The VUS Dilemma: When Genetic Tests Can't Give Clear Answers
Imagine receiving a genetic test result that might indicate increased cancer risk, but being told that scientists simply don't have enough information to know for sure. This scenario plays out daily in clinics across the world, particularly among people of non-European ancestry.
Variant of Uncertain Significance
Genetic changes where the connection to health conditions is unclear, often because they're so rare in the population that little information exists about them 1 .
Personalized Cancer Care
The resolution of these uncertain variants represents the next frontier in personalized cancer care, potentially unlocking more precise risk assessment and treatment strategies.
Understanding Variants of Uncertain Significance (VUS)
The "Gray Area" of Genetics
A variant of uncertain significance is essentially a genetic change whose health implications are unknown 1 . As Dr. Teri Manolio of the National Human Genome Research Institute explains, "The great majority of new variants that pop up in examining an individual person's genome can't definitely be classified as disease-causing or not" 1 .
The fundamental challenge lies in the reference datasets used to interpret genetic variants. When most genomic research has focused on European populations, variants more common in other groups naturally become "unclassifiable." This creates a troubling disparity: Hispanic/Latino patients and other underrepresented groups receive inconclusive results more frequently, limiting the clinical utility of genetic testing 1 6 .
VUS Classification Challenge
Distribution of variant classifications in underrepresented populations
The Ripple Effects of Uncertainty
- Experience significant distress and anxiety about their cancer risk
- Cannot make informed decisions about preventive measures
- May undergo unnecessary increased cancer surveillance
- Face limitations in accessing targeted therapies
Colorectal Cancer in Hispanic/Latino Communities: An Urgent Need
Projected Global CRC Burden by 2030
Source: Global cancer projections 3
The Growing Burden of CRC
Colorectal cancer represents a significant health concern for Hispanic/Latino communities. By 2030, the global burden of colorectal cancer is expected to increase to more than 2.2 million new cases and 1.1 million deaths worldwide 3 .
Within the United States, Latinos face unique cancer disparities, including being diagnosed at later stages for certain cancers and having lower participation in clinical trials 4 .
The Genetic Diversity Gap
The Hispanic/Latino population represents a richly genetically admixed community with varying proportions of Indigenous American, European, African, and other ancestries 2 5 . This genetic diversity, while scientifically valuable, has been underrepresented in cancer genomic studies 2 .
As a result, the molecular drivers of colorectal cancer in these populations remain insufficiently characterized, creating a critical knowledge gap in our understanding of the disease.
Hispanic/Latino Genetic Ancestry
Key Research: Mapping the Genomic Landscape of Hispanic/Latino CRC
The Latino Colorectal Cancer Consortium (LC3) Study
To address this disparity, researchers formed the Latino Colorectal Cancer Consortium (LC3), conducting one of the most comprehensive genomic studies of colorectal cancer in this population to date. The team analyzed whole-exome sequencing data from 718 individuals with colorectal cancer, specifically examining how genetic ancestry influences tumor characteristics 2 .
Study Highlights
- 718 participants
- Whole-exome sequencing
- Ancestry-mutation associations
- Independent validation cohort
Methodology: Connecting Ancestry to Somatic Changes
The research approach involved several sophisticated genomic techniques:
Genetic Ancestry Estimation
Using computational tools to quantify global proportions of African, Asian, European, and Native American ancestry
Somatic Mutation Profiling
Identifying acquired genetic changes in tumors compared to normal tissue
Ancestry-Mutation Association
Examining correlations between genetic ancestry and specific mutational patterns
Independent Validation
Replicating findings in separate datasets to confirm results
| Key Characteristics of LC3 Study Participants | |
|---|---|
| Total Participants | 718 individuals |
| Data Type | Whole-exome sequencing of tumor/normal pairs |
| Ancestry Estimation | African, Asian, European, and Native American proportions |
| Primary Analysis | Association between ancestry and somatic mutational features |
| Validation Cohort | MSK-IMPACT dataset |
Groundbreaking Findings: Ancestry-Specific Mutational Patterns
The LC3 study revealed several significant connections between genetic ancestry and colorectal cancer biology:
These findings demonstrate that colorectal cancer does not present identically across populations, and that ancestry-informed genomics can reveal important biological differences that may influence cancer risk, progression, and treatment response.
| Genetic Ancestry | Associated Molecular Feature | Potential Clinical Relevance |
|---|---|---|
| African | Higher odds of KRAS mutations | May impact response to EGFR inhibitors |
| African | Associated with SMAD2 mutations | Potential prognostic implications |
| Native American | Lower MSI-H tumors | May affect immunotherapy eligibility |
| Native American | SBS11 mutational signature | Potential diagnostic applications |
Bridging the Gap: Integrating Germline and Somatic Data
The Power of Combined Analysis
Resolving variants of uncertain significance requires integrating two types of genetic information: germline variants (inherited genetic changes present in all cells) and somatic mutations (acquired genetic changes found only in tumor cells).
By analyzing both data types together, researchers can identify patterns that help distinguish harmless genetic variations from disease-driving mutations.
This integrative approach is particularly powerful in admixed populations like Hispanic/Latinos, where the combination of ancestral genetic backgrounds creates unique challenges and opportunities for variant interpretation.
Integrative Genomic Approach
Germline Variants
Inherited genetic changes present in all cells
Somatic Mutations
Acquired genetic changes found only in tumor cells
Integrated Analysis
Pattern recognition to distinguish pathogenic from benign variants
Clinical Application
Improved risk assessment and personalized treatment
Technical Approaches for VUS Resolution
Several cutting-edge methods are advancing VUS resolution:
Population Databases
Expanding diverse genomic references to improve variant classification
Multi-omics Integration
Combining genomic data with transcriptomic, proteomic, and clinical information
| Tool/Technique | Function | Application in VUS Resolution |
|---|---|---|
| Next-generation sequencing | Comprehensive genetic analysis | Identifying variants in cancer predisposition genes |
| CRISPR/Cas9 screening | High-throughput functional testing | Determining pathogenicity of thousands of variants 6 |
| Ancestry estimation algorithms | Quantifying genetic ancestry | Connecting ancestral background to mutation patterns |
| Multi-omics platforms | Integrating different data types | Contextualizing variants within biological pathways |
The BRCA2 Precedent: A Model for Progress
Recent research on BRCA2 variants offers a promising model for what's possible in colorectal cancer genetics. A landmark study used CRISPR/Cas9 targeting to analyze an astounding 7,000 BRCA2 variants, classifying 785 as pathogenic or likely pathogenic and about 5,600 as benign or likely benign 6 . This left only 608 as VUS—a dramatic reduction from the initial 5,500 VUS 6 .
This approach could be adapted for colorectal cancer genes, potentially reclassifying thousands of uncertain variants and providing clearer guidance for patients and clinicians.
The Path Forward: Toward Inclusive Genomic Medicine
Expanding Diverse Representation in Research
Addressing the VUS challenge requires fundamental changes to how genomic research is conducted. As noted in one study, "At present, there is much more extensive genomic information about people of European ancestry than any other group leading to many more VUS's in those other groups" 1 . Solving this problem requires:
- Conscious inclusion of diverse populations in genetic studies
- Community engagement to build trust and participation
- Ethical frameworks that ensure equitable benefit from genomic advances
- Collaborative consortia like the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) 8
Future Research Priorities
Clinical Implications and Future Directions
Improved Risk Assessment
Enabling better personalized cancer screening recommendations based on resolved VUS and ancestry-informed risk models.
Therapeutic Targeting
Identifying patients who may benefit from existing targeted therapies based on their specific genetic profile.
Drug Development
Revealing new ancestry-informed molecular targets for precision medicines tailored to diverse populations.
Reduced Disparities
Ensuring equitable access to advancing genomic medicine for all populations regardless of ancestry.
As research continues to unravel the complex interplay between genetic ancestry, somatic mutations, and cancer development, the goal remains clear: transforming variants of uncertain significance from sources of anxiety and clinical paralysis into actionable information that benefits all patients, regardless of their ethnic background.
From Uncertainty to Precision
The journey to resolve variants of uncertain significance in Hispanic/Latino colorectal cancer patients represents more than a technical challenge—it embodies the promise of truly equitable precision medicine.
By acknowledging and addressing the genomic diversity gap, researchers are not only solving a scientific problem but also advancing health justice.
As we continue to build more inclusive genomic databases and develop more sophisticated analytical approaches, we move closer to a future where genetic testing provides clear, actionable information for all patients, regardless of their ancestry. The resolution of VUS in Hispanic/Latino communities will mark a significant milestone in this journey, ensuring that the benefits of genomic medicine are shared by everyone.