The New York Genome Center CLIA laboratory has been providing New York State approved molecular diagnostic whole genome and whole transcriptome sequencing (WGTS) since October 2018. Indications for testing are cancers (solid tumors or hematological malignancies) where a mutational profile from multiple genes would be informative for disease stratification, prognosis, treatment options or alternative treatments or clinical trials. Germline analysis for ACMG designated cancer predisposition variants also is performed for consented patients. To date we have provided clinical next generation sequencing (NGS) genomic profile reports for 139 oncological cases from 31 different cancer types including GBM (41 cases), Pancreas (17), CRC (15), Lung (8) and others. The clinical interpretation of WGTS data of molecular tumor markers from NGS encompasses automated variant calling tools with human interpretation. The final mostly manual review of data is intensive, involving highly trained scientists engaged in substantial literature review and interpretation for each case alongside pathologists, molecular geneticists, and treating oncologists. We first present the technical challenges of validating a WGTS oncological diagnostic assay for appropriate clinical grade accuracy and sensitivity acceptable for patient care. We then present case studies illustrating the varying degree of tumor profiling and analysis outlining the current clinical utility and challenges of precision oncology medicine and therapeutic associations from sequencing of cancer patient tumors. We conclude with a previously unreported summary of therapeutic actionability derived from WGTS for all cancer cases sequenced at NYGC. We show that 28% percent of all samples in our cohort contain a tier 1 variant but additional second line therapies (or off-label drugs) can be considered for over 75% of WGTS sequenced cancer patients. Our case studies being in both solid tumor and hematological cancers illustrate the variability in sequencing data and the individual patient specificities in each interpretation of clinical findings. We show how NGS sequencing can offer multiple treatment outcomes when combining all genomic aberrations (copy number, structural variants and SNV/indels) found in a subtype of prostate cancer. We present hematological malignancies that show how certain DNA mutations point to RNA aberrations leading to therapeutic associations. In pancreatic cancer we present how a unique alteration in BRAF can lead to second line treatment with clinical benefit. We therefore demonstrate that more complete NGS assays those examining both the whole genome and transcriptome have added value in precision oncology practice enabling to find second-line treatment options or alternative therapeutic options when primary approaches fail or are not identified following a targeted sequencing approach.

Citation Format: Kazimierz O. Wrzeszczynski, Heather Geiger, Sowmya T. Srinivasa, Marilena Melas, Valisha Shah, Vanessa Felice, Luisa Suarez, Endre Hegedus, Shruti Phadke, Saurav Guha, Dina Manaa, Dino Robinson, Lena Fielding, Vaidehi Jobanputra. Clinical interpretation and utility of whole genome and whole transcriptome sequencing for precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 757.