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Background <p>Breast cancer represents the most prevalent form of tumors among females and is characterized by a significant genetic component. The brain is a frequent site of metastasis for breast cancer. Although numerous loci associated with breast cancer brain metastasis (BCBM) have been identified, the critical regulatory genes underlying BCBM remain largely unclear.</p> Methods <p>The FinnGen R11 dataset was combined with Genotype-Tissue Expression Project (GTEx) for Transcriptome-wide Association Study (TWAS). The Unified Test for Molecular Signatures (UTMOST), Multimarker Analysis of Genomic Annotation (MAGMA), and Functional Summary-based Imputation (FUSION) were used to identify candidate genes. Summary-data-based mendelian randomization (SMR) and co-localization were performed further to elucidate the association between key genes and BCBM. Finally, multiple external cohorts were obtained to validate the findings.</p> Result <p>In our study, 12 new genes associated with breast cancer were identified with TWAS. Subsequently, both SMR and co-localization have shown that CAPS8 was only expressed in brain tissues including frontal cortex and cerebellar hemispheres associated with breast cancer. Potential regulation of CASP8 could occur in BCBM. Finally, the findings were ultimately validated by external clinical cohorts.</p> Conclusion <p>Our study identified key gene CASP8, which was associated with BCBM, providing new insights into the occurrence of BCBM.</p>

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Novel insight of critical genes involved in breast cancer brain metastasis: evidence from a cross-tissue transcriptome association study and validation through external clinical cohorts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月16日

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  • Jinsong Liu,
  • Xiao Guan,
  • Songlin Gao,
  • Liuliu Quan,
  • Min Dou,
  • Jian Yue,
  • Mengwu Shi,
  • Peng Yuan

摘要

Background

Breast cancer represents the most prevalent form of tumors among females and is characterized by a significant genetic component. The brain is a frequent site of metastasis for breast cancer. Although numerous loci associated with breast cancer brain metastasis (BCBM) have been identified, the critical regulatory genes underlying BCBM remain largely unclear.

Methods

The FinnGen R11 dataset was combined with Genotype-Tissue Expression Project (GTEx) for Transcriptome-wide Association Study (TWAS). The Unified Test for Molecular Signatures (UTMOST), Multimarker Analysis of Genomic Annotation (MAGMA), and Functional Summary-based Imputation (FUSION) were used to identify candidate genes. Summary-data-based mendelian randomization (SMR) and co-localization were performed further to elucidate the association between key genes and BCBM. Finally, multiple external cohorts were obtained to validate the findings.

Result

In our study, 12 new genes associated with breast cancer were identified with TWAS. Subsequently, both SMR and co-localization have shown that CAPS8 was only expressed in brain tissues including frontal cortex and cerebellar hemispheres associated with breast cancer. Potential regulation of CASP8 could occur in BCBM. Finally, the findings were ultimately validated by external clinical cohorts.

Conclusion

Our study identified key gene CASP8, which was associated with BCBM, providing new insights into the occurrence of BCBM.