Etiological roles of core promoter variation in triple-negative breast cancer

Abnormal gene expression plays key role in cancer development. Acore promoter is located around the transcriptional start site. Through interaction between core promoter se-quences and transcriptional factors, core promoter controls transcriptional initiation. We hy-pothesized that in cancer, core promoter sequences could be mutated to interfere the interaction with transcriptional factors, resulting in altered transcriptional initiation and abnormal gene expression and cancer development. We used triple-negative breast cancer (TNBC) as a model to test our hypothesis. We collected genome-wide core promoter variants from 279 TNBC genomes. After extensive filtering of normal genomic polymorphism, we iden-tified 19,427 recurrent somatic variants in 1,238 core promoters of 1,274 genes and 1,694 recurrent germline variants in 272 core promoters of 294 genes. Many of the affected genes were oncogenes and tumor suppressors. Analysis of RNA-seq data from the same patient cohort identified increased or decreased gene expression in 439 somatic and 85 germline variants-affected genes, and the results were validated by luciferase reporter assay. By comparing with the core promoter variation data from 610 unclassified breast cancer, we observed that core promoter variants in TNBC were highly TNBC-specific. We further identified the drugs targeting the genes with core promoter variation. Our study demonstrates that core promoter is highly mutable in cancer, and can play etiological roles in TNBC and other types of cancer through influencing transcriptional initiation. ?? 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Automated summary

Abnormal gene expression plays a key role in cancer development. We hypothesized that in cancer, core promoter sequences could be mutated to interfere with transcriptional factors' interaction, resulting in altered transcriptional initiation, abnormal gene expression, and cancer development. Using triple-negative breast cancer (TNBC) as a model, we identified somatic and germline variants in core promoters of genes that affect gene expression and validated the findings. Comparison with core promoter variation data from unclassified breast cancer revealed TNBC-specific core promoter variants. This study demonstrates the mutability of core promoters in cancer and their impact on transcriptional initiation in TNBC and other cancer types.