Review of FSCN1 polymorphism and susceptibility to breast cancer in Egyptian and Chinese patients

INTRODUCTION

Breast cancer continues to represent a major public health challenge, contributing substantially to cancer-related morbidity and mortality worldwide. Data from international cancer surveillance consistently indicate that it is one of the most commonly diagnosed malignancies among women. Recent global estimates underscore the magnitude of this burden and emphasise the ongoing need to improve risk stratification approaches, including the identification of genetic susceptibility markers, as a foundation for more effective prevention and early detection strategies.^[1]

Breast carcinogenesis is a biologically complex and heterogeneous process shaped by interactions among environmental exposures, hormonal influences, and genetic factors. In addition to well-established high-penetrance genes, a wide range of common genetic variants may confer smaller yet clinically relevant increases in disease risk, either independently or in combination within broader genetic risk profiles. Within this context, growing research interest has focused on genes involved in cytoskeletal organisation and cell motility, as these processes play a critical role in malignant transformation, tumour invasion, and metastatic spread.^[2]

Fascin-1, encoded by the FSCN1 gene, is an actin-bundling protein that plays a key role in the organisation of parallel actin filaments, thereby facilitating cell migration and invasion. In a wide range of human malignancies, increased FSCN1 expression has consistently been associated with more aggressive tumour behaviour and poorer clinical outcomes, supporting its biological relevance in cancer progression and, potentially, tumour initiation. Mechanistic and translational studies have further highlighted FSCN1 as a promising biomarker and potential therapeutic target.^[3] In the context of breast cancer, elevated fascin-1 expression has been particularly observed in more aggressive molecular subtypes, with immunohistochemical studies indicating its utility as a diagnostic marker, especially in triple-negative breast cancer.^[4]

In view of the established role of FSCN1 in cytoskeletal remodelling, genetic variation within this gene may contribute to breast cancer susceptibility through effects on gene regulation, expression, or linkage with functional haplotypes. Several genetic association studies have investigated multiple FSCN1 single-nucleotide polymorphisms (SNPs) in relation to breast cancer risk and clinicopathological characteristics. A notable study examined a panel of FSCN1 variants, including rs56156320, rs3801004, and rs2966447, and identified associations with both disease susceptibility and tumour progression markers.^[5] A recent case–control study conducted in specific populations has reported statistically significant associations for selected variants, such as rs3801004 and rs852479/rs1640233 in Egyptian cohorts.^[6,7] Furthermore, emerging evidence has linked the rs2966447 polymorphism not only to breast cancer risk but also to circulating fascin-1 levels, suggesting a potential correlation between genetic variation and phenotypic expression that may enhance the biological interpretation of these genetic associations.^[8]

However, the overall evidence base remains fragmented across populations, SNP panels, genotyping approaches, and adjustment strategies, with findings that may vary by ethnicity, molecular subtype, and clinical context. Therefore, a systematic review is warranted to critically appraise and synthesise the available genetic association evidence, clarify which FSCN1 polymorphisms show the most consistent relationship with breast cancer susceptibility, and identify gaps requiring higher-powered, multi-ethnic, and functionally informed studies.

MATERIAL AND METHODS

Search strategy

Electronic databases (Embase, PubMed, Cochrane Library databases, and Web of Science) were searched by us until December 31, 2025, using the following keywords: “FSCN1 or Fascin-1” and “Polymorphism or variation or mutation or genotypes or SNP” and “breast cancer or breast tumour or breast carcinoma”. In addition, a manual search was needed for references of relevant articles in order to identify potentially eligible publications. The study selection process was conducted according to the PRISMA guidelines and is depicted in Figure 1.

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Figure 1: Flow diagram. *Out of the 12 articles, 8 were from PubMed, 4 from Scopus, 0 from Cochrane Library, and 0 from manual searching.

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RESULTS

DISCUSSION

In this systematic evaluation of FSCN1 polymorphisms and breast cancer risk, the cumulative evidence suggests that genetic variation in FSCN1 may contribute to disease susceptibility in a context-dependent and allele-specific manner. Although only a limited number of studies have examined associations between FSCN1 single-nucleotide polymorphisms (SNPs) and breast cancer, the observed patterns align with established roles of fascin-1 as a regulator of cytoskeletal dynamics, cell motility, and invasive behaviour.

Fascin-1, encoded by FSCN1, is an actin-bundling protein normally expressed in neuronal and mesenchymal tissues but typically absent in quiescent epithelial cells. In malignant contexts, increased fascin-1 expression correlates with enhanced formation of filopodia and invadopodia, facilitating extracellular matrix interaction and metastatic potential. This mechanistic role has been documented across several cancers, including breast carcinoma, where fascin-1 overexpression associates with aggressive phenotypes and poor clinical outcomes. Functional studies have demonstrated that fascin expression in breast cancer cells establishes pro-metastatic gene profiles and increases motility.^[9] In addition, elevated fascin-1 protein expression has been observed at significantly higher rates in triple-negative breast cancer (TNBC) compared to other subtypes, supporting its role as a marker of invasiveness.^[4]

The biological relevance of fascin-1 in cancer supports the hypothesis that FSCN1 genetic variation may influence individual susceptibility to breast cancer. Candidate gene studies have evaluated several FSCN1 SNPs, such as rs3801004, rs56156320, and rs2966447, with mixed associations reported across populations. For example, specific alleles at rs56156320 were reported to increase breast cancer risk in a Chinese cohort, whereas rs3801004 demonstrated protective associations in another ethnic group.^[6] These divergent findings likely reflect population heterogeneity in linkage disequilibrium patterns, allele frequencies, and environmental exposures, emphasising the importance of verifying associations across multiple ancestries.

The heterogeneity of genetic effects observed in FSCN1 mirrors broader findings in breast cancer genetics, where common risk variants identified through genome-wide association studies (GWAS) often exhibit population-specific effect sizes and directionality. Large GWAS meta-analyses have identified numerous susceptibility loci for breast cancer at genome-wide significance, including both European and Asian cohorts, but these loci together explain only a fraction of familial risk, and 2017 follow-up studies further expanded the catalogue of risk variants.^[10,11] The limited GWAS coverage of FSCN1 underscores that candidate genes with strong functional rationale may not be tagged adequately by arrays, particularly if causal variants are rare or have modest effect sizes. Differences in linkage disequilibrium structure between populations can also lead to inconsistent tagging of causal alleles at the same locus.^[12]

While the mechanistic rationale for FSCN1 involvement in carcinogenesis is strong, interpretation of high effect estimates for specific SNPs should be cautious. Some studies report large odds ratios for particular genotypes, such as homozygous rare alleles, but these estimates are often accompanied by wide confidence intervals. Such inflation is a known artefact of small sample sizes and low minor allele frequencies, particularly in candidate gene studies with limited statistical power.^[13] Without replication in larger, independent cohorts, it remains uncertain whether observed associations represent true causal effects or are attributable to sampling variability or population stratification.

The association of FSCN1 variants with functional outcomes also remains underexplored. Neither expression quantitative trait locus (eQTL) analyses nor studies integrating genotype with tumour-specific fascin-1 expression have been reported in the context of these SNPs. Establishing a functional link between germline variation, gene expression, and phenotypic consequences in breast tissue would significantly strengthen causal inference. For example, eQTL analyses could reveal whether risk alleles correlate with elevated FSCN1 transcription in normal or neoplastic breast tissue, providing mechanistic evidence beyond statistical association.

In comparison to expression studies, the genetic data provide complementary but preliminary evidence. Immunohistochemical analyses show that fascin-1 protein levels are significantly higher in TNBC and associate with aggressive clinicopathological features, suggesting that fascin-1 contributes to tumour progression.^[4] These expression patterns align with functional studies in vitro and in vivo, reinforcing the pro-invasive role of fascin-1. However, whether germline SNPs in FSCN1 directly modulate these expression patterns or act through regulatory networks remains to be elucidated.

This review’s findings have several implications for future research. First, larger, well-powered studies across ethnically diverse populations are required to validate FSCN1 SNP associations and quantify effect sizes with sufficient precision. Integration with GWAS data and polygenic risk scores may help position FSCN1 within broader genetic risk architectures. Second, functional genomics approaches, such as CRISPR perturbation of candidate variants in breast epithelial models, or allele-specific expression analysis, could clarify causal mechanisms linking genotype to phenotype. Lastly, studies combining germline genetics with tumour expression and clinical outcomes could assess the potential utility of FSCN1 variants as biomarkers for risk stratification or therapeutic targeting.

TAKE HOME MESSAGE

The current evidence supports a plausible role for FSCN1 genetic variation in breast cancer susceptibility. The findings are provisional and require replication and functional validation. The convergence of biological plausibility, expression associations, and preliminary genetic signals justifies further investigation within larger, multi-ethnic cohorts and integrative functional studies. Clarifying the contribution of FSCN1 polymorphisms to breast carcinogenesis may ultimately advance understanding of tumour invasiveness and enable more precise risk prediction models.