Secondary lymphedema is a frequent complication of breast cancer associated with surgery, chemotherapy, or radiation following breast cancer treatment. The potential contribution of genetic susceptibility to risk of developing secondary lymphedema following surgical trauma, radiation, and other tissue insults has not been studied.

To determine if women with breast cancer and secondary lymphedema had mutations in candidate lymphedema genes, we undertook a case - control study of 188 women diagnosed with breast cancer recruited from the University of Pittsburgh Breast Cancer Program (http://www.upmccancercenter.com/breast/index.cfm) between 2000–2010.

Candidate lymphedema genes, GJC2 (encoding connexin 47 [Cx47]), FOXC2, HGF, MET, and FLT4 (encoding VEGFR3), were sequenced for mutation. Bioinformatics analysis and in vitro functional assays were used to confirm significance of novel mutations.

Cx47 mutations were identified in individuals having secondary lymphedema following breast cancer treatment but not in breast cancer controls or normal women without breast cancer. These novel mutations are dysfunctional as assessed through in vitro assays and bioinformatics analysis, and provide evidence that altered gap junction function leads to lymphedema.

Our findings challenge the view that secondary lymphedema is solely due to mechanical trauma and support the hypothesis that genetic susceptibility is an important risk factor for secondary lymphedema. A priori recognition of genetic risk 1) raises the potential for early detection and intervention for a high risk group, and 2) allows the possibility of altering surgical approach and/or chemo- and radiation therapy, or direct medical treatment of secondary lymphedema with novel connexin modifying drugs.

Secondary lymphedema is a frequent and serious chronic complication of breast cancer treatment. Our finding of four independent mutations in Cx47, including one shared mutation previously reported in primary lymphedema, not only supports these mutations as a genetic risk to the development of secondary lymphedema but raises the likelihood that other genes may contribute to such a genetic risk to secondary lymphedema as well.