Connexin 47 Mutations Increase Risk for Secondary Lymphedema Following Breast Cancer Treatment.

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Connexin 47 Mutations Increase Risk for Secondary Lymphedema Following
Breast Cancer Treatment.

Mar 2012

Finegold DN, Baty CJ, Knickelbein KZ, Perschke S, Noon SE, Campbell D,
Karlsson JM, Huang D, Kimak MA, Lawrence EC, Feingold E, Meriney SD,
Brufsky AM, Ferrell RE.

Source

Authors' Affiliations: Departments of Pediatrics, Cell Biology &
Physiology, and Medicine, University of Pittsburgh School of Medicine;
Department of Human Genetics, University of Pittsburgh Graduate School
of Public Health; and Department of Neuroscience, University of
Pittsburgh, Pittsburgh, Pennsylvania.

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. Clin Cancer Res; 18(8); 1-9.

http://clincancerres.aacrjournals.org/content/early/2012/03/28/1078-0432.CCR-11-2303.long