Abstract
There is an inherent unresolved paradox that is implicit in what is known about breast cancer-associated (and other forms of cancer-associated) lymphedema: it is clear that cancer- and cancer treatment-related variables do not explain the observed cases of lymphedema.1,2 Accordingly, by inference, the majority of individuals who sustain substantial iatrogenic trauma to the lymphatic circulatory structures nevertheless remain functionally normal. What, then, explains the intolerance of the smaller numbers of affected individuals to a comparable insult?
In the search for biologically relevant risk factors to explain this disparity,3,4 it is inevitable that genetic factors might be suspected to play a role. 3 It has been hypothesized that individual cases of acquired lymphedema are conditioned by mutations in genes that might cause primary lymphedema, thereby influencing development or function, and that, furthermore, individual genetic variability in the lymphatic injury response has the capacity to afford protection from, or, conversely, to contribute to relative risk for the appearance of lymphedema after breast cancer therapy.5,6
In the current issue of Lymphatic Research and Biology, Visser and colleagues have performed a systematic review of the literature surrounding the genetic predisposition to breast cancer-related lymphedema. Having assembled 459 records for review, the authors are able to conclude that mutations in 18 specific genes may bear a significant relationship to this problem: HGF, MET, GJC2, IL1-a, IL4, IL6, IL10, IL13, VEGF-C, NFKB2, LCP-2, NRP-2, SYK, VCAM1, FOXC2, VEGFR2, VEGFR3, and RORC.
The findings serve to solidify the conceptual framework in which there is likely to exist a set of constitutional predispositions to the acquisition of secondary lymphedema in the context of cancer. The identification of putative causal gene variations opens the door to future mechanisms of risk stratification and, potentially, therapeutic intervention.