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Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom’s syndrome, is associated with breast cancer in Slavic populations

  • Epidemiology
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Abstract

Bloom’s syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic BLM mutations predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case–control study. In the present work, we have investigated the prevalence of this Slavic BLM founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case–control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel–Haenszel OR 5.1, 95 % CI 1.2; 21.9, p = 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9, p = 3.7 × 10−4). A meta-analysis for all published truncating mutations further supports the association of BLM with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6, p = 1.9 × 10−5). Altogether, these data indicate that BLM is not only a gene for Bloom’s syndrome but also might represent a breast cancer susceptibility gene.

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Acknowledgments

We thank the patients and healthy volunteers for their participation and the clinicians at hospitals in Belarus, Kazakhstan, Russia, and Ukraine for their support of this work. We cordially thank Evgeny Imyanitov and his group for providing us with a positive control for this study. D.P. was supported by travel funds from the German Ministry of Education and Research and by grant 12-04-97026 of the Russian Foundation for Basic Research. N.B. was supported by an intramural Hannelore-Munke stipend at Hannover Medical School. I.D. was supported by a German Academic Exchange Program (DAAD). The Hannover laboratory was furthermore supported by the Rudolf Bartling Foundation.

Ethical Standards

The experiments in the present study comply with the current laws of the country in which they were performed.

Conflict of interest

None of the authors declares a conflict of interest.

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Authors and Affiliations

  1. Institute of Biochemistry and Genetics, Ufa Science Center, Ufa, Russia

    Darya Prokofyeva, Marina Bermisheva, Zalina Takhirova & Elza Khusnutdinova

  2. Clinics of Obstetrics and Gynaecology, Gynaecology Research Unit, Hannover Medical School, Hannover, Germany

    Darya Prokofyeva, Natalia Bogdanova, Natalia Dubrowinskaja, Marina Bermisheva, Nurzhan Turmanov, Ihor Datsyuk, Tjoung-Won Park-Simon, Peter Hillemanns & Thilo Dörk

  3. Bashkir State University, Ufa, Russia

    Darya Prokofyeva & Elza Khusnutdinova

  4. Clinics of Radiation Oncology, Hannover Medical School, Hannover, Germany

    Natalia Bogdanova & Hans Christiansen

  5. Clinics of Urology and Urological Cancer, Hannover Medical School, Hannover, Germany

    Natalia Dubrowinskaja

  6. N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus

    Natalia Antonenkova

  7. Almaty Oncology Center, State Oncology Institute, Almaty, Kazakhstan

    Nurzhan Turmanov

  8. R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences, Kyiv, Ukraine

    Ihor Datsyuk

  9. Medical State University of the Republic Bashkortostan, Ufa, Russia

    Shamil Gantsev

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  1. Darya Prokofyeva
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Correspondence to Thilo Dörk.

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10549_2012_2357_MOESM1_ESM.tif

Supplementary material 1 (TIFF 269 kb): Identification of the BLM mutation p.Q548X by means of high-resolution melting analysis (top) and direct sequencing (bottom). Top: Normalized fluorescence graph for high-resolution melting analysis of the mutant amplicon carrying the p.Q548X mutation in comparison with wildtype controls. Bottom: Direct sequencing of exon 7 in the BLM gene, sense strand, in a sample with heterozygosity for mutation p.Q548X (C/T, asterisk)

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Prokofyeva, D., Bogdanova, N., Dubrowinskaja, N. et al. Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom’s syndrome, is associated with breast cancer in Slavic populations. Breast Cancer Res Treat 137, 533–539 (2013). https://doi.org/10.1007/s10549-012-2357-1

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