Abstract P06: Cellular-resolution Multiplexed-CNV FISH Captures Spatial Copy Number Heterogeneity and Clonal Architecture of Colorectal Cancer

Key Points

Multiplexed-CNV FISH identified subclonal CNVs in colorectal cancer tumors, indicating significant intra-tumor heterogeneity.
Analysis showed that this approach can reveal CNVs previously undetected by traditional methods, enhancing understanding of tumor biology.
The study emphasizes that spatial resolution of CNVs can inform prognosis and therapeutic strategies in cancer treatment.
This novel assay provides crucial spatial information, enhancing sensitivity to detect rare CNVs that are associated with therapy resistance.

Abstract

Abstract In tumors, clonal populations of malignant cells evolve a diverse repertoire of copy number variants (CNVs), often resulting in profound intra-tumor heterogeneity (ITH). ITH is associated with poor prognosis, cancer progression, increased risk of therapy resistance, metastasis and relapse. Traditionally, researchers have studied clonal heterogeneity and tumor evolution using bulk-tissue assays, however, these techniques provide little or no spatial information and have low sensitivity for focal/low copy-number CNVs, particularly when they are subclonal or rare. DNA FISH is the gold standard for detecting CNVs at cellular resolution, but it is limited to one gene per tissue section. To overcome the above limitations, we developed multiplexed-CNV FISH, a spatial omics assay that detects gain and loss of DNA loci at single-gene (∼10kb) and single-cell resolution in human tissues. Remarkably, CNV-FISH analysis of CRC tumor sections identified small and subclonal CNVs not detected by existing methods with resolution of CNV spanning whole chromosome arms. Our results indicate that CNV-FISH can reveal unexpected and previously undetected CN heterogeneity within tumors, which could potentially underlie treatment resistance and eventual metastasis of cancer cells. Citation Format: Mei Suen KONG, Hui Ting Grace YEO, Jiamin TOH, Lin Li, Jonathan Shaozhong Aow, Joanito Irwan IGNASIUS, Jeeranan BOONRUANGKAN, Jen Yi WONG, Nirmala ARUL RAYAN, Lavanya MUTHUKRISHNAN, Dominique Camat MACALINAO, Wei Qiang LEOW, Kiat Hon LIM, Bee Huat Iain TAN, Kok Hao CHEN, Shyam PRABHAKAR. Cellular-resolution Multiplexed-CNV FISH Captures Spatial Copy Number Heterogeneity and Clonal Architecture of Colorectal Cancer abstract. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85 (15Suppl): Abstract nr P06.

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