Age at Diagnosis Drives Molecular Pathology and Prognosis in Diffuse Large B-Cell Lymphoma
Results/Description/Main Outcome Measures: Of the 180 DLBCL driver genes analyzed, 16 were found to mutate at a different frequency by age of diagnosis. These included both well-known oncogenes, namely BCL10, BCL2, CD79B, MYC, MYD88, PIM1, and tumor-suppressor genes, namely FAS and SIN3A. Mutations in DDX3X, MYC, and SIN3A were much more prevalent in younger patients ≤ 18 years of age. In contrast, BCL2, PIM1, and MYD88 mutations were more frequent in patients aged ≥ 40 years. Of the 51 CNA regions analyzed, none were statistically significant in association with age at diagnosis. In survival analysis, older patients exhibited poorer survival, with patients aged ≥ 70 having the highest mortality. In multivariable Cox regression models, age at diagnosis was one of the most significant predictors of survival (HR= 1.04, p-value = < 0.001) in DLBCL patients, second only to initial treatment response. The other significant clinical variables were high IPI scores and cell of origin subtypes. In analysis of the age-associated driver genes, KLHL14, which was more frequently mutated in older patients, was prognostic for overall survival. Patients with KLHL14 mutations had the worst survival outcomes, which remained significant after adjusting for age (HR = 1.68, P = 0.012).
Conclusions: In a large DLBCL patient population pooled from multiple studies, we identified somatic mutational differences in multiple known driver genes based on the age of diagnosis, which signifies the impact of age in defining DLBCL molecular pathology.
