Race-specific alternative splicing patterns reveal biological mechanisms behind prostate cancer disparities
For years, scientists have known that prostate cancer doesn't affect all men equally. Striking population disparities have persisted, with African American men experiencing 1.6-fold higher incidence and 2.4-fold higher mortality rates compared to European American men 1 . While socioeconomic factors and healthcare access play significant roles, these alone cannot explain the biological aggressiveness often seen in prostate cancers from men of African ancestry 1 .
The answer may lie not in which genes are expressed, but in how they're edited—a sophisticated cellular process called alternative splicing that creates multiple protein versions from a single gene. Recent research reveals that race-specific patterns in this splicing process may hold the key to understanding why some prostate cancers become aggressive much faster than others.
Imagine a movie editor cutting and rearranging scenes from the same raw footage to create different versions of a film—this is essentially what alternative splicing does with our genes .
and non-coding regions (introns)
and exons are spliced together
of exons to be included in the final messenger RNA
to produce multiple protein variants with distinct functions 1
This process explains a long-standing mystery in human biology: how can we have more than 250,000 distinct proteins with only about 20,000 genes? The answer lies in alternative splicing, which occurs in >90% of human genes 1 .
In cancer, the splicing process can go awry, creating protein variants that drive tumor growth and spread. Notable examples in prostate cancer include:
Can be spliced into either pro-apoptotic Bcl-xS or anti-apoptotic Bcl-xL variants with opposite effects on cell survival 1
The AR-V7 splice variant is overexpressed in treatment-resistant prostate cancer and correlated with poor survival 1
Different splice variants are associated with epithelial-to-mesenchymal transition, a key step in cancer metastasis 1
In a comprehensive 2017 study, researchers analyzed 35 prostate cancer and 35 patient-matched normal prostate specimens from African American (AA) and European American (EA) men using advanced exon array technology 1 . The results were striking:
identified when comparing AA versus EA prostate cancers
with 1,876 unique to this comparison 1
These splicing events weren't random—they disproportionately affected cancer-related pathways and showed a significant preference for in-frame events that produce functional proteins in AA cancers 1 .
Data adapted from 2025 study on genetic ancestry-concordant RNA splicing 4
Several critical cancer genes showed distinct splicing patterns between racial groups:
Examples of differentially spliced genes occurring only in AA versus EA prostate cancer 1
To confirm the functional significance of these splicing differences, researchers designed a comprehensive experiment focusing on the PIK3CD-S variant:
The AA-enriched PIK3CD-S splice variant was cloned into expression vectors
EA prostate cancer cell lines were engineered to ectopically overexpress PIK3CD-S
The cellular changes were measured through proliferation, invasion, signaling, and treatment response tests
Mouse xenograft models were used to confirm findings in living organisms 1
The experimental results demonstrated that the AA-enriched PIK3CD-S variant was not merely a passive marker but an active driver of cancer aggression:
Experimental results showing the functional impact of PIK3CD-S expression 1
AKT/mTOR pathway activation was significantly increased 1
Proliferative and invasive capacities were boosted in vitro 1
Mouse xenograft models showed resistance to CAL-101 treatment 1
High PIK3CD-S expression in patient specimens associated with poor survival 1
Recent 2025 research has expanded these findings, analyzing prostate tumors and paired tumor-adjacent normal tissues from self-reported Black and White patients with estimated genetic ancestry 4 . This GENomics of CAncer DisparitiEs (GENCADE) study revealed:
The number of alternative splicing events between tumors and normal tissues differed between Black and White patients with both high-grade and low-grade PCa 4
Black patients with high-grade prostate cancer had increased risk of biochemical recurrence 4
Estimated genetic ancestry showed concordance with self-reported race in the study cohort 4
| Genetic Factor | Association with Prostate Cancer | Potential Clinical Application |
|---|---|---|
| rs35148638 (5q14.3) | Associated with Gleason score and aggressive disease | Risk stratification biomarker 7 |
| rs78943174 (3q26.31) | Associated with disease aggressiveness | Prognostic indicator 7 |
| BRCA2, ATM pLOF variants | Increase aggressive prostate cancer risk | Informing screening protocols 5 |
| Stemness gene SNPs | Racial disparities in susceptibility | Understanding biological differences 8 |
Affymetrix Human Exon 1.0 ST GeneChip enabled genome-wide detection of differential splicing events 1
High-depth RNA sequencing provides exon-level resolution of transcriptome, identifying both known and novel splicing events 4
Mouse models allow testing of functional significance of splice variants in living organisms 1
The discovery of race-related alternative splicing variants represents a paradigm shift in understanding cancer disparities. As Dr. Steven R. Patierno noted, "Cancer disparities are the result of a complex interplay among social, structural (health system), lifestyle, and biological determinants of health" .
Splice variants could help identify patients at risk for aggressive disease
Splicing-specific treatments might overcome resistance mechanisms
Race-aware clinical trials could develop more effective treatments for all populations
The future of addressing prostate cancer disparities may lie not only in ensuring equal access to care but in understanding these fundamental biological differences—developing precisely targeted treatments that account for the unique splicing patterns in each patient's cancer.
As research progresses, the hope is that these insights will lead to targeted therapies that can correct aberrant splicing or exploit splice-specific vulnerabilities, ultimately reducing and eliminating the stark disparities in prostate cancer outcomes.