100PComprehensive pan-cancer analysis of somatic mutations in drug transporters to reveal acquired and intrinsic drug resistance in 3149 metastatic cancer patients

Abstract Background Systemic anti-cancer treatment is hampered by drug resistance (DR). However, little is known about the pharmacokinetic consequences of genetic changes in tumor cells. We hypothesize that somatic point mutations, small indels, copy number variations (sCNV) and/or structural variations in genes encoding drug transporters are drivers of DR mechanisms in tumor cells. We therefore performed an explorative analysis to quantify somatic aberrations that could reflect DR mechanisms and, in parallel, identify their stressors. Methods We interrogated whole-genome sequencing (WGS) data from a Dutch pan-cancer cohort of metastatic cancer patients (N = 3149 at ∼118x and matched peripheral blood at∼38x read depth), of which more than half had failed previous systemic treatment. Somatic aberrations (germline filtered) were analyzed in drug transporters (N = 51), present on the Drug Metabolizing Enzymes and Transporters (DMET™ plus) panel (v.32). Enrichment of somatic DR variants was estimated by assessing nonsynonymous/synonymous mutation ratio deviations (dN/dS) and sCNV were detected with GISTIC2. Results In total, 5137 somatic variants (2645 in treatment-naive and 2484 in pretreated patients) in drug transporter genes were observed in 1651 patients (52.4%) of whom 55.1% were systemically pretreated. Three genes (ABCB4, ABCC5, SLCO1B1) showed dN/dS enrichment (p = 0.0142 - 0.0364). sCNVs (N = 7656; 5849 deep gene-level gains and 1807 deletions) were observed in 1906 patients (60.5%). Interestingly, we identified 20 somatic DR-related variants in 12 patients (58.3% pretreated), not present in the matching germline samples, that were identical to SNP variants on DMET™ plus. Conclusions In the largest metastatic pan-cancer WGS cohort worldwide, we characterized the pharmacogenomic drug transporter landscape in tumor cells. Potentially, the incidence of somatic variants in pharmacogenes accounts for acquired DR in pretreated patients and/or intrinsic DR. We will extend our study with analyses of prior treatments and germline variations, in order to assess the clinical consequences of the variations and improve clinical decision-making. Clinical trial identification NCT01855477. Legal entity responsible for the study The authors. Funding This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study. Di