Triple-negative breast cancer (TNBC) commonly occurs among African American (AA) women as compared to any other racial group. This subtype shows 10% to 15% cases of all breast cancer diagnoses, and the absence of expression of the progesterone and estrogen receptors identifies it. The epidemiology of TNBC shows a high incidence with 25.2 cases per 100,000 among AA women. Multi-omic breast tumor evaluation was important in TNBC classification for several diseases.
RNA sequencing analysis and whole-exome sequencing (WES) were performed on matched tumor and normal samples from five population-based studies. The breast cancer studies based on populations of AA women were examined for clinical significance using available pooled data. The Institutional Review Board (IRB) of each concerned institution authorized the study from which the patient data and samples were obtained and examined.
In the absence of tumor blocks, complete sections were removed of superfluous wax and nontumor tissues. The Agilent Bioanalyzer was then used for pre-analytic quality control (QC) to verify the size distribution following the extraction process. WES should be performed in the translational genomics laboratory by using the Keck Genomics Platform. The Nova Seq 6000 system was used to perform next-generation sequencing (NGS), including 150-bp paired-end reads.
Around 0.3 trillion paired-end reads were produced by sequencing 513 pairs of similar tumor samples and normal DNA. 478 pairings of tumor-normal samples remaining after 10 samples were mismatched with tumor samples. 4 samples with cryptic similarity were eliminated from the study. It was observed that 20 tumor samples and 1 normal sample did not match the desired sequencing depth.
Potential erroneous calls caused by unobserved germline events and homopolymers were eliminated to evaluate putative indels using a re-alignment procedure. Based on the WES data from a tailored sequencing library, FACETS63 was used to perform somatic copy number alteration (SCNA) and tumor segmentation. In the WES data, double-base substation mutations were rare and not examined, while SBS and signals were recovered. The five tumor samples, including hypermutation phenotypes, were not analyzed with mutation signature analysis.
The germline genotyping data obtained from matched normal samples of WES were used to estimate the global genetic background. Researchers identified 36,059 single-nucleotide variations (SNVs) and 39,103 mutations in the coding area. Out of these, 259 mutations were identified by WES at the RNA level, specifically in TP53 mutations. In other NOTCH family genes, the non-synonymous mutations were detected with an accumulated mutation of 14%.
These results refute the existence of ethnic variations in TNBC biology at the somatic mutation level. Subtype 1 exhibits two B-cell signatures and a greater immune cytolytic activity signature compared to subtype 3 in the gene expression study. The study shows inequalities and treatment weaknesses of TNBC in AA women, which will expand knowledge of breast cancer studies.
References: Yao S, Wei L, Hu Q, et al. Mutational landscape of triple-negative breast cancer in African American women. Nat Genet. 2025. doi:10.1038/s41588-025-02322-y
