RESEARCH ARTICLE Diagnostic significance of alternative splice variants of REST and DOPEY1 in the peripheral blood of patients with breast cancer Ave Kris Lend & Anna Kazantseva & Anri Kivil & Vahur Valvere & Kaia Palm Received: 18 September 2014 /Accepted: 14 November 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014 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 effec- tiveness of therapy in the neoadjuvant setting. Keywords Alternative splicing . Locally advanced breast cancer . Neoadjuvant therapy . Blood . REST . DOPEY1 Introduction Recent developments in the field of cancer research focusing on biomarkers are towards simple, cost-effective, and non- invasive tests. These tests are expected to indicate cancer risk, allow early detection, patient stratification for therapy, and monitor disease progression. For a long time, breast cancer, the second leading cause of death in women, has been classi- fied according to the clinical and pathological criteria for treatment specification. However, molecular characterization has identified at least five different subtypes of breast cancer, allowing more detailed insight into the nature of this disease [1–3]. Given that breast cancer is a highly heterogeneous disease, the use of molecular analysis methods is highly justified, hence pushing the road towards a personalized med- icine approach. Ave Kris Lend and Anna Kazantseva contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s13277-014-2860-6) contains supplementary material, which is available to authorized users. A. K. Lend : A. Kazantseva : A. Kivil : K. Palm (*) Protobios LLC, Mäealuse 4, 12618 Tallinn, Estonia e-mail: kaia@protobios.com A. K. Lend e-mail: avekris@protobios.com A. Kazantseva e-mail: anna@protobios.com A. Kivil e-mail: anri@protobios.com A. K. Lend : V. Valvere : K. Palm Competence Center for Cancer Research, Akadeemia tee 15, 12618 Tallinn, Estonia V. Valvere e-mail: Vahur.Valvere@regionaalhaigla.ee A. Kivil : K. Palm The Department of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia V. Valvere Clinic of Hematology and Oncology, North Estonia Medical Center, J. Sütiste tee 19, 13419 Tallinn, Estonia Tumor Biol. DOI 10.1007/s13277-014-2860-6