Abstract
Whole genome sequencing (WGS) has revolutionized clinical practice, ushering in a new era of personalized medicine. It has allowed researchers to uncover complex genomic perturbations beyond single nucleotide variants (SNV), to large copy number variations (CNV) and inter-chromosomal structural variant (SV) events implicated in cancer progression and therapeutic resistance. In our studies, we utilize WGS coupled with gene expression data of patient tumors to 1) comprehensively profile the genomic landscape of 752 newly diagnosed multiple myeloma (NDMM) patients and uncover the impact of rare genomic events on disease biology, and 2) identify driver genes implicated in therapeutic failure to CD19 targeted CAR-T therapy in 54 large B-cell lymphoma (LBCL) patients. We identified rare events in 94% of NDMM tumors, strongly enriched in comparison to precursor states and naïve B-cells. These events significantly altered expression of target genes 1) directly by impacting the gene body through copy number change and bisecting breaks, and 2) indirectly through superenhancer remodeling. In LBCL patients, rare SV events impacted immune modulating genes such as PDL1, CD58, and HLA. We further interrogated the LBLC genome to identify genes enriched in patients who progress on CD19 CAR-T therapy as candidate drivers of resistance. Utilizing our clinically informed computational driver discovery pipeline, we identified the essential B-cell development transcriptional repressor ETV6. Patients with loss of ETV6 exhibited significant reduction in CD19 and IRF4 expression, and upregulation of CDKN2A expression. These data show a multi-faceted approach of tumor-intrinsic mechanisms of escape to targeted immunotherapies by 1) modulating interactions with the immune environment to establish a tumor protective niche, and 2) modulating cell surface target antigen presentation via transcriptional networks to escape surveilling CAR-T cells. Together, these two studies illustrate the power of WGS to uncover genomic events underlying tumorigenic processes and therapeutic evasion.