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Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe

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Abstract

RECQL is a DNA helicase required for genomic stability. Two studies have recently identified RECQL as a novel breast cancer susceptibility gene. The most common RECQL mutation, the 4 bp-deletion c.1667_1667+3delAGTA, was five-fold enriched in Polish breast cancer patients, but the exact magnitude of the risk is uncertain. We investigated two hospital-based breast cancer case–control series from Belarus and Germany, respectively, comprising a total of 2596 breast cancer patients and 2132 healthy females. The mutation was found in 9 cases and 6 controls, with an adjusted Odds Ratio 1.23 (95% CI 0.44–3.47; p = 0.69) in the combined analysis. Among the cases, heterozygosity for c.1667_1667+3delAGTA was linked with estrogen-receptor positive breast cancer. There was no significant difference in age at diagnosis between carriers and non-carriers, and only one of the carriers reported a first-degree family history. Meta-analysis with the initial study from Poland suggests an about two-fold increase in risk for this mutation (OR 2.51; 95% CI 1.13–5.57, p = 0.02). Altogether, the data indicate that RECQL* c.1667_1667+3delAGTA is not a high-risk mutation for breast cancer though it could represent a moderate-risk breast cancer susceptibility allele. Further studies will be required to determine the clinical significance of testing for this RECQL mutation.

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References

  1. Easton D, Pharoah PD, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL, Devilee P, Meindl A, Couch FJ, Southey M, Goldgar DE, Evans DG, Chenevix-Trench G, Rahman N, Robson M, Domchek SM, Foulkes WD (2015) Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372:2243–2257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bogdanova N, Helbig S, Dörk T (2013) Hereditary breast cancer: ever more pieces to the polygenic puzzle. Hered Cancer Clin Pract 11(1):12

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ghoussaini M, Pharoah PD, Easton DF (2013) Inherited genetic susceptibility to breast cancer: the beginning of the end or the end of the beginning? Am J Pathol 183(4):1038–1051

    Article  CAS  PubMed  Google Scholar 

  4. Croteau DL, Popuri V, Opresko PL, Bohr VA (2014) Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem 83:519–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bernstein KA, Gangloff S, Rothstein R (2010) The RecQ DNA helicases in DNA repair. Annu Rev Genet 44:393–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Larsen NB, Hickson ID (2013) RecQ Helicases: conserved guardians of genomic integrity. Adv Exp Med Biol 767:161–184

    Article  CAS  PubMed  Google Scholar 

  7. Sami F, Sharma S (2013) Probing genome maintenance functions of human RECQ1. Comput Struct Biotechnol J 6:e201303014

    Article  PubMed  PubMed Central  Google Scholar 

  8. Banerjee T, Sommers JA, Huang J, Seidman MM, Brosh RM Jr (2015) Catalytic strand separation by RECQ1 is required for RPA-mediated response to replication stress. Curr Biol 25(21):2830–2838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M, Odreman F, Glatter T, Graziano S, Mendoza-Maldonado R, Marino F, Lucic B, Biasin V, Gstaiger M, Aebersold R, Sidorova JM, Monnat RJ Jr, Lopes M, Vindigni A (2013) Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol 20(3):347–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Parvathaneni S, Stortchevoi A, Sommers JA, Brosh RM Jr, Sharma S (2013) Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks. PLoS ONE 8(5):e62481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sami F, Lu X, Parvathaneni S, Roy R, Gary RK, Sharma S (2015) RECQ1 interacts with FEN-1 and promotes binding of FEN-1 to telomeric chromatin. Biochem J 468(2):227–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Popuri V, Hsu J, Khadka P, Horvath K, Liu Y, Croteau DL, Bohr VA (2014) Human RECQL1 participates in telomere maintenance. Nucleic Acids Res 42(9):5671–5688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sun J, Wang Y, Xia Y, Xu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Lou H, Xie Y (2015) Mutations in RECQL gene are associated with predisposition to breast cancer. PLoS Genet 11(5):e1005228

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cybulski C, Carrot-Zhang J, Kluźniak W, Rivera B, Kashyap A, Wokołorczyk D, Giroux S, Nadaf J, Hamel N, Zhang S, Huzarski T, Gronwald J, Byrski T, Szwiec M, Jakubowska A, Rudnicka H, Lener M, Masojć B, Tonin PN, Rousseau F, Górski B, Dębniak T, Majewski J, Lubiński J, Foulkes WD, Narod SA, Akbari MR (2015) Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet 47(6):643–646

    Article  CAS  PubMed  Google Scholar 

  15. Kwong A, Shin VY, Cheuk IW, Chen J, Au CH, Ho DN, Chan TL, Ma ES, Akbari MR, Narod SA (2016) Germline RECQL mutations in high risk Chinese breast cancer patients. Breast Cancer Res Treat 157(2):211–215

    Article  CAS  PubMed  Google Scholar 

  16. Bogdanova N, Feshchenko S, Cybulski C, Dörk T (2007) CHEK2 mutation and hereditary breast cancer. J Clin Oncol 25(19):e26

    Article  PubMed  Google Scholar 

  17. Bogdanova N, Feshchenko S, Schürmann P, Waltes R, Wieland B, Hillemanns P, Rogov YI, Dammann O, Bremer M, Karstens JH, Sohn C, Varon R, Dörk T (2008) Nijmegen breakage syndrome mutations and risk of breast cancer. Int J Cancer 122:802–806

    Article  CAS  PubMed  Google Scholar 

  18. Bogdanova N, Cybulski C, Bermisheva M, Datsyuk I, Yamini P, Hillemanns P, Antonenkova NN, Khusnutdinova E, Lubinski J, Dörk T (2009) A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer. Breast Cancer Res Treat 118:207–211

    Article  CAS  PubMed  Google Scholar 

  19. Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Hillemanns P, Dörk T (2010) High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet 78:364–372

    Article  CAS  PubMed  Google Scholar 

  20. Prokofyeva D, Bogdanova N, Dubrowinskaja N, Bermisheva M, Takhirova Z, Antonenkova N, Turmanov N, Datsyuk I, Gantsev S, Christiansen H, Park-Simon TW, Hillemanns P, Khusnutdinova E, Dörk t (2013) 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(2):533–539

    Article  CAS  PubMed  Google Scholar 

  21. Noskowicz M, Bogdanova N, Bermisheva M, Takhirova Z, Antonenkova N, Khusnutdinova E, Bremer M, Christiansen H, Park-Simon TW, Hillemanns P, Dörk T (2014) Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe. Fam Cancer 13(2):137–142

    Article  CAS  PubMed  Google Scholar 

  22. Couch FJ, Nathanson KL, Offit K (2014) Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 343:1466–1470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sokolenko AP, Iyevleva AG, Preobrazhenskaya EV, Mitiushkina NV, Abysheva SN, Suspitsin EN, Kuligina ESh, Gorodnova TV, Pfeifer W, Togo AV, Turkevich EA, Ivantsov AO, Voskresenskiy DV, Dolmatov GD, Bit-Sava EM, Matsko DE, Semiglazov VF, Fichtner I, Larionov AA, Kuznetsov SG, Antoniou AC, Imyanitov EN (2012) High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia. Int J Cancer 130:2867–2873

    Article  CAS  PubMed  Google Scholar 

  24. Thompson ER, Doyle MA, Ryland GL, Rowley SM, Choong DY, Tothill RW, Thorne H, KConFab, Barnes DR, Li J, Ellul J, Philip GK, Antill YC, James PA, Trainer AH, Mitchell G, Campbell IG (2012) Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet 8(9):e1002894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ellingson MS, Hart SN, Kalari KR, Suman V, Schahl KA, Dockter TJ, Felten SJ, Sinnwell JP, Thompson KJ, Tang X, Vedell PT, Barman P, Sicotte H, Eckel-Passow JE, Northfelt DW, Gray RJ, McLaughlin SA, Moreno-Aspitia A, Ingle JN, Moyer AM, Visscher DW, Jones K, Conners A, McDonough M, Wieben ED, Wang L, Weinshilboum R, Boughey JC, Goetz MP (2015) Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy. Breast Cancer Res Treat 153(2):435–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sokolenko AP, Preobrazhenskaya EV, Aleksakhina SN, Iyevleva AG, Mitiushkina NV, Zaitseva OA, Yatsuk OS, Tiurin VI, Strelkova TN, Togo AV, Imyanitov EN (2015) Candidate gene analysis of BRCA1/2 mutation-negative high-risk Russian breast cancer patients. Cancer Lett 359(2):259–261

    Article  CAS  PubMed  Google Scholar 

  27. Lindor NM, Hopper J, Dowty J (2016) Estimating cumulative risks for breast cancer for carriers of variants in uncommon genes. Fam Cancer 15:367–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kushniarevich A, Utevska O, Chuhryaeva M, Agdzhoyan A, Dibirova K, Uktveryte I, Möls M, Mulahasanovic L, Pshenichnov A, Frolova S, Shanko A, Metspalu E, Reidla M, Tambets K, Tamm E, Koshel S, Zaporozhchenko V, Atramentova L, Kučinskas V, Davydenko O, Goncharova O, Evseeva I, Churnosov M, Pocheshchova E, Yunusbayev B, Khusnutdinova E, Marjanović D, Rudan P, Rootsi S, Yankovsky N, Endicott P, Kassian A, Dybo A, Genographic Consortium, Tyler-Smith C, Balanovska E, Metspalu M, Kivisild T, Villems R, Balanovsky O (2015) Genetic heritage of the balto-slavic speaking populations: a synthesis of autosomal mitochondrial and Y-chromosomal data. PLoS ONE 10(9):e0135820

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lucic B, Zhang Y, King O, Mendoza-Maldonado R, Berti M, Niesen FH, Burgess-Brown NA, Pike AC, Cooper CD, Gileadi O, Vindigni A (2011) A prominent β-hairpin structure in the winged-helix domain of RECQ1 is required for DNA unwinding and oligomer formation. Nucleic Acids Res 39(5):1703–1717

    Article  CAS  PubMed  Google Scholar 

  30. Pike AC, Gomathinayagam S, Swuec P, Berti M, Zhang Y, Schnecke C, Marino F, von Delft F, Renault L, Costa A, Gileadi O, Vindigni A (2015) Human RECQ1 helicase-driven DNA unwinding, annealing, and branch migration: insights from DNA complex structures. Proc Natl Acad Sci USA 112(14):4286–4291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the patients and healthy volunteers for their participation and the many clinicians at hospitals in Belarus and Hannover for their support of this work. The Hannover laboratory was supported by the Rudolf Bartling Foundation, the Lower Saxonian Cancer Society and the Claudia von Schilling Foundation for Breast Cancer Research.

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Authors and Affiliations

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

    Natalia Bogdanova, Katja Pfeifer, Peter Schürmann, Peter Hillemanns, Tjoung-Won Park-Simon & Thilo Dörk

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

    Natalia Bogdanova & Hans Christiansen

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

    Natalia Antonenkova

  4. Hospital DIAKOVERE Henriettenstift, Hannover, Germany

    Wulf Siggelkow

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  1. Natalia Bogdanova
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  9. Thilo Dörk
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Correspondence to Thilo Dörk.

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The authors have no disclosures and declare there is no conflict of interest in the writing, preparing, or finalizing of this manuscript.

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

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Natalia Bogdanova and Katja Pfeifer are joint first authors.

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Bogdanova, N., Pfeifer, K., Schürmann, P. et al. Analysis of a RECQL splicing mutation, c.1667_1667+3delAGTA, in breast cancer patients and controls from Central Europe. Familial Cancer 16, 181–186 (2017). https://doi.org/10.1007/s10689-016-9944-y

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  • DOI: https://doi.org/10.1007/s10689-016-9944-y

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