Cytokine Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery

Leung, Geraldine; Baggott, Christina; West, Claudia; Elboim, Charles; Paul, Steven M.; Cooper, Bruce A.; Abrams, Gary; Dhruva, Anand; Schmidt, Brian L.; Kober, Kord M.; Merriman, John D.; Leutwyler, Heather; Neuhaus, John; Langford, Dale J.; Smoot, Betty; Aouizerat, Bradley E.; Miaskowski, Christine

doi:10.1089/lrb.2013.0024

Cited by 56 publications

(48 citation statements)

References 55 publications

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“…Our study found genotype IL4 rs2070874 homozygous T/T increased in 2.76 odds for phenotype of fluid accumulation and IL4 rs2243250 (IL-4) homozygous T/T 2.07 odds for phenotype of fluid accumulation in comparison with homozygous C/C. IL4 has the ability to activate macrophages into M2 macrophages which function in tissue repair, fibrosis and the regulation of inflammation (23). Further research is needed to evaluate the role of IL4 in the development of lymphedema, especially phenotype of fluid accumulation and impaired limb mobility.…”

Section: Discussionmentioning

confidence: 83%

“…Yet, genes related to inflammation, IL1- a rs17561, IL4 rs2070874 and rs2243250, IL6 rs1800795, IL-13 rs1800925, and gene strong for regulating lymphangiogenesis, VEGF-C rs3775203, are found associated with symptom count phenotype of ≥8 symptoms and symptom cluster phenotype of impaired limb mobility, fluid accumulation, and discomfort. Only one study evaluated genes related to inflammation with lymphedema defined by bioimpedance ratio and found that IL4 rs2227284 homozygous (C/C + C/A vs A/A) had a 69% decrease in the odds of developing lymphedema (23–24). Our study found genotype IL4 rs2070874 homozygous T/T increased in 2.76 odds for phenotype of fluid accumulation and IL4 rs2243250 (IL-4) homozygous T/T 2.07 odds for phenotype of fluid accumulation in comparison with homozygous C/C.…”

Section: Discussionmentioning

confidence: 99%

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Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction

Conley

Axelrod

et al. 2016

The Breast

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Lymphedema following breast cancer surgery is considered to be mainly due to the mechanical injury from surgery. Recent research identified that inflammation-infection and obesity may be the important predictors for lymphedema. The purpose of this exploratory research was to prospectively examine phenotype of arm lymphedema defined by limb volume and lymphedema symptoms in relation to inflammatory genes in women treated for breast cancer. A prospective, descriptive and repeated-measure design using candidate gene association method was used to enroll 140 women at pre-surgery and followed at 4–8 weeks and 12 months post-surgery. Arm lymphedema was determined by a perometer measurement of ≥5% limb volume increase from baseline of pre-surgery. Lymphedema symptom phenotype was evaluated using a reliable and valid instrument. Saliva samples were collected for DNA extraction. Genes known for inflammation were evaluated, including lymphatic specific growth factors (VEGF-C & VEGF-D), cytokines (IL1-a, IL-4, IL6, IL8, IL10, & IL13), and tumor necrosis factor-a (TNF-a). No significant associations were found between arm lymphedema phenotype and any inflammatory genetic variations. IL1-a rs17561 was marginally associated with symptom count phenotype of ≥8 symptoms. IL-4 rs2070874 was significantly associated with phenotype of impaired limb mobility and fluid accumulation. Phenotype of fluid accumulation was significantly associated with IL6 rs1800795, IL4 rs2243250 and IL4 rs2070874. Phenotype of discomfort was significantly associated with VEGF-C rs3775203 and IL13 rs1800925. Precision assessment of heterogeneity of lymphedema phenotype and understanding the biological mechanism of each phenotype through the exploration of inherited genetic susceptibility is essential for finding a cure. Further exploration of investigative intervention in the context of genotype and gene expressions would advance our understanding of heterogeneity of lymphedema phenotype.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction

Conley

Axelrod

et al. 2016

The Breast

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“…Known risk factors for lymphedema include obesity (196), elevated blood pressure, adjuvant radiation therapy following lumpectomy, the location of removed lymph nodes, and a greater number of lymph nodes removed during surgery (185). Additionally, combinations of genetic risk factors predispose patients to developing secondary lymphedema (197). …”

Section: Impaired Lymphatic Function In Lymphedemamentioning

confidence: 99%

The Lymphatic System in Disease Processes and Cancer Progression

Padera

Meijer

Munn

2016

Annu. Rev. Biomed. Eng.

198

139

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Advances in our understanding of the structure and function of the lymphatic system have made it possible to identify its role in a variety of disease processes. Because it is involved not only in fluid homeostasis but also in immune cell trafficking, the lymphatic system can mediate and ultimately alter immune responses. Our rapidly increasing knowledge of the molecular control of the lymphatic system will inevitably lead to new and effective therapies for patients with lymphatic dysfunction. In this review, we discuss the molecular and physiological control of lymphatic vessel function and explore how the lymphatic system contributes to many disease processes, including cancer and lymphedema.

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“…In our previous studies (Leung et al, 2014; Miaskowski et al, 2013), increased BMI, increased number of lymph nodes removed, higher stage of disease at diagnosis, and having had an ALND, were associated with an increased risk for LE. Preliminary findings from our research group (Leung et al, 2014; Miaskowski et al, 2013) and others (Finegold et al, 2012; Finegold et al, 2008; Newman et al, 2012) suggest that variations in lymphatic, angiogenic, and pro-inflammatory cytokine genes are associated with increased risk for the development of LE after breast cancer treatment.…”

mentioning

confidence: 67%

“…Preliminary findings from our research group (Leung et al, 2014; Miaskowski et al, 2013) and others (Finegold et al, 2012; Finegold et al, 2008; Newman et al, 2012) suggest that variations in lymphatic, angiogenic, and pro-inflammatory cytokine genes are associated with increased risk for the development of LE after breast cancer treatment. However, these associations did not explain all of the variability in the occurrence of LE.…”

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confidence: 70%

Potassium Channel Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery

et al. 2017

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Background Potassium (K+) channels play an important role in lymph pump activity, lymph formation, lymph transport, and the functions of lymph nodes. No studies have examined the relationship between K+ channel candidate genes and the development of secondary lymphedema (LE). Objective The study purpose was to evaluate for differences in genotypic characteristics in women who did (n = 155) or did not (n = 387) develop upper extremity LE following breast cancer treatment based on an analysis of single nucleotide polymorphisms (SNPs) and haplotypes in 10 K+ channel genes. Methods Upper extremity LE was diagnosed using bioimpedance resistance ratios. Logistic regression analyses were used to identify those SNPs and haplotypes that were associated with LE while controlling for relevant demographic, clinical, and genomic characteristics. Results Patients with LE had a higher body mass index, a higher number of lymph nodes removed, had more advanced disease, received adjuvant chemotherapy, received radiation therapy, and were less likely to have undergone a sentinel lymph node biopsy. One SNP in a voltage-gated K+ channel gene (KCNA1 rs4766311); four in two inward rectifying K+ channel genes (KCNJ3 rs1037091 and KCNJ6 rs2211845, rs991985, rs2836019); and one in a two pore K+ channel gene (KCNK3 rs1662988) were associated with LE. Discussion These preliminary findings suggest that K+ channel genes play a role in the development of secondary LE.

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Cytokine Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery

Abstract: These genetic associations suggest a role for a number of pro- and anti-inflammatory genes in the development of LE following breast cancer treatment.

Cited by 56 publications

References 55 publications

Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction

Precision assessment of heterogeneity of lymphedema phenotype, genotypes and risk prediction

The Lymphatic System in Disease Processes and Cancer Progression

Potassium Channel Candidate Genes Predict the Development of Secondary Lymphedema Following Breast Cancer Surgery

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