Population-specific Mutation Patterns in Breast Tumors from African American, European American, and Kenyan Patients

Abstract

Women of African descent have the highest breast cancer mortality in the United States and are more likely than women from other population groups to develop an aggressive disease. It remains uncertain to what extent breast cancer in Africa is reminiscent of breast cancer in African American or European American patients. Here, we performed whole-exome sequencing of genomic DNA from 191 breast tumor and non-cancerous adjacent tissue pairs obtained from 97 African American, 69 European American, 2 Asian American, and 23 Kenyan patients. Our analysis of the sequencing data revealed an elevated tumor mutational burden in both Kenyan and African American patients, when compared with European American patients. TP53 mutations were most prevalent, particularly in African American patients, followed by PIK3CA mutations, which showed similar frequencies in European American, African American, and the Kenyan patients. Mutations targeting TBX3 were confined to European Americans and those targeting the FBXW7 tumor suppressor to African American patients whereas mutations in the ARID1A gene that are known to confer resistance to endocrine therapy were distinctively enriched among Kenyan patients. A Kyoto Encyclopedia of Genes and Genomes pathway analysis could link FBXW7 mutations to an increased mitochondrial oxidative phosphorylation capacity in tumors carrying these mutations. Finally, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures in tumors correlated with the occurrence of driver mutations, immune cell profiles, and neighborhood deprivation with associations ranging from being mostly modest to occasionally robust. To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer. Significance: The study describes differences in tumor mutational profiles between African American, European American, and Kenyan breast cancer patients. It also investigates how these profiles may relate to the tumor immune environment and the neighborhood environment in which the patients had residence. Finally, it describes an overrepresentation of ARID1A gene mutations in breast tumors of the Kenyan patients.

Whole exome-seq and RNA-seq data reveal unique neoantigen profiles in Kenyan breast cancer patients

“…In contrast to most populations where TP53, PIK3CA and GATA3 are the most mutated genes (Pan et al, 2020;Pipek et al, 2023;Tang et al, 2023), in our study population, three genes MUC16, MUC17 and TTN were highly mutated in over 50% of the samples and produced the highest number of neoantigens. MUC16 has been reported to take part in breast cancer progression and metastasis when overexpressed due to its influence on cell cycle and survival through the JAK2/STAT3 pathway (Lakshmanan et al, 2012).…”

“…Although most of the top 10 mutated genes (80%) were also the top 10 in the number of neoantigens generated, genes like TP53 and PIK3CA that are reported to be highly mutated in most patient cohorts were not among the top 10 mutated genes in this study, but generated among the highest number of neoantigens (Figure 6; Figure 7). ARID1A gene, which showed unique mutational profile in Kenyan population using exome data compared to African American and Asian population (Tang et al, 2023), was not among the highly mutated, but produced neoantigens. We found that most neoantigens were derived predominantly from missense mutations (88%), compared to indels and frameshift mutations (12%).…”

“…For TTN, Oh et al (2020) found that mutations in TTN correlate with tumor mutational burden and high Neoantigens profiling in Kenyan BC patients microsatellite instability, which is associated with poor breast cancer prognosis. Thus, the role of MUC17 and TTN should further be investigated on how mutations in them may relate to early onset of breast cancer in Kenyan patients (Tang et al, 2023).…”

“…WES was performed by the company, Psomagen (https://www.psomagen.com/). This service provider is Clinical Laboratory Improvement Amendments-certified and College of American Pathologists (CAP)-accredited, achieving a sequence depth of 250x for tumor tissues and 150x for adjacent non-cancerous tissues, as previously described by us (Tang et al, 2023). Total RNA from the 23 sample pairs was processed by a NCI Leidos core facility, where library preparation was performed using the TruSeq Poly A kit (Illumina, San Diego, USA ).…”