gOS: A total molecular oncology interpretation framework applied to repaired FFPE and heme whole genome and clinical targeted assays

Cancer molecular diagnostics remain fragmented across multiple assays and disjointed software, leaving molecular pathologists to manually link QC, purity/ploidy, and variant classes before oncologists can act on recommendations. We address this with two complementary, genome-wide WGS assays-a repaired-FFPE solid tumor test and a blood-only heme test-that consolidate SNVs/indels, CNAs, SVs/fusions, LOH, and signatures into a single DNA workflow with panel-like performance. In parallel, we built the total genome Oncology System (gOS), which integrates WGS, targeted panels, methylation, and RNA fusions into a coherent browser with variant tiering, clinical validation, and discovery-oriented exploration. At NYU, standard care comprises NYU-PACT (607-gene DNA panel), Illumina MethylationEPIC v2.0 for solid tumors, and Oncomine (40-gene DNA) plus Myeloseqer for driver heme fusions. To pilot a WGS drop-in for DNA/RNA panels, we used enzymatic shearing (Watchmaker Genomics) and a FFPE damage-repair step that improves coverage uniformity and lowers artifacts. We analyzed 23 mixed solid tumors with paired normals and 22 hematologic malignancies; seven solid FFPE were also prepped without repair for comparison. gOS processed all 55 cases via an integrated Nextflow pipeline and provided interactive WGS vs SoC comparison. Unrepaired FFPE showed AT-rich dropout and megabase-scale coverage bias; repair restored uniformity and suppressed artifacts. In a BRCA1-mutant/LOH case, HRD was obscured in unrepaired WGS (HRDetect 0.004; B1+2 0.2) but recovered with repair (HRDetect 0.99; B1+2 0.78). Across 23 repaired FFPE solids, WGS vs NYU-PACT achieved 96% sensitivity (298/310 hotspots) and near-100% specificity (1/6,740 SoC-wild-type positions). Heme WGS showed 100% concordance with Myeloseqer fusions and Oncomine mutations. Together, the complementary WGS assays and gOS deliver panel-like accuracy with broader, pan-variant coverage and a single, coherent interpretive view, supporting WGS as a practical replacement for fragmented DNA/RNA panels-especially in historically challenging FFPE tissue-and enabling expanded clinical utility through unified multi-omic interpretation.