4. The clinical implementation of technologies utilized for macrogenomic event detection in solid tumors

Macrogenomic events (MGE) are large genomic alterations that together contribute to complex, genome-wide mutational or structural signatures. These include aneuploidy, structural variants, changes in copy number, regions of copy neutral loss of heterozygosity, mutation signatures, homologous recombination deficiency, and microsatellite instability. Although there are several existing and emerging technologies for the detection of MGE, limited work has been done to systematically assess their utility within solid tumor testing. Thus, we formed the CGC MGE Working Group to summarize the strengths and limitations of various technologies for solid tumor MGE detection at multiple resolutions, to evaluate those in current clinical use, and to provide an assessment of feasibility of clinical implementation for newer assays. Technologies under consideration are whole genome sequencing (short- and long-read), optical genome mapping, microarray (chromosomal and methylation), karyotyping, targeted sequencing technologies (i.e., Sanger, ddPCR, qPCR, targeted sequencing panels), FISH, and Hi-C. Through a review of the literature and local laboratory protocols, we defined 15 data capture criteria by which each of these tests are being assessed, ranging from sample requirements (e.g., fresh-frozen versus formalin-fixed paraffin embedded tissue), to breakpoint precision and the types of MGE detected. Although this effort is ongoing, preliminary findings suggest that while a 'perfect' test menu may not exist, common indications for testing and existing laboratory infrastructure may help determine test prioritization. In addition, our group identified several barriers to solid tumor testing (e.g., percent tumor requirements, precision of breakpoints required, RNA vs DNA-based testing) to consider when assessing overall clinical utility.