Joe Visser,BSc,1 Michel van Geel, PhD,2,3 Anouk J.M. Cornelissen, MD,1 Rene´R.W.J.vanderHulst,MD,PhD,1 and Shan Shan Qiu, MD, PhD1. Lymphatic Research Biology 2018

Main findings

• Research on possible risk factors for the development of lymphedema show largely inconsistent relationships, although evidence is mounting for treatment-, disease- and patient-related factors.
• It is becoming increasingly apparent that the binary categorization of lymphedema into the primary and secondary variant might be inaccurate, as substantial overlap between primary and secondary populations can exist. It can be hypothesized that some cases of secondary lymphedema are conditioned by mutations in genes that cause primary lymphedema, thus influencing development or function; and that individual genetic variation in the response to lymphatic injury might contribute to a relative risk for or protection from the development of lymphedema following breast cancer therapy.
• In this study the presence of genetic variations in women suffering from lymphedema following breast cancer treatment was the primary outcome.
  A total of 6 original articles. The studies included involved a total of 1379 participants.
  All included articles reported on the association between genetic variation and development of lymphedema in women who had received breast cancer treatment. A total of 18 genes possibly associated with this type of lymphedema were found. Affected genes include GJC2, possibly HGF and MET, and possibly associated genes, IL1A, IL4, IL6, IL10, IL13, VEGF-C, NFKB2, LCP-2, NR -2, SYK, VCAM1, FOXC2, KDR, FLT4, and RORC.6–8,10,11,13 Of these, only missense mutations in GJC2 affecting amino acids in the protein, connexin 47 (Cx47) may be causally linked to predisposing to lymphedema.
• A categorization of these genes according to their overall function revealed a substantial overlap with those mutated in the development of primary lymphedema due to erroneous lymphangiogenesis, supporting the notion that the traditional binary categorization of lymphedema into a primary and secondary variant might be inaccurate.
• The level of evidence regarding the relationship between genetic predisposition and the development of breast cancer related lymphedema was relatively low. The evidence was limited by small sample sizes, as recognized and described by different groups of authors. 3 Risk of bias was introduced in three of six included articles by missing data on the method of genotyping.
• The low level of evidence and the considerable heterogeneity of the included studies resulted in an inability to draw definite conclusions from the available literature.