P1220: exploring tp53 biology in diffuse large b-cell lymphoma: a genomic and transcriptomic meta-analysis

Topic: 20. Lymphoma Biology & Translational Research Background: Mutations in TP53 occur in over 20% of diffuse large B-cell lymphomas (DLBCL) and constitute an independent risk factor for poor outcome. However, only a subset of patients with TP53mut suffer adverse outcomes, while others exhibit robust responses to frontline immunochemotherapy similar to the wild-type population (TP53wt). The clinical and molecular features associated with TP53mut that mediate poor prognosis in DLBCL remain incompletely characterized. Aims: We aimed to characterize the genomic and transcriptomic correlates of pathogenicity of TP53mut DLBCL through assembly of a large composite cohort with comprehensive clinical and molecular profiling. Methods: Data was derived from 9 cohorts of patients with DLBCL treated with RCHOP/RCHOP-like regimens, including clinical and survival data, cell-of-origin (COO), histopathology (FISH, IHC), genomic variants (SNV/indels, CNA) via targeted or whole-exome sequencing, and bulk RNA-seq. To harmonize data across sources SNV/indels were re-annotated and RNA-seq was re-processed to yield gene-level counts. Genetic clusters were determined with the LymphGen algorithm. Mutations in TP53 were annotated using predicted phenotypes and pathogenicity from The TP53 Database and from phenotypic annotation of TP53 mutations (PHANTM). The primary outcome measures were overall and progression-free survival (OS/PFS). Results: We analyzed a composite cohort of 2,818 patients. RNA-seq was available for 1,026 of these cases. TP53 mutations were observed in 21% of cases, most being missense; >97% occurred in the DNA binding domain of the p53 protein with 36% at known hotspots codons. There were no significant differences in sex, age, IPI risk, or COO between TP53mut and TP53wt. TP53mut was associated with an inferior prognosis (2yPFS 63% vs. 76% TP53wt). Most mutations (>70%) were predicted to adversely impact WT p53 function, including nonfunctional transactivation activity and dominant negative effect on the WT allele. The majority were also predicted to be highly pathogenic by bioinformatic methods (AGVGD, SIFT, PolyPhen2, PHANTM, REVEL, BayesDel). However, none of these features correlated with outcome. The type and number of TP53 lesions (single SNV or CNA vs. multi-hit) did not mediate outcome, nor did CNA or SNV load. Alterations in TP53 were associated with similarly poor prognosis as translocations in MYC and BCL2 or BCL6 (HGBL-DH/TH), seen in 7% of cases. These abnormalities rarely co-occurred (1.5%), but featured exceedingly poor prognosis (HR 3.3, p=8x10-7). Among TP53mut cases, we identified CDKN2A copy loss with poor prognosis (HR 1.5, p=0.046), and BCL6 copy loss with protective effect (HR 0.34, p=0.03). Compared to TP53wt, TP53mut conferred a different prognosis within different genomic clusters. It was associated with inferior prognosis in the EZB cluster (HR 1.7, p=4x10-4), and approached significantly inferior prognosis in the MCD cluster (HR 1.7, p=0.06), but not within other clusters or unclassified samples. Evaluating RNA-seq data, higher expression of CAMKV was associated with a resistant phenotype among TP53mut cases (LFC 1.9, FDR 0.12). Summary/Conclusion: The pathogenicity of TP53 alterations in DLBCL appears dependent on genomic context, as represented by LymphGen subtypes. Co-occurring losses of CDKN2A and BCL6 may modulate TP53 pathogenicity across TP53mut cases. Expression of CAMKV may be a transcriptional correlate of poor outcome in TP53mut DLBCL. Concurrent TP53 mutations and translocations in MYC and BCL2 or BCL6 are rare and exhibit markedly poor prognosis.Keywords: DLBCL, TP53, RNA-seq, Genomics