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Variable number tandem repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG

Abstract

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, in a pilot study with a retrospective cohort design, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of the BRCA1 185delAG pathogenic variant, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, tested the association of VNTRs and breast cancer risk using Cox regression models, and estimated the effect size using a retrospective likelihood approach. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at diagnosis of breast cancer in carriers of the risk alleles compared to those without the risk alleles for seven of eight VNTRs. One example is a VNTR in exon 2 of LINC01973 with a per-allele hazard ratio of 1.58 (1.07–2.33) and 5.28 (2.79–9.99) for the homozygous risk-allele genotype. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for breast cancer.

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Fig. 1: VNTRs and samples included in the analysis.
Fig. 2: Kaplan–Meier estimates of the cumulative probability of breast cancer diagnosis.
Fig. 3: Association of VNTR558420 with ZNF501 gene expression by luciferase assay.

Data availability

Data generated as part of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the women for participating in the study.

Funding

This work was supported by the Basser Foundation (SLN and EF) and the Beckman Research Institute of City of Hope Excellence Awards Program. Sequencing of the VNTRs was performed in the Integrative Genomics Core supported by the National Cancer Institute of the National Institutes of Health under grant number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SLN is partially supported by the Morris and Horowitz Families Professorship. VB and JP were supported in part by R01GM114362, R01HG010149 and RO1HG011558 from the NIH.

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Contributions

SLN and EF conceived of the idea, developed the design, and obtained funding to conduct the study. VB, MB, and JP did the analysis of the sequencing data to obtain genotypes. AA and CP prepared the DNA libraries for sequencing, conducted the luciferase assays, and the validation of the VNTR genotypes. YCD did quality control of the VNTR genotypes and conducted the association statistical analysis. SLN, EF, JW, and YL contributed DNA samples and data. All authors have contributed to, read, and approved the manuscript.

Corresponding author

Correspondence to Susan L. Neuhausen.

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Competing interests

V.Bafna is a co-founder, paid consultant, SAB member and has equity interest in Boundless Bio, inc. and Abterra, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. None of the other authors have any potential competing interests.

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Ding, Y.C., Adamson, A.W., Bakhtiari, M. et al. Variable number tandem repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG. Eur J Hum Genet 31, 216–222 (2023). https://doi.org/10.1038/s41431-022-01238-z

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