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Diagnostic significance of alternative splice variants of REST and DOPEY1 in the peripheral blood of patients with breast cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Changes in alternative splicing have been linked to cancer development. We hypothesized that changes occurring in tumor tissue can also be detected in the peripheral blood of cancer patients leading to discovery of blood biomarkers of breast cancer. Alternative splicing profiles of 94 genes were examined in cancerous breast tissue. Discriminating splice variants were analyzed in the peripheral blood of early stage (BCI/II) (stage I–II; n = 26), neoadjuvant receiving locally advanced breast cancer patients (LABC) (stage IIb–IIIa, b; n = 10) and healthy volunteers (n = 26) using qRT-PCR analysis. Changes in marker expression during neoadjuvant therapy were analyzed at 15 timepoints. High expression of REST-N50, the alternatively spliced variant of REST, was detected in the blood of LABC patients but not in BCI/II and healthy controls (p = 0.0032 and p = 0.0029, respectively). Expression levels of DOPEY1v2, the alternative splice variant of DOPEY1, in the blood could differentiate cancer from healthy controls (p = 0.024) and discriminate between patient groups (BCI/II vs LABC, p = 0.002). Positive response to neoadjuvant therapy of REST-N50-positive LABC patients correlated with a decrease in REST-N50 levels (p < 0.0001). Assessment of REST-N50 and DOPEY1v2 may prove useful in diagnostic blood tests of breast cancer. REST-N50 shows a high potential as a blood biomarker for evaluating the effectiveness of therapy in the neoadjuvant setting.

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Acknowledgments

This study was supported by Protobios’s grants from the Enterprise of Estonia and baseline financing from the Estonian Ministry of Education and Research. We are grateful to Dr. Jõeste and NEMC for the tissue samples. We thank K.J.M. Rand for the work with in silico database, primer design, and cloning; Dr. Pruunsild and Prof. Timmusk for the resources provided; and K. Taal and H. Verev for the technical help in sample handling.

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Authors and Affiliations

  1. Protobios LLC, Mäealuse 4, 12618, Tallinn, Estonia

    Ave Kris Lend, Anna Kazantseva, Anri Kivil & Kaia Palm

  2. Competence Center for Cancer Research, Akadeemia tee 15, 12618, Tallinn, Estonia

    Ave Kris Lend, Vahur Valvere & Kaia Palm

  3. The Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 12618, Tallinn, Estonia

    Anri Kivil & Kaia Palm

  4. Clinic of Hematology and Oncology, North Estonia Medical Center, J. Sütiste tee 19, 13419, Tallinn, Estonia

    Vahur Valvere

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  1. Ave Kris Lend
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  2. Anna Kazantseva
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  3. Anri Kivil
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  4. Vahur Valvere
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  5. Kaia Palm
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Correspondence to Kaia Palm.

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Ave Kris Lend and Anna Kazantseva contributed equally to this work.

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Lend, A.K., Kazantseva, A., Kivil, A. et al. Diagnostic significance of alternative splice variants of REST and DOPEY1 in the peripheral blood of patients with breast cancer. Tumor Biol. 36, 2473–2480 (2015). https://doi.org/10.1007/s13277-014-2860-6

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  • DOI: https://doi.org/10.1007/s13277-014-2860-6

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