Identifying the Potential Mechanism of Action of SNPs Associated With Breast Cancer Susceptibility With GVITamIN

Frontiers in Bioengineering and Biotechnology

卷:8

An-phi Nguyen⁵  Paola Nicoletti⁶  María Rodríguez Martínez⁶  Damien Arnol⁸  Andrea Califano⁹ 

[1] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, United States;

[2] Department of Biomedical Informatics, Columbia University, New York, NY, United States;

[3] Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States;

[4] Department of Systems Biology, Columbia University, New York, NY, United States;

[5] ETH-Zürich, Zurich, Switzerland;

[6] Herbert Irving Cancer Research Center, Columbia University Medical Center, New York, NY, United States;

[7] Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, United States;

[8] IBM Research–Zurich, Zurich, Switzerland;

[9] J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, United States;

关键词: cancer-susceptibility SNP;    SNP mechanism of action;    transcription factor dysregulation;    breast cancer;    multi-omics integration;    nonparametric hypothesis test;   

DOI  :  10.3389/fbioe.2020.00798

来源: DOAJ

【 摘 要 】

In the last decade, a large number of genome-wide association studies have uncovered many single-nucleotide polymorphisms (SNPs) that are associated with complex traits and confer susceptibility to diseases, such as cancer. However, so far only a few heritable traits with medium-to-high penetrance have been identified. The vast majority of the discovered variants only leads to disease in combination with other still unknown factors. Furthermore, while many studies aimed to link the effect of SNPs to changes in molecular phenotypes, the analysis has been often focused on testing associations between a single SNP and a transcript, hence disregarding the dysregulation of gene regulatory networks that has been shown to play an essential role in disease onset, notably in cancer. Here we take a systems biology approach and develop GVITamIN (Genetic VarIaTIoN functional analysis tool), a new statistical and computational approach to characterize the effect of a SNP on both genes and transcriptional regulatory programs. GVITamIN exploits a novel statistical approach to combine the usually small effect of disease-susceptibility SNPs, and reveals important potential oncogenic mechanisms, hence taking one step further in the direction of understanding the SNP mechanism of action. We apply GVITamIN on a breast cancer cohort and identify well-known cancer-related transcription factors, such as CTCF, LEF1, and FOXA1, as TFs dysregulated by breast cancer-associated SNPs. Furthermore, our results reveal that SNPs located on the RAD51B gene are significantly associated with an abnormal regulatory activity, suggesting a pivotal role for homologous recombination repair mechanisms in breast cancer.

【 授权许可】

Unknown