title: Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Finegold
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Baty
authors.forename: Kelly Z
authors.initials: KZ
authors.lastname: Knickelbein
authors.forename: Shelley
authors.initials: S
authors.lastname: Perschke
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Noon
authors.forename: Diana
authors.initials: D
authors.lastname: Campbell
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Karlsson
authors.forename: Diana
authors.initials: D
authors.lastname: Huang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kimak
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Lawrence
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Meriney
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brufsky
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D017630:Connexins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D008209:Lymphedema / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D017630:Connexins; C427305:connexin 47