EDEMA OF THE ARM after axillary lymph node dissection is reported to be the most common cause of lymphedema in the United States. 1 In general, across treatments and times since treatment, approximately one in four women will develop arm edema after treatment of breast cancer. 2 Despite improvements in surgical and radiotherapeutic techniques, the protection from lymphedematous complications is far from complete. 3, 4 The complications of axillary lymph node dissection, including lymphedema, have, even recently, been documented to occur commonly. 5 Significant confusion continues to surround the inherent predisposition to overt lymphatic insufficiency in the population of patients at risk for postmastectomy lymphedema. 6 The inability to reliably identify the precipitating factors that cause the lymphedema to appear or to worsen has served to foster fear and frustration in patients who are at risk by virtue of prior breast cancer therapy. It can be conjectured that individual, genetically endowed variation in the regenerative response to lymphatic injury (lymphangiogenesis) might confer relative risk for, or, conversely, protection from, the development of overt evidence of lymphatic insufficiency following breast cancer therapy. In this regard, it has been instructive to consider the recent, remarkable advances that have been forthcoming from investigations of the genetics of the primary lymphedemas. 7, 8, 9, 10, 11, 12 While many genes have been identified that play a role in lymphatic development13, 14 only three (FLT4, FOXC2, and SOX18) have been demonstrated to be associated with the development of primary lymphedema in affected individuals. Nevertheless, it remains likely that many more of these genetic pathways may give rise to primary lymphedema and, in parallel, contribute to predisposition for the risk of acquired lymphedema following surgicallyinduced lymphatic trauma.

In the current issue of Lymphatic Research and Biology, Finegold et al. 15 provide evidence that a newly identified mutation in the HGF/MET pathway is shared by patients with both primary and secondary lymphedema, lending further credence to this hypothesis. The identification of this genetic substrate creates an additional path to the stratification of lymphedema risk and also represents a novel approach to be exploited within lymphedema therapeutics. In a companion manuscript, the same group of investigators has completed an important investigation in which they have attempted to identify additional genes that cause familial lymphedema. 16 Four out of the biologically plausible candi-