Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age

Abstract

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.

The RNA helicase DDX3 and its role in c-MYC driven germinal center-derived B-cell lymphoma

“…For instance, the reasons for the differences in clinical outcome between pediatric and adult BL patients after initial therapy and poor survival rates at relapse on both pediatric and adult BL remain poorly understood. A recent clinical study comparing adult and pediatric cohorts showed that mutations in the BCL2 and YY1AP1 genes are characteristic of adult patients, while mutations in ID3, DDX3X, ARID1A and SMARCA4 are more frequent in pediatric patients (123). The DDX3X gene is one of the most frequently mutated in c-MYC translocated pediatric BL after TP53, ID3 and TCF3 in this study (122)(123)(124)(125), but also in others.…”

“…A recent clinical study comparing adult and pediatric cohorts showed that mutations in the BCL2 and YY1AP1 genes are characteristic of adult patients, while mutations in ID3, DDX3X, ARID1A and SMARCA4 are more frequent in pediatric patients (123). The DDX3X gene is one of the most frequently mutated in c-MYC translocated pediatric BL after TP53, ID3 and TCF3 in this study (122)(123)(124)(125), but also in others. While the role and mechanistic consequences of loss-of-function (LOF) mutations in TP53, ID3 and TCF3 have been clarified to a large part, it remains unclear why mutation in the DDX3X gene are selected in BL and the question remains whether this protein is indeed a tumor suppressor or not, or whether it exerts both roles in a context-dependent manner (126).…”

“…DDX3X is also mutated in tumors from the IC-BL subgroup but almost never altered in the quiet TP53 BL tumors (113). Another study highlights that DDX3X mutations are more frequent in pediatric tumors versus adult tumors (123).…”

“…These missense mutations detected in BL and DLBCL are characterized as LOF mutations. In addition, a relevant frequency of nonsense mutations and rarer frameshift mutations have been detected in BL and DLBCL (48,123). Although not clearly demonstrated, they are very likely causing a LOF, particularly when these mutations occur early in the amino acid sequence.…”

Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

“…Intriguingly, recent studies indicate age-dependent mutation patterns for ARID1A. In Burkitt lymphoma, in contrast to TP53 and CCND3, mutation frequencies of which are not age related, samples from pediatric patients showed a higher frequency of mutations in ARID1A than those from adults [ 32 ]. Similarly, comparison of younger to older women with luminal A tumors revealed significant differences in somatic alterations in three prevalent driver genes.…”