Commercialization of a highly-sensitive, scalable and low-input compatible kit-based solution fordiscovery of translocations from FFPE tumor biopsiesArima Genomics/Despite decades of research, cancer takes the lives of nearly 600,000 people every year in the US. The cancerresearch community has made key advancements towards improving the precision of cancer diagnosis andrecently substantial efforts have been put forth into the genetic profiling of tumors. Specifically, efforts havebeen focused on developing methods to profile genetic alterations such as translocations that are prognostic incancer. Knowledge of an individual's translocation profile can be used to uncover the mechanistic basis ofcancer, accelerating cancer research towards development of new precision therapies. Current standard,including NGS, are limited in their ability to characterize translocations. This is because for NGS (WGS or genepanel seq.) to profile translocations, breakpoint-spanning reads are needed and NGS does not enrich for suchreads. FISH enriches for breakpoint info by capturing spatial conformation of the genome within cells and but ithas limited utility due to its low-throughput nature and its requirement of apriori info of the translocationpartners. Spectral Karyotyping (SKY) needs living cells and cannot be performed on FFPE samples, which is amajor sample type for cancer samples. Altogether, a method that is (a) high-throughput along the lines of NGS;(b) enriches translocations along the lines of FISH; (c) not requiring apriori indo of translocating partners toenable promiscuous translocation detection; and (d) compatible with FFPE samples - would result in a highlysensitive and scalable solution for translocation discovery. We satisfy the unmet need via a leapfrog solution.We use HiC to capture conformation on the lines of FISH and couple it with NGS (HiC-Seq) to detecttranslocations at high sensitivity, high precision, high PPV and low FP. Our team has unmatchable expertise inthe science of HiC and its commercialization. Specifically, we commercialized Arima-HiC kits in 2018 forstudying conformation in the context of Epigenetics research and generated $1.2M in revenue in the 1st year ofcommercialization with 200+ customers, all from 1 sales executive. However, these kits are not compatible toFFPE, is manual, labor- and time-intensive and cannot handle batches of >10-20 samples at a time - to enablebroad adoption toward cancer research, we have shown the development a boxed kit, the "T-Seq Kit", basedon enhanced HiC optimized for performance, speed, ease of use that is compatible to low-input FFPE, freshand frozen samples. We validate the technology development from sample to insight in a patient-derived FFPEGIST biopsy and demonstrate that we can sensitively profile translocations even from low tumor purity samples(or low MAF). As part of this direct-2-phase II program, we propose to further develop our technology into arobust kit-based "T-Seq Solution", comprising same day 8hr sample to sequencing, full 96-plate automated andversatile HiC protocols (to all sample types) that is compatible with existing NGS (ILMN) workflow for customerconvenience and bundled with cloud-based push-button bioinformatics equipped with tools for sensitivegenome-wide and targeted translocation discovery. We also propose rigorous and essential productdevelopment experiments, to ensure commercialization of a robust, premium-performance kit-based product.Upon successful completion of the technical and commercial developments in Aims 1 & 2, we propose tobenchmark and validate the sample-to-insight T-Seq Solution through collaboration and prototype (beta) kitand bioinformatics evaluations with key opinion leaders (KOLs) across customer segments of large sequencingcenters, academic labs, and pharma.
Public Health Relevance Statement: Commercialization of a highly-sensitive, scalable and low-input compatible kit-based solution for
discovery of translocations from FFPE tumor biopsies
Arima Genomics
Project Narrative
Translocations are hallmarks of Cancer. Current methods to profile translocations suffer from deficiencies of
low sensitivity (WGS, Bianano), high costs (WGS, Bionano, PacBio), incompatibility to FFPE samples (SKY,
Bionano, PacBio, 10X), or require direct breakpoint information (FISH and gene-panels). We have a leapfrog
solution from combining FISH-type chromatin conformation capture with NGS - referred to as HiC assay with
NGS sequencing (HiC-Seq). We transform the time-, labor- intensive, FFPE-incompatible and manual HiC
procedure into a rapid "same day" sample to sequencing, fully automated boxed kit that handles all sample
types including FFPE, fresh and frozen, and even fine needle aspirates toward high sensitivity and low cost
translocation profiling. We combine the kit with push-button cloud-based informatics to enable the sample to
insight T-Seq solution. Via being compatible to existing NGS workflows, our T-Seq solution offers maximum
convenience, economy and sensitivity for genome-wide and targeted translocation discovery.
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