Comprehensive genomic analysis of MCL patients enrolled in the OAsIs trial. (A) Schematic representation of the experimental design to identify therapeutic resistance in MCL. Patients with MCL were included in the OAsIs clinical trial (obinutuzumab [anti-CD20], ibrutinib [BTK-i], and venetoclax [BCL2-i]). Blood or BM samples were collected at inclusion (incl.) or relapse (Rel) and targeted DNA-seq of 49 selected genes plus the 9p21 region was performed. (B-D) Landscape of recurrent mutations (SNV/indel) and copy number variations (gain/deletion) in the patients enrolled in OAsIs and detected by deep DNA-seq at incl. (n = 12) (B), Rel (n = 5) (C), or in longitudinal samples (D). Each column represents an individual sample/patient. Only genes with at least 2 anomalies detected in the cohort and with a variant frequency >5% are represented. Statistical significance was determined by a 2-tailed Fisher exact test. (E) The fish plot shows the clonal evolution pattern of patient 34 based on the variant frequency (VaF) measured at diagnosis (Diag), incl., and Rel (supplemental Table 2) and normalized to the TP53^Y220C VaF. (F) Schematic representation of CARD11 domains and the mutations found in the Refract-Lyma cohort (n = 62 sequenced for CARD11), including patients enrolled in the OAsIs trial. CR, complete response; PD, progression disease; PR, partial response; SNV, single nucleotide variant; SD, stable disease.