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Vol. 26, No. 2 - Research Perspective: A Synopsis: Understanding Genetic Predisposition to Lymphedema Following Breast Cancer Treatment

By: Tulsi Patel, RN, MSN, ACNP-BC, OCN, AOCNP, New York University; Jeanna M. Qiu, Summer Research Intern, New Jersey Livingston High School; Mei R. Fu, PhD, RN, ACNS-BC, FAAN, New York University

 Vol. 26 No. 2 - Lymphlink Reprint, Archived April 2014 

Women who are treated for breast cancer are at a life time risk of lymphedema.1 Most of those patients who develop lymphedema experience it within 12 to 18 months following breast surgery.2 Axillary lymph node dissection and sentinel lymph node biopsy are part of most breast cancer surgeries. These dissections involving the removal of lymph nodes and lymphatic vessels compromise the lymphatic system and can adversely affect how the fluid drains from the arm, breast, and chest.3, 4 Current knowledge about the cause of lymphedema remains limited; however, recent studies suggest genetics may play an essential role in its development.5,6 Genetic research has helped to identify genes linked to primary or familial lymphedema, a genetic condition marked by late onset of symptoms, often without any established injuries or surgical interventions.7 Familial lymphedema is associated with the following genes: VEGFR (flt4), FOXC2, and SOX18, whereas lymphangiogenesis in the embryo is related to the following genes: VEGFC, VEGFD (or FIGF), VEGFR2 (KDR), RORC, LYVE1, ADM (OR Adrenomedullin,) and PROX1.5,6 Researchers have speculated that these same genes may also have an important role in the development of secondary lymphedema following breast cancer treatment. 

This paper summarizes a recent genetic study on secondary lymphedema after breast cancer treatment. The complete reference of this study is: Newman B, Lose F, Kedda MA, Francois M, Ferguson K, Janda M, Yates P, Spurdle AB, Sandra C. Hayes SC. (2012). Possible Genetic Predisposition to Lymphedema after Breast Cancer. Lymphatic Research and Biology; 10(1):1-12. DOI: 10.1089/lrb.2011.0024. Readers are encouraged to read the original publication. 

Summary of the Research

The purpose of this study was to evaluate genetic variations in the 10 genes mentioned above and investigate if hereditary susceptibility is linked to the development of secondary lymphedema following breast cancer treatment. Newman and colleagues conducted a nested case-control study involving patients who had developed lymphedema within the first 18 months of their breast cancer diagnosis. This group included patients with lymphedema and patients without lymphedema who served as controls. The patients in the study were identified from a prospective, population-based, cohort study called the “Pulling Through Study” in Queensland, Australia. The “Pulling Through Study” was designed to track and assess the physical and psychosocial recovery of women after breast cancer treatment.8  The researchers collected patients’ personal and clinical information before the surgery. There were 22 patients who developed lymphedema in the first 18 months after their breast cancer surgery, and those patients were categorized as cases of lymphedema (n= 22). The researchers chose a subset of (n= 98) subjects from the “Pulling Through Study” who did not develop lymphedema to serve as controls. In the “Pulling Through Study,” data were collected every 3 months for a total of five data collection points over the course of 6 to 18 months following breast cancer diagnosis. The size of the arm was measured with a tape measure. Lymphedema was defined as a difference in score of >5 cm between the treated and untreated arms when the measurements from the tape were added together. Participants in the trial who had this >5cm difference were considered to have lymphedema. The genetic data were collected by obtaining blood samples.

The findings of the genetic associations were reported as an odds ratio (OR) and indicated the probability of having lymphedema in relation to certain genetic patterns. An OR of <0.5 or >2.0 was associated with a profound risk estimate and a p value <0.05 set statistical significance. Single nucleotide polymorphisms were from the following gene types: SOX18, VEGFC, VEGFD, VEGFR2, VEGFR3, RORC, FOXC2, LYVE1, ADM, and PROX1. Multiple SNPs were linked to lymphedema within three genes, VEGFR2, VEGFR3, and RORC. More than one SNP within these three genes revealed a statistically significant correlation with lymphedema. Vascular endothelial growth factor (VEGF) is vital for processes such as angiogenesis and lymphangiogenesis; VEGF interacts with proteins such as VEGFC and VEGFD and their ligands promote lymphatic vessel growth, which has been shown to cause secondary lymphedema in mice. A statistically significant association was also noted between a SNP and lymphedema in the RORC gene. The function of this gene remains unclear in humans; however, studies have identified a similar gene in mice, which is responsible for lymphoid organogenesis.

Conclusion and Implications

Current known risk factors for secondary lymphedema offer an incomplete explanation for the development of the condition after breast cancer treatment. Therefore, it is possible that genetic susceptibility may influence secondary lymphedema risk. The results of this study by Newman and colleagues provided preliminary evidence for this hypothesis. The identification of genetic variations linked to secondary lymphedema can subsequently help health care professionals to provide better and more personalized care for patients. While the findings of this small nested case-control study have set the course for this line of research, further large scale clinical trials are warranted.

References:

  1. Petrek, J.A., Senie, R.T., Peters, M., Rosen, P.P. (2001). Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer, 92(6),1368-77.
  2. Paskett, E.D., Naughton, M.J., McCoy, T.P., Case, L.D., Abbott, J.M. (2007). The epidemiology of arm and hand swelling in premenopausal breast cancer survivors. Cancer Epidemiology, Biomarkers & Prevention, 16(4), 75-82.
  3. Olszewski, W.L. (2003). Pathophysiological aspects of lymphedema of human limb: I. Lymph protein composition. Lymphatic Research and Biology, 1(3), 235-243.
  4. Stanton, A.W., Modi, S., Mellor, R.H., Levick, J.R., & Mortimer, P.S. (2009).Recent advances in breast cancer-related lymphedema of the arm: lymphatic pump failure and predisposing factors. Lymphatic Research & Biology, 7(1):29-45.
  5. Miaskowski C, Dodd M, Paul SM, West C, Hamolsky D, et al. (2013) Lymphatic and Angiogenic Candidate Genes Predict the Development of Secondary Lymphedema following Breast Cancer Surgery. PLoS ONE 8(4): e60164. doi:10.1371/journal.pone.0060164
  6. Newman B, Lose F, Kedda MA, Francois M, Ferguson K, Janda M, Yates P, Spurdle AB, Sandra C. Hayes SC. (2012). Possible Genetic Predisposition to Lymphedema after Breast Cancer. Lymphatic Research and Biology; 10(1):1-12. DOI: 10.1089/lrb.2011.0024
  7. Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, et al. (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. Journal American Society Nephrology 15: 603–612. doi: 10.1097/01.ASN.0000113316.52371.2E.
  8. Hayes, S.C, Janda, M., Cornish, B., Battistutta, D., Newman, B., (2008) Lymphoedema following breast cancer: Incidence, risk factors and effect on upper body function. Journal of Clinical Oncology, 26:3536-3542.

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