Identification of primary mediastinal B-cell lymphomas with higher clonal dominance and poorer outcome

In this study, we deciphered the BCR and TCR repertoires of a large multicenter cohort of primary mediastinal B-cell lymphoma (PMBL) patients using a 5'RACE assay on routine FFPE samples. Our results provide a representative description of the Ig repertoires of the tumoral compartment in PMBL. We confirmed the existence of a high level of somatic mutations in the V(D)J segments and also observed very frequent isotype switching. In addition, our 5'RACE analyses also revealed that 15% of PMBL patients carried fusion transcripts involving Ig loci, involving genes targeted by somatic mutations in PMBL (CIITA, SOCS, IgVH, and IgVL). We then identified a subgroup of 12/75 patients (16%) with a worse prognosis (progression-free survival (PFS): HR [95% CI]=17 [3.2-88]; overall survival (OS): HR=21 [2.1-210]) associated with the highest clonal dominance status (HCD), defined by the dominant clonotype representing >81.1% and >78.6% of all CDR3 sequences for IgVH and IgVL, respectively. Compared to other patients, this subgroup had similar clinical characteristics but a greater median allele frequency for all somatic variants, decreased BCR diversity, and greater expression of PDL1/PDL2 and MS4A1 genes, suggesting a greater tumoral infiltration. According to a multivariate model integrating AID expression and BCR diversity, only HCD status was associated with outcome (PFS: HR=14.6 [2.46-86.8]; OS: HR=11.4 [1-128.8]). We confirmed this poorer prognosis in an independent validation cohort, in which 6/37 (16%) patients exhibited HCD (PFS: HR=12 [3-46]; OS: HR=17 [1.8-170]).