Researchers from Vanderbilt University Medical Center, the National Cancer Institute, and other U.S. centers have uncovered previously underappreciated genetic contributors to lung cancer risk among individuals of African ancestry, who experience disproportionately high rates of the disease and often face more aggressive forms at diagnosis.
The findings, published in the American Journal of Human Genetics, expand understanding of lung cancer genetics in African ancestry populations, which have historically been underrepresented in genomic studies.
Large-Scale, Ancestry-Aware Analysis
The study analysed genotyping profiles from 2,390 African ancestry individuals with lung cancer and 4,100 ancestry-matched, unaffected controls. Researchers employed both a standard genome-wide association study (GWAS) and a local ancestry-aware GWAS using a statistical framework called Tractor. Analyses were further stratified by smoking status.
Among the participants, 4,877 reported ever having smoked, and 1,613 were classified as never-smokers. Within the ever-smoker group, 2,222 had developed lung cancer, while 2,655 served as controls. In the never-smoker group, 168 participants had lung cancer and 1,445 were controls.
Key Genetic Findings
- Researchers confirmed strong genome-wide associations at the chromosome 15q25.1 locus, previously linked to lung cancer.
- Nine additional loci, either new or previously suggested, showed potential links when considering African- or European-derived alleles.
- Three newly identified risk sites on chromosomes 8, 13, and 15 were validated in replication analyses with 2,109 additional African ancestry participants.
“These latest results confirm prior robust associations at 15q25 and highlight additional loci connected to lung cancer risk in African ancestry populations,” explained Melinda Aldrich, a genetic medicine researcher at Vanderbilt. “We find variants near genes associated with tumor suppression and cancer metastasis.”
Multi-Ancestry Meta-Analysis
To strengthen their findings, the team conducted a broader meta-analysis incorporating over 73,800 participants from East Asian, European, and African ancestry studies. This approach not only validates previously identified loci but also uncovers three new risk sites on chromosomes 2, 4, and 6.
Notably, the locus on chromosome 4 near ZFP42 and TRIML2, previously linked to lung function in chronic obstructive pulmonary disease – highlights a potential shared biological pathway between lung function and cancer risk.
By comparing results across ancestries, the study distinguishes universal from ancestry-specific genetic contributors, enhances the accuracy of future polygenic risk scores, and ensures discoveries are globally relevant and more inclusive for underrepresented populations.
Pathway Insights and Potential Targets
Through fine-mapping, gene set enrichment, and transcriptome-wide association analyses combining RNA sequences, genotyping profiles, and cell type-specific gene expression data, the researchers identified 16 SNPs likely to have a causal role in lung cancer in African ancestry individuals. The affected genes were enriched in pathways related to cancer progression, cytokine interactions, JAK-STAT signaling, and PI3K-AKT signaling.
“These findings illuminate biological pathways involved in lung cancer and suggest potential opportunities for drug target identification,” Aldrich said. The research could also improve identification of high-risk individuals who might benefit from targeted lung cancer screening.
Equitable Genomic Data and the Role of Federation
Currently, roughly 80% of genetic data originates from individuals of European ancestry, while African, Latin American, South Asian, and Indigenous populations are dramatically underrepresented, together accounting for less than 20% of the data. This Eurocentric bias limits discovery and clinical utility for diverse populations.
Zetta Genomics is actively working to federate genomic data across major global genome projects, including initiatives in Africa (H3Africa), Asia (GenomeAsia100K, SG10K), Latin America, and the U.S. (All of Us, 100,000 Genomes Project). If fully federated, the representation of non-European ancestry could increase from ~20% to 50–60%, dramatically improving equity in genomic research and enabling discoveries in populations historically overlooked, including African ancestry groups.
Federated approaches allow secure collaboration and data sharing while respecting privacy and governance, ensuring that findings like those in lung cancer are more broadly applicable and clinically meaningful.
Looking Ahead
Follow-up studies are underway to develop genetic risk scores for African ancestry populations, and further research will explore how genetic background interacts with environmental exposures to influence lung cancer risk. Federated, equitable genomic data initiatives are expected to play a key role in these efforts, helping to ensure that the next wave of discoveries benefits all populations, not just majority-represented groups.
Sources
- Vanderbilt University Medical Center News: Genetic analysis of people with African ancestry reveals lung cancer susceptibilities
- American Journal of Human Genetics: Genetic analysis in African ancestry populations reveals lung cancer risk factors
- Zetta Genomics Official Website
