Exploring gene-environment interactions in breast cancer-related lymphedema among African women: a narrative review

¹Department of Gynaecology and Obstetrics, Faculty of Medicine and Health Sciences, Walter Sisulu University, Mthatha, South Africa

^&Corresponding author
Jean Paul Muambangu Milambo, Department of Gynaecology and Obstetrics, Faculty of Medicine and Health Sciences, Walter Sisulu University, Mthatha, South Africa

Introduction    

Breast cancer-related lymphedema (BCRL) is a common and debilitating complication for breast cancer survivors, characterized by chronic swelling in the arms or breasts, significantly affecting patients' quality of life. Approximately 20-30% of women treated for breast cancer develop this condition, influenced by genetic predisposition, treatment-related factors such as lymph node dissection and radiation therapy, and environmental factors including obesity and infections [1,2]. Understanding these variables is essential for identifying individuals at higher risk and improving prevention and management strategies [3].

Extensive research in the United States and Europe has identified key risk factors for BCRL, including the number of lymph nodes removed during surgery, radiation therapy, chemotherapy, and obesity [4,5]. In these regions, BCRL affects 15-30% of breast cancer survivors [6]. However, these findings may not be fully applicable to African populations due to differences in healthcare infrastructure, genetic profiles, and environmental exposures [7,8].

In Africa, data on BCRL remains limited, and the condition is underrecognized and underreported. Many African breast cancer survivors experience delayed diagnoses and insufficient healthcare access, exacerbating the risk of developing BCRL [9]. Environmental factors such as malnutrition, obesity, and high rates of infectious diseases further increase the likelihood of lymphedema in this population [10]. The underreporting and lack of appropriate management call for urgent research and tailored interventions to address the unique challenges in the African context [9].

Genetic factors have been identified as significant contributors to BCRL, with markers like FLT4 (vascular endothelial growth factor receptor 3) linked to lymphatic dysfunction and increased susceptibility to lymphedema [10]. However, most studies have focused on populations in developed countries, leaving a gap in research for African women. Understanding how genetic and environmental factors interact in these populations emphasizes the need for region-specific genomic research. This review highlights the importance of addressing these gaps and offers recommendations for targeted genetic studies, enhanced healthcare infrastructure, and better management policies to reduce the burden of BCRL among African women [10].

Research question: what genetic and environmental factors contribute to the development of breast cancer-related lymphedema (BCRL) in African women, and how do gene-environment interactions influence its development?

Methods     

Study design and protocol: this study was conducted as a narrative review to explore the genetic and environmental factors contributing to breast cancer-related lymphedema (BCRL) in African women, with a focus on gene-environment interactions. The review follows narrative synthesis principles and is structured to identify evidence gaps and summarize key findings relevant to clinical and public health contexts. The review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; Registration No. CRD420170727), ensuring methodological transparency and adherence to good research practice.

Eligibility criteria: studies were included if they (1) involved breast cancer survivors, (2) examined genetic or environmental contributors to BCRL, and (3) provided insights into gene-environment interactions. Studies specific to African populations were prioritized, though relevant data from global sources were also included to address gaps. Eligible literature comprised observational studies, genetic association studies, and peer-reviewed articles published in English between March 2018 and December 2024. Studies lacking focus on gene-environment interaction or relevance to African populations were excluded.

Search strategy and selection process: a targeted literature search was carried out in PubMed, Embase, and the Cochrane Library, covering publications from March 2018 to December 2024. Keywords included “breast cancer-related lymphedema”, “BCRL”, “genetic markers”, “environmental risk factors”, “African women”, and “gene-environment interaction”. Boolean operators and Medical Subject Headings (MeSH) were used to enhance precision. Articles were screened by title and abstract, with eligible full texts reviewed to confirm relevance and alignment with the research question.

Data charting and synthesis: extracted data included author, year, study population, genetic markers investigated, environmental risk factors, and reported outcomes. A narrative synthesis was applied to summarize findings and contextualize the interplay between genetic susceptibility and environmental exposures. Although many studies were conducted in high-income settings, findings were extrapolated to highlight implications for African populations. Notably, gaps were identified in African-based genomic data and context-specific environmental risk studies, underscoring the need for more regionally grounded research. Table 1 provides the risk factors of BCRL patients among the African population.

Results     

A total of 150 studies were initially retrieved through a systematic database search. After applying eligibility criteria, only five studies were found to report on genetic risk factors associated with the development of breast cancer-related lymphedema (BCRL). These studies primarily originated from high-income countries and focused on non-African populations, including European, Asian, and African American cohorts. Despite the global burden of BCRL, particularly in low- and middle-income settings, no genetic or genomic studies have been identified that investigate the presence of specific genetic markers associated with BCRL in African populations. The results summarized in Table 1 highlight global disparities in genetic research related to Breast Cancer-Related Lymphedema (BCRL). Studies from the USA and Europe have identified key genetic markers such as FLT4, VEGFA, and APOE, with reported BCRL prevalence ranging from 10% to 30%, often considering additional risk factors like surgery and BMI. Asian studies indicate emerging interest, with SNPs linked to genetic susceptibility. However, there is a notable lack of data from African populations, where no genetic studies were identified, underscoring a significant gap in global genomic research. Overall, the average BCRL prevalence across studies is approximately 20%, but representation remains limited, particularly in under-researched regions like Africa. Table 1 and Table 2 provide the genetic risk factors associated with BCRL development among the African population and globally. Figure 1 provides a pathway of BCRL in development. Figure 1 describes the possible pathways for BCRL development.

Discussion     

This review is the first narrative synthesis to explicitly highlight the absence of genomic research on breast cancer-related lymphedema (BCRL) among African populations. Employing a systematic methodology guided by PRISMA and narrative synthesis approaches, the review collates existing evidence on the genetic and environmental contributors to BCRL, drawing attention to key genetic markers such as FLT4, VEGFA, and APOE that have been implicated in studies from Europe and North America [8]. These genes are known to affect lymphatic development, vascular regeneration, and tissue repair, all of which are crucial in post-treatment recovery for breast cancer patients. While these markers provide a foundation for future investigation, their relevance to African populations remains uncertain due to the complete lack of Africa-specific genomic studies [9].

Despite its strengths, the review also faces notable limitations. Chief among them is the absence of African genomic data, which restricts the ability to draw population-specific conclusions or guide tailored interventions. Additionally, heterogeneity in BCRL definitions and diagnostic criteria across studies introduces variability that complicates cross-study comparisons [10]. The exclusive focus on English-language, peer-reviewed publications may have excluded valuable regional data published in other languages or non-indexed journals. Furthermore, the narrative design of this review does not permit meta-analytic calculations or pooled effect estimates, limiting its capacity to quantify risk magnitudes. Nonetheless, this synthesis provides a crucial foundation for identifying knowledge gaps and research priorities related to BCRL in African settings.

The lack of genomic research in Africa has substantial clinical implications. Without African-specific genetic data, healthcare providers lack the tools to stratify risk, monitor high-risk patients, or develop precision surveillance protocols for BCRL [9]. Personalized medicine remains underutilized in African oncology due to limitations in infrastructure, trained personnel, and investment in genetic testing. In addition, environmental factors such as rising obesity rates, widespread malnutrition, and high burdens of infectious diseases in many African regions may interact with genetic susceptibility in ways that differ significantly from those in high-income countries [7]. These complex gene-environment interactions call for a multifaceted clinical response that considers both biological and social determinants of health [7,9]. To address these gaps, several key actions are recommended. First, genomic studies focused on African breast cancer survivors should be initiated, ideally through multicenter cohort collaborations. Second, building biobanks and regional genetic databases is essential to support long-term research and ensure representation [9]. Third, fostering interdisciplinary collaborations between oncologists, geneticists, public health experts, and policymakers will be critical for advancing BCRL research in Africa. Integrating gene-environment screening tools into clinical practice may improve risk prediction, while investment in infrastructure and training can enhance the continent´s capacity for genomic medicine. Addressing these needs will not only improve outcomes for African women with BCRL but also contribute to global equity in cancer survivorship research and care.

Recommendations for future research and public health policy: 1) conduct African-specific genetic studies: future research should prioritize large-scale studies focusing on African populations to identify genetic markers predictive of BCRL and explore how these markers interact with local environmental exposures; 2) investigate environmental risk factors: further studies should examine how factors such as obesity, malnutrition, and infections interact with genetic markers to increase BCRL risk in African women; 3) enhance healthcare access: efforts should be made to improve healthcare infrastructure, with an emphasis on early diagnosis, genetic testing, and prevention strategies tailored to African settings.

Conclusion     

The review confirms a critical research gap in understanding the gene-environment contributions to BCRL among African women. Although several genetic markers such as FLT4, VEGFA, and APOE are implicated in non-African populations, no studies have yet investigated these in African settings. This gap limits the applicability of global research findings and restricts the development of equitable health interventions. Urgent efforts are needed to conduct genomic studies focusing on African women and explore the specific environmental factors that exacerbate BCRL risks in this demographic.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Jean Paul Muambangu Milambo designed the study, developed the search strategy, registered the review, wrote the protocol, performed data extraction, assessed the risk of bias, and conducted data analysis. The author read and approved the final version of this manuscript.

Acknowledgments     

We thank Prof. John Akudugu and Prof. Peter Nyasulu from Stellenbosch University for their assistance in developing the conceptual framework.

Tables and figure     

Table 1: incidence and genetic studies of breast cancer-related lymphedema across continents

Table 2: pathways of genetic risk factors in breast cancer-related lymphedema development

Figure 1: pathways of genetic risk factors in breast cancer-related lymphedema development

References