Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

To determine whether 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 and 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.

RESULTS:

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.

CONCLUSIONS:

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 (i) raises the potential for early detection and intervention for a high-risk group and (ii) 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.

• Authors: David N Finegold, Catherine J Baty, Kelly Z Knickelbein, Shelley Perschke, Sarah E Noon, Diana Campbell, Jenny M Karlsson, Diana Huang, Mark A Kimak, Elizabeth C Lawrence, Eleanor Feingold, Stephen D Meriney, Adam M Brufsky, Robert E Ferrell
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 8 Pg. 2382-90 (Apr 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22351697 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Connexins
• connexin 47

Topics

• Adult
• Aged
• Aged, 80 and over
• Base Sequence
• Breast Neoplasms (drug therapy, genetics, pathology, surgery)
• Case-Control Studies
• Cell Line, Tumor
• Connexins (genetics)
• Female
• Genetic Predisposition to Disease
• HeLa Cells
• Humans
• Lymphedema (drug therapy, genetics)
• Middle Aged
• Risk Factors
• Sequence Analysis, DNA
• Young Adult