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Abstract Despite numerous technological advances, including the widespread adoption of next-generation sequencing, many clinically relevant cancer driver mutations go undetected. The reason for this gap in understanding is two-fold: 1) Structural variants (SVs) are particularly challenging to detect using shotgun or long read-based approaches, particularly in heterogenous samples; and 2) It is increasingly accepted that epigenetic dysregulation may be a driver of disease state through mechanisms such as enhancer hijacking or changes to 3D genome organization. To address this gap in understanding, we developed VariLink: a dual-purpose proximity ligation library protocol that yields high-quality, high-resolution, unbiased Hi-C libraries capable of sensitive detection of structural variants and chromatin topological features from a single data set. Importantly, the VariLink protocol can be performed in under 8 hours—less than half of the time required for conventional Hi-C protocols. In the current study, we demonstrate the performance of VariLink for the detection of variants within the primary sequence (such as SVs, SNVs/Indels, and CNVs) in addition to high-resolution reporting of 3D chromatin conformation. We performed benchmarking analyses for both genetic variant detection and chromatin topology in two well-characterized lymphoblast cell lines (GM12878 and K562). We demonstrate the capability of VariLink data to detect interchromosomal translocations with 10-fold higher sensitivity over shotgun. Furthermore, using hybridization capture to detect the BCR-ABL1 fusion in K562 cells, we show that fewer than 100k read pairs is sufficient to detect this fusion with high confidence in VariLink libraries. We find that the shotgun-like, uniform coverage of VariLink data also enables detection of SNVs/Indels with improved sensitivity and precision over conventional Hi-C methods. Importantly, we demonstrate that VariLink libraries maintain topological features consistent with biologically relevant topologically-associated domains (TADs) and chromatin loops, providing insight into novel epigenetic cancer drivers. VariLink enables higher-resolution assessments of chromatin topology over conventional multi-RE-based Hi-C approaches, as demonstrated by 50% more TADs and loops called at 5-kb resolution. Taken together, our data demonstrate that VariLink is a next-generation Hi-C method that enables sensitive detection of clinically relevant structural variants and high-resolution chromatin topology in a single, rapid workflow. Citation Format: Jonathan Torchia, Mital Bhakta, Cory Padilla, Meredith L. Carpenter, Philip Uren, Lisa Munding. VariLink: A rapid, high-resolution proximity ligation method for the detection of structural variants and chromatin topology features in cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB287.
Torchia et al. (Fri,) studied this question.