Introduction: Pancreatic ductal adenocarcinoma (PDAC) has seen increasing global rates and notable racial disparities in its rates of incidence, severity, as well as mortality. Black patients are disproportionately affected in comparison with White and Asian patients as seen through data analysis. The genetic and epigenetic reasons behind these differences have not been thoroughly investigated and are thus poorly understood.
This study used data from The Cancer Genome Atlas (TCGA) drawn from UCSC Xena Browser to explore the molecular characteristics of PDAC in a racially diverse group of patients. We confirmed our findings by examining the expression of GATA6, a transcription factor involved in PDAC, in tumors from black and white patients.
Materials and
Methods: 2.1. Datasets Data from The Cancer Genome Atlas (TCGA) was utilized to identify and collect information on patients diagnosed with PDAC, including their race, somatic mutation profiles, gene expression, and methylation rate. Specifically, the study focused on Pancreas Cancer cases from the TCGA-PAAD data. Both DNA methylation (level 3) and normalized expression data (RNA-seqV2, level 3) were obtained from the UCSC Xena Browser.
2.2. Mutation Profiling We analyzed level 3 data to compare mutational loads and frequencies among the racial groups defined in TCGA. Using the somatic mutations listed in the TCGA MAF file, we compared gene mutation frequencies across 132 Caucasian, 6 African American, and 9 Asian patients. The analysis included computing and comparing the most frequently documented, non-silent somatic mutations.
2.3. DNA Methylation Analysis In DNA methylation analysis, we excluded CpG sites with over 80% missing values, those on X and Y chromosomes, those associated with single nucleotide polymorphisms (SNPs), and cross-reactive probes. Analysis was conducted on the filtered 249,163 CpG sites, and DNA methylation levels were determined using β-values (through conversion to percentage values). Statistical filtering (q-value < 0.05) was applied to identify differentially methylated regions (DMRs) among race groups.
2.4. Statistical Correlation Data was summarized using frequency and percentage for categorical variables, and median and range for continuous variables. Tests for significance were ANOVA, with significance set at p < 0.05.
Results, Conclusions, and Discussions: We have concluded that Black patients with higher GATA6 expression had shorter survival times compared to white patients. We found distinct patterns in somatic mutations, gene expression, and methylation profiles among different races. Black patients showed unique molecular profiles with frequent mutations in genes including RYR1, SAMD7, and CDKN2A. Their tumors also had higher differential gene expression compared to those of white and Asian patients as evidenced by the genes: EWSAT1, SLC5A8, SLC10A2 amongst other genes. This research underscores the significant molecular differences in PDAC among races and the urgent need for more black patient data in genetic research. These insights into the genetic and epigenetic mechanisms behind racial disparities in PDAC can help develop targeted treatments and contribute to the ongoing battle against healthcare inequity.
