Abstract 716: Discovery of biomarkers of brain metastasis using Genomic Proximity Mapping (GPM) on formalin-fixed paraffin-embedded head and neck squamous cell carcinomas
Authors: Emily Reister, Maika Malig, Mary Wood, Alexander Muratov, Ivan Liachko, Stephen Eacker, Ida Deichaite
Journal: Cancer Research (2025)

Abstract Introduction: Head and neck squamous cell carcinoma (HNSCC) encompass a heterogenous classification of solid tumors that account for ∼5% of the total new cancer cases globally. HNSCC presents as metastatic disease at estimated rates of 4-25%, most commonly in bone, liver and lung. Brain metastasis (BM) is uncommon and is particularly deadly. There is a need to better understand biomarkers that may presage brain metastasis in hopes of identifying those patients requiring aggressive treatment to head-off metastatic disease. Furthermore, identification of common biomarkers may elucidate therapeutic strategies to treat this disease. To compliment ongoing targeted sequencing efforts, we have applied high-resolution cytogenomic analysis using the genomic proximity mapping (GPM) platform, CytoTerra, to investigate chromosomal abnormalities associated with BM HNSCC. Methods: GPM uses proximity ligation and short-read sequencing to detect alterations in genomic structure. This technology is compatible with formalin-fixed paraffin-embedded tissue samples because it uses formalin fixation to capture genomic proximity information. 15 µm molecular curls were used as inputs for library preparation from 2 primary tumors of BM HNSCC and 3 samples of non-BM HNSCC. Chromosomal abnormalities were detected using the cloud-based CytoTerra analytic platform which utilizes a suite of AI-based and bioinformatic tools. Results: GPM libraries with sufficient QC statistics were generated from all five samples. Evaluation of HNSCC genomes revealed a wide array of structural alterations commonly observed in cancer, including balanced and unbalanced translocations, inversions, chromothripsis, deletions, duplications, and copy-neutral loss of heterozygosity. Notably structural rearrangements involving the JAK1 and EGFR loci were observed in BM HNSCC samples. In addition we identified a novel NRG1::FAM110B fusion in one case of BM HNSCC. None of these rearrangement involved the disruption of the coding sequence of the gene and therefore would escape detection through standard panel sequencing. Non-BM HNSCC showed similar classes of chromosomal abnormalities and included a deletion of KDM6A. Variants identified in serial sampling of neighboring HNSCC lesions in non-BM HNSCC demonstrated a high degree of overlap, demonstrating reproducibility. Uniquely identified variants allow inferences on tumor evolution between the two lesions. Conclusion: GPM with the CytoTerra next generation cytogenomic platform successfully identified chromosome abnormalities in FFPE HNSCC samples. BM HNSCC samples demonstrated structural alterations in known and targetable oncogenes suggesting that CytoTerra can be a useful tool for novel biomarker discovery in solid tumors, including HNSCC. Citation Format: Emily Reister, Maika Malig, Mary Wood, Alexander Muratov, Ivan Liachko, Stephen Eacker, Ida Deichaite. Discovery of biomarkers of brain metastasis using Genomic Proximity Mapping (GPM) on formalin-fixed paraffin-embedded head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 716.