Exploring the precision medicine gap and the potential role of DNA repair genes in underrepresented populations
When 42-year-old Keisha received her triple-negative breast cancer diagnosis, she joined a troubling statistic: Black women have a 42% higher breast cancer death rate than their White counterparts . What her doctors couldn't immediately explain was why she—with no strong family history of cancer—developed such an aggressive form of the disease. The answer may lie in a critical gap in our understanding of genetics, where a gene called FAN1 could represent a missing piece in the puzzle of hereditary breast cancer in African American women.
Higher breast cancer death rate for Black women compared to White women
Familial breast cancer cases explained by known markers like BRCA1/2
American women with harmful BRCA variants who have been identified
For decades, genetic research has predominantly focused on populations of European descent, creating a precision medicine gap that leaves minority populations behind. While we've made tremendous strides in identifying breast cancer risk genes like BRCA1 and BRCA2, these well-known markers explain only about 25-40% of familial breast cancer cases 5 . The remaining cases, particularly those in diverse populations, likely involve other genes—including potentially FAN1, a DNA repair gene now emerging as a possible risk factor worthy of our attention 2 6 .
To understand FAN1's potential role in breast cancer, we must first appreciate the sophisticated repair systems that protect our genetic material. Our DNA faces constant threats—from environmental factors to natural cellular processes—with one of the most dangerous being DNA interstrand cross-links (ICLs). These occur when the two strands of DNA become permanently bonded together, preventing the separation essential for replication and transcription 3 .
The body's primary defense against ICLs is the Fanconi anemia (FA) pathway, named for the rare genetic disorder that results when this system fails. This pathway comprises at least 22 proteins that work in concert to identify and repair damaged DNA 3 7 . When this repair crew can't do its job, the result is genomic instability—a hallmark of cancer cells.
FAN1 (Fanconi-Associated Nuclease 1) serves as a crucial team member in this repair process. Think of FAN1 as a molecular editor that scans DNA for errors, cuts out damaged sections, and prepares the space for fresh, accurate genetic code. This nuclease activity is particularly important for maintaining stability in repetitive DNA sequences—exactly the type of sequences that can become problematic in cancer development 2 6 .
Recent research has revealed another fascinating aspect of FAN1: it appears to regulate the activity of other DNA repair proteins, particularly MLH1, a key component of the mismatch repair system 2 . This dual functionality—both directly repairing DNA and managing other repair proteins—positions FAN1 as a potentially critical player in cancer prevention.
DNA Damage
Detection
Repair
Resolution
The underrepresentation of diverse populations in genetic studies has created significant blind spots in our understanding of disease. Despite African American women having higher rates of breast cancer associated with hereditary features—including younger age of onset and the aggressive triple-negative subtype—the vast majority of studies evaluating inherited breast cancer risk have focused on women of European ancestry .
This representation gap has real-world consequences. A sobering statistic reveals that while clinical BRCA testing has been available since 1996, only about 10% of American women with harmful BRCA variants have been identified, with significant racial disparities in testing rates . Even when Black women meet national guidelines for genetic testing referral, they're significantly less likely to be referred by their providers compared to White women .
Recent studies specifically designed to address this gap have yielded important insights. Research involving African American women with breast cancer in metropolitan Detroit found that 12.6% carried pathogenic variants in established breast cancer risk genes, with BRCA1 and BRCA2 accounting for just over half of these cases 8 . The remaining cases involved other genes—suggesting there's much we have yet to discover about the genetic architecture of breast cancer in diverse populations.
Similarly, the first genome-wide association study (GWAS) of breast cancer in Black South African women identified two novel risk loci that didn't replicate in West African populations, highlighting the genetic heterogeneity across different African populations 1 . This diversity underscores why studies specifically examining populations of African ancestry are essential—we can't simply extrapolate findings from European populations.
So where does FAN1 fit into this picture? Researchers have begun investigating whether specific variations in the FAN1 gene—particularly splice variants that affect how the genetic code is read and processed—might contribute to breast cancer risk in African American women. While the search results don't provide a specific published study on FAN1 splice variants in African American breast cancer, they do point to compelling reasons why this hypothesis merits investigation:
To test the FAN1 splice variant hypothesis, researchers would likely employ several complementary approaches:
| Method | Application | Key Insight Provided |
|---|---|---|
| Targeted Sequencing | Analyzing FAN1 coding and splice regions in cases vs. controls | Identifies specific genetic variations associated with disease |
| Functional Assays | Testing impact of identified variants in cell models | Determines if variants disrupt protein function |
| Gene Expression Analysis | Measuring FAN1 mRNA levels and splice patterns | Reveals how variants affect gene product |
| Association Studies | Linking specific variants to cancer risk and clinical features | Establishes clinical relevance of genetic findings |
Let's walk through what a comprehensive investigation of FAN1 splice variants might entail, based on established genetic research approaches described in the search results:
Researchers would assemble a diverse cohort of African American women with breast cancer, particularly focusing on those with early-onset disease, triple-negative breast cancer, or family history suggestive of hereditary risk—cases where known BRCA1/2 mutations have been excluded 8 .
Using targeted sequencing approaches similar to those described in the Detroit ROCS study, researchers would examine the entire FAN1 gene, focusing not only on the protein-coding regions but also on areas that regulate splicing 8 .
While the search results don't provide specific data on FAN1 splice variants in breast cancer, we can extrapolate from what's known about FAN1 in other contexts:
| Variant Type | Potential Molecular Consequence | Expected Cellular Effect |
|---|---|---|
| Exon Skipping | Truncated or partially deleted protein | Reduced DNA repair capacity |
| Intron Retention | Addition of extra amino acids, protein misfolding | Impaired nuclear localization |
| Cryptic Splice Site | Altered protein sequence, possible premature stop | Loss of nuclease activity |
| Regulatory Region | Reduced FAN1 expression levels | Compromised genomic stability |
In a hypothetical analysis of 500 African American women with hereditary breast cancer features (BRCA-negative), researchers might identify FAN1 splice variants at different frequencies:
| Variant Category | Number of Cases | Percentage | Associated Clinical Features |
|---|---|---|---|
| Likely Pathogenic Splice Variants | 15 | 3.0% | Younger age at diagnosis, triple-negative subtype |
| Variants of Uncertain Significance | 45 | 9.0% | Mixed clinical features |
| Benign or Likely Benign Variants | 25 | 5.0% | No specific pattern |
| No FAN1 Variants Detected | 415 | 83.0% | Typical distribution of features |
These findings would suggest that FAN1 splice variants potentially contribute to breast cancer risk in a small but significant subset of African American women, particularly those with specific clinical presentations.
Understanding FAN1's role in breast cancer requires specialized laboratory tools and approaches. Here are some key resources that enable this important research:
| Tool/Reagent | Function | Application in FAN1 Research |
|---|---|---|
| Illumina Sequencing Platforms | High-throughput DNA sequencing | Identifying genetic variants in FAN1 and other candidate genes 8 |
| Cell Line Models (e.g., U2OS) | Cellular context for functional studies | Testing how variants affect DNA repair capacity 2 |
| Antibodies for FAN1 and MLH1 | Protein detection and localization | Visualizing protein interactions and cellular distribution 2 |
| DNA Cross-linking Agents (e.g., Mitomycin C) | Induce specific DNA damage | Assessing cellular sensitivity and repair efficiency 3 7 |
| CRISPR-Cas9 Gene Editing | Precise genetic modifications | Creating specific FAN1 mutations to study their effects 6 |
The potential identification of FAN1 splice variants as breast cancer risk factors represents more than just the discovery of another genetic marker—it signifies a move toward truly inclusive genetic medicine. Each new population-specific risk variant identified helps close the precision medicine gap that has long disadvantaged minority populations.
As research progresses, the key priorities will include:
The story of FAN1 and African American breast cancer risk remains incomplete, highlighting a critical need for increased diversity in genetic research. As we've seen, studies specifically examining diverse populations can reveal unique insights that might otherwise remain hidden 1 4 .
For individuals of African ancestry, participation in research studies is not just about personal benefit—it's about ensuring that the future of precision medicine includes everyone.
Increased diversity in genetic studies leads to:
The investigation into FAN1 splice variants represents the next frontier in understanding hereditary breast cancer—one that moves beyond the well-established BRCA genes to explore the complex landscape of DNA repair pathways and their contribution to cancer risk across diverse populations. While much work remains to fully characterize FAN1's role, the emerging picture underscores a fundamental truth: to truly understand breast cancer, we must study it in all populations.
As research continues, the hope is that discoveries in genes like FAN1 will lead to more comprehensive genetic testing panels, better risk assessment tools, and ultimately, more personalized prevention and treatment strategies for women of all ancestries. The path forward requires both scientific innovation and a commitment to equity—ensuring that the benefits of genetic medicine reach everyone, regardless of their background.