Skip to main content

Advertisement

SpringerLink
Log in

Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene

  • Brief Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

There is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by BRCA1 and BRCA2 genes. In this report, next-generation sequencing (NGS) techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility.

Methods

Using whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene ATM (c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in BRCA1/2 (BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer.

Results

Although the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the ATM gene revealed 1.78% prevalence of mutations in the ATM gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about ATM mutations were very limited.

Conclusion

ATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Melchor L, Benitez J (2013) The complex genetic landscape of familial breast cancer. Hum Genet 132(8):845–863. doi:10.1007/s00439-013-1299-y

    Article  CAS  PubMed  Google Scholar 

  2. Cybulski C, Carrot-Zhang J, Kluzniak W, Rivera B, Kashyap A, Wokolorczyk D, Giroux S, Nadaf J, Hamel N, Zhang S, Huzarski T, Gronwald J, Byrski T, Szwiec M, Jakubowska A, Rudnicka H, Lener M, Masojc B, Tonin PN, Rousseau F, Gorski B, Debniak T, Majewski J, Lubinski J, Foulkes WD, Narod SA, Akbari MR (2015) Germline RECQL mutations are associated with breast cancer susceptibility. Nat Genet 47(6):643–646. doi:10.1038/ng.3284

    Article  CAS  PubMed  Google Scholar 

  3. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873–875. doi:10.1038/ng1837

    Article  CAS  PubMed  Google Scholar 

  4. Southey MC, Goldgar DE, Winqvist R, Pylkäs K, Couch F, Tischkowitz M, Foulkes WD, Dennis J, Michailidou K, van Rensburg EJ, Heikkinen T et al (2016) PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet. doi:10.1136/jmedgenet-2016-103839

    Google Scholar 

  5. Taylor AM, Lam Z, Last JI, Byrd PJ (2015) Ataxia telangiectasia: more variation at clinical and cellular levels. Clin Genet 87(3):199–208. doi:10.1111/cge.12453

    Article  CAS  PubMed  Google Scholar 

  6. Brunet J, Gutierrez-Enriquez S, Torres A, Berez V, Sanjose S, Galceran J, Izquierdo A, Menendez JA, Guma J, Borras J (2008) ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations. Clin Genet 73(5):465–473. doi:10.1111/j.1399-0004.2008.00987.x

    Article  CAS  PubMed  Google Scholar 

  7. Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N, Verheijen F, Catsman-Berrevoets CE, Wulffraat NM, Cobben JM, Hiel J, Brunt ER, Peeters EA, Gomez Garcia EB, van der Knaap MS, Lincke CR, Laan LA, Tijssen MA, van Rijn MA, Majoor-Krakauer D, Visser M, van ‘t Veer LJ, Kleijer WJ, van de Warrenburg BP, Warris A, de Groot IJ, de Groot R, Broeks A, Preijers F, Kremer BH, Weemaes CM, Taylor MA, van Deuren M, Willemsen MA (2012) Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat 33(3):561–571. doi:10.1002/humu.22016

    Article  CAS  PubMed  Google Scholar 

  8. Claes K, Depuydt J, Taylor AM, Last JI, Baert A, Schietecatte P, Vandersickel V, Poppe B, De Leeneer K, D’Hooghe M, Vral A (2013) Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives. Neuromol Med 15(3):447–457. doi:10.1007/s12017-013-8231-4

    Article  CAS  Google Scholar 

  9. Kiiski JI, Pelttari LM, Khan S, Freysteinsdottir ES, Reynisdottir I, Hart SN, Shimelis H, Vilske S, Kallioniemi A, Schleutker J, Leminen A, Bützow R, Blomqvist C, Barkardottir RB, Couch FJ, Aittomäki K, Nevanlinna H (2014) Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. PNAS 111(42):15172–15177. doi:10.1073/pnas.1407909111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomäki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, Andrulis IL, Radice P, Tondini C, Manoukian S, Toland AE, Miron P, Weitzel JN, Domchek SM, Poppe B, Claes KB, Yannoukakos D, Concannon P, Bernstein JL, James PA, Easton DF, Goldgar DE, Hopper JL, Rahman N, Peterlongo P, Nevanlinna H, King MC, Couch FJ, Southey MC, Winqvist R, Foulkes WD, Tischkowitz M (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371(6):497–506. doi:10.1056/NEJMoa1400382

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, Thornton A, Norquist BM, Casadei S, Nord AS, Agnew KJ, Pritchard CC, Scroggins S, Garcia RL, King MC, Swisher EM (2014) Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20(3):764–775. doi:10.1158/1078-0432.CCR-13-2287

    Article  CAS  PubMed  Google Scholar 

  12. Hirotsu Y, Nakagomi H, Sakamoto I, Amemiya K, Oyama T, Mochizuki H, Omata M (2015) Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer. Mol Genet Genomic Med 3(5):459–466. doi:10.1002/mgg3.157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kurian AW, Hare EE, Mills MA, Kingham KE, McPherson L, Whittemore AS, McGuire V, Ladabaum U, Kobayashi Y, Lincoln SE, Cargill M, Ford JM (2014) Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32(19):2001–2009. doi:10.1200/JCO.2013.53.6607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, Devilee P, Russell NS, van Leeuwen FE, van ‘t Veer LJ (2000) ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am J Hum Genet 66(2):494–500. doi:10.1086/302746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Diez O, Osorio A, Duran M, Martinez-Ferrandis JI, de la Hoya M, Salazar R, Vega A, Campos B, Rodriguez-Lopez R, Velasco E, Chaves J, Diaz-Rubio E, Jesus Cruz J, Torres M, Esteban E, Cervantes A, Alonso C, San Roman JM, Gonzalez-Sarmiento R, Miner C, Carracedo A, Eugenia Armengod M, Caldes T, Benitez J, Baiget M (2003) Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat 22(4):301–312. doi:10.1002/humu.10260

    Article  CAS  PubMed  Google Scholar 

  16. Byrd PJ, McConville CM, Cooper P, Parkhill J, Stankovic T, McGuire GM, Thick JA, Taylor AM (1996) Mutations revealed by sequencing the 5′ half of the gene for ataxia telangiectasia. Hum Mol Genet 5(1):145–149. doi:10.1093/hmg/5.1.145

    Article  CAS  PubMed  Google Scholar 

  17. Telatar M, Wang Z, Udar N, Liang T, Bernatowska-Matuszkiewicz E, Lavin M, Shiloh Y, Concannon P, Good RA, Gatti RA (1996) Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation screening. Am J Hum Genet 59(1):40–44

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cavalieri S, Funaro A, Porcedda P, Turinetto V, Migone N, Gatti RA, Brusco A (2006) ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions. Hum Mutat 27(10):1061. doi:10.1002/humu.9454

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all the members of the Human Genotyping Unit (CEGEN), Human Genetics Programme (Spanish National Cancer Centre, CNIO) for their collaboration in this project. WES was funded by the National Centre for Genomic Analysis (CNAG) as part of the Project “300 exomes to elucidate rare diseases”. This study was partially supported  by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Network on Rare Diseases (CIBERER) by the Health Ministry PI12/00070, FEDER funds and H2020 (BRIDGES Project, Number 634935) and FIS 15/00059. ATT is a recipient of La-Caixa foundation scholarship. LPC was funded by the Torres-Quevedo programme PTQ-12-05350 from the Ministry of Science and Innovation of Spain.

Author information

Authors and Affiliations

  1. Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain

    A. Tavera-Tapia, M. I. Ceballos, A. Barroso, J. Benitez & A. Osorio

  2. Medical Genetics Unit, Sistemas Genómicos, Parque Tecnológico de Valencia, Ronda G. Marconi 6, 46980, Paterna, Spain

    L. Pérez-Cabornero, V. Felipe-Ponce & S. Santillan-Garzón

  3. Hereditary Cancer Unit, Medical Oncology Service, Hospital Morales Meseguer, Av Marqués de los Vélez, s/n, 30008, Murcia, Spain

    J. A. Macías

  4. Monoclonal Antibody Unit, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain

    G. Roncador

  5. Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC, Calle del Prof Martín Lagos, s/n, 28040, Madrid, Spain

    M. de la Hoya & T. Caldés

  6. Medical Oncology Department, Hospital Reina Sofía, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain

    R. Serrano-Blanch

  7. Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, Av. de Valdecilla, s/n, 39008, Santander, Spain

    C. Hinojo

  8. Medical Genetics Unit, Biochemistry Service, Miguel Servet Hospital, Paseo Isabel la Católica, 1-3, 50009, Saragossa, Spain

    M. D. Miramar-Gallart

  9. Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain

    M. Urioste

  10. Spanish Network on Rare Diseases (CIBERER), Monforte de Lemos 3-5. Pabellón 11. Planta 0, 28029, Madrid, Spain

    J. Benitez & A. Osorio

  11. Genotyping Unit, CEGEN, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain

    J. Benitez

Authors
  1. A. Tavera-Tapia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Pérez-Cabornero
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. A. Macías
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. I. Ceballos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Roncador
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. de la Hoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Barroso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V. Felipe-Ponce
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. Serrano-Blanch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. Hinojo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. D. Miramar-Gallart
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M. Urioste
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. T. Caldés
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S. Santillan-Garzón
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J. Benitez
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. A. Osorio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Osorio.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All the participants of this study signed an informed consent approved by the Ethics Committee of Carlos III Institute of Health (Madrid, Spain).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 14 kb)

Supplementary material 2 (XLSX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tavera-Tapia, A., Pérez-Cabornero, L., Macías, J.A. et al. Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene. Breast Cancer Res Treat 161, 597–604 (2017). https://doi.org/10.1007/s10549-016-4058-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-016-4058-7

Keywords

Search

Navigation