Agricultural pesticide exposure and the molecular connection to lymphomagenesis

Abstract

The t(14;18) translocation constitutes the initiating event of a causative cascade leading to follicular lymphoma (FL). t(14;18) translocations are present in blood from healthy individuals, but there is a trend of increased prevalence in farmers exposed to pesticides, a group recently associated with higher risk of t(14;18) + non-Hodgkin's lymphoma development. A direct connection between agricultural pesticide use, t(14;18) in blood, and malignant progression, however, has not yet been demonstrated. We followed t(14;18) clonal evolution over 9 yr in a cohort of farmers exposed to pesticides. We show that exposed individuals bear particularly high t(14;18) frequencies in blood because of a dramatic clonal expansion of activated t(14;18) + B cells. We further demonstrate that such t(14;18) + clones recapitulate the hallmark features of developmentally blocked FL cells, with some displaying aberrant activation-induced cytidine deaminase activity linked to malignant progression. Collectively, our data establish that expanded t(14;18) + clones constitute bona fide precursors at various stages of FL development, and provide a molecular connection between agricultural pesticide exposure, t(14;18) frequency in blood, and clonal progression.

The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications

“…It is interesting that some persons may carry several different clones with the t(14;18), although usually one of them largely predominates over the others, suggesting that these clones may arise in a context that facilitates the translocation and subsequent expansion. 78 Interestingly, some patients with hepatitis C virus have clones carrying the t(14;18) that may disappear after antiviral therapy. 79 Early involvement of lymph nodes by cells carrying the t(11;14) translocation and overexpressing cyclin D1 have been reported in several individual cases.…”

Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins

“…Although the translocation disrupts one Ig allele, expression of surface Ig (sIg) is retained, suggesting a role for sIg in tumor cell behavior. Interestingly, normal subjects can have B cells with the characteristic translocation (2), and cells with features of "precursor" cells have been detected, especially after exposure to environmental toxins (3). These observations suggest a multistep route to lymphomagenesis.…”

Short Communication Assessment of BCL2/J(H) translocation in healthy individuals exposed to low-level radiation of 137CsCl in Goiânia, Goiás, Brazil

“…Several investigators have postulated that the prevalence and/or frequency of t(14;18)-positive cells in healthy individuals may be related to the environmental exposure to carcinogens (Fuscoe et al, 1996), pesticides (Agopian et al, 2009) and excessive smoking (Bell et al, 1995). In our study, the unexposed individual that carried the BCL2/J(H) MBR rearrangement stated that they smoke more than 30 cigarettes/day, which could be responsible for the presence of this translocation in the peripheral blood.…”

“…Together with the recent findings indicating that pesticide exposure is specifically associated with a higher risk of t(14;18)+ NHL development, the first direct connection between t(14;18) frequency in blood and malignant progression data was provided (Agopian et al, 2009).…”

“…The t(14;18)+ clones, which are particularly prominent in farmers exposed to pesticides, constitute bona fide FL precursors occurring at various stages of tumor progression (Agopian et al, 2009). Together with the recent findings indicating that pesticide exposure is specifically associated with a higher risk of t(14;18)+ NHL development, the first direct connection between t(14;18) frequency in blood and malignant progression data was provided (Agopian et al, 2009).…”