Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation

Abstract

Incidence rates of follicular lymphoma (FL) inexplicably vary markedly between Western and Asian countries. A hallmark of FL is thebcl-2 translocation, characterized by 1 of 2 common breakpoints known as major breakpoint region (MBR) and minor cluster region (mcr). We analyzed previously published data to compare rates ofbcl-2 translocation in FL across geographic regions. Available data from the literature suggest that the incidence ofbcl-2 in healthy persons in the absence of FL may be as high as 50% in Western and Asian populations. However, in FL our results show that the frequency of bcl-2 positivity was significantly higher for US than for Asian populations (P < .0001). This pattern persisted for MBR and mcr subgroups. We conclude that a significant gradient exists in thebcl-2 frequency between these FL populations. We therefore suggest that the relatively low incidence of FL in Asian populations is caused not by a lower frequency of bcl-2 rearrangements in healthy populations but by distinct molecular pathways developing in different geographic regions that nonetheless culminate in FL, which is morphologically similar but molecularly distinct. Studies demonstrating differences in clinical characteristics according to the presence or absence of bcl-2 rearrangements support this concept. Thus we hypothesize that FL may in fact be a heterogeneous malignancy encompassing entities with distinct molecular pathogenesis and potentially distinct clinical manifestations. If these findings were confirmed in prospective studies, it would imply that different etiologic or genetic factors might influence the development of FL across separate regions.