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ATM allelic variants associated to hereditary breast cancer in 94 Chilean women: susceptibility or ethnic influences?

  • Epidemiology
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Abstract

Besides BRCA1 and BRCA2, two genes accounting for a small proportion of breast cancer cases, ATM has been widely proposed as a low-penetrance susceptibility gene. Several nucleotide changes have been proposed to be associated with breast cancer, still remaining a high controversy in this sense. We screened the ATM gene in 94 breast cancer patients selected from 78 high-risk families, not presenting a mutation in BRCA1 or BRCA2. We found three novel allelic variants: IVS64 + 51delT and p.L752L, not showing association with hereditary breast cancer, and p.L694L found in one family in two breast cancer patients. Two amino acid substitutions p.S707P and p.F858L, previously reported to be associated with breast cancer, were present in our study in cases and controls, lacking of association with breast cancer. A positive association of c.5557G>A (p.D1853N) was found (OR 2.52, P = 0.008), when analyzed alone and in combination with an intronic variant IVS24-9delT (OR 3.97; P = 0.0003). We postulate that our discrepancies with other reports related to the associated ATM alleles to hereditary breast cancer, as well as discrepancies in the literature between other groups, could be explained by the diversity in the ethnic origins of families gathered in a sole study, and the selection of the control group. In relation to this issue, and based on genetic markers, we found that the Chilean group of breast cancer families in this study has a stronger European genetic component than our control sample selected randomly from the Chilean population.

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References

  1. Gallardo M, Silva A, Rubio L, Alvarez C, Torrealba C, Salinas M, Tapia T, Faundez P, Palma L, Riccio ME, Paredes H, Rodriguez M, Cruz A, Rousseau C, King MC, Camus M, Alvarez M, Carvallo P (2006) Incidence of BRCA and BRCA2 mutations in 54 Chilean families with breast/ovarian cancer, genotype–phenotype correlations. Breast Cancer Res Treat 95:81–87

    Article  PubMed  CAS  Google Scholar 

  2. Ahmed M, Rahman N (2006) ATM and breast cancer susceptibility. Oncogene 25:5906–5911

    Article  PubMed  CAS  Google Scholar 

  3. Swift M, Morrell D, Massey RB, Chase CL (1991) Incidence of cancer in 161 families affected by ataxia–telangiectasia. N Engl J Med 325:1831–1836

    Article  PubMed  CAS  Google Scholar 

  4. Athma P, Rappaport R, Swift M (1996) Molecular genotyping shows that ataxia–telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 92:130–134

    Article  PubMed  CAS  Google Scholar 

  5. Lavin MF, Shiloh Y (1997) The genetic defect in ataxia–telangiectasia. Annu Rev Immunol 15:177–202

    Article  PubMed  CAS  Google Scholar 

  6. Morrell D, Cromartie E, Swift M (1986) Mortality and cancer incidence in 263 patients with ataxia–telangiectasia. J Natl Cancer Inst 77:89–92

    PubMed  CAS  Google Scholar 

  7. Swift M, Reitnauer PJ, Morrell D, Chase CL (1987) Breast and other cancers in families with ataxia–telangiectasia. N Engl J Med 316:1289–1294

    Article  PubMed  CAS  Google Scholar 

  8. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NGJ, Taylor A, Malcolm R, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749–1753

    Article  PubMed  CAS  Google Scholar 

  9. Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G (1995) The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet 11:2025–2032

    Article  Google Scholar 

  10. Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A (1997) Ataxia–telangiectasia locus sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene. Genome Res 7:592–605

    PubMed  CAS  Google Scholar 

  11. Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM (1997) Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90:425–435

    Article  PubMed  CAS  Google Scholar 

  12. Lakin ND, Weber P, Stankovic T, Rottinghaus ST, Taylor AM, Jackson SP (1996) Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. Oncogene 13:2707–2716

    PubMed  CAS  Google Scholar 

  13. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14:927–939

    PubMed  CAS  Google Scholar 

  14. Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    Article  PubMed  CAS  Google Scholar 

  15. Cortez D, Wang Y, Qin J, Elledge SJ (1999) Requirement of ATM-dependent phosphorylation of BRCA 1 in the DNA damage response to double-strand breaks. Science 286:1162–1166

    Article  PubMed  CAS  Google Scholar 

  16. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281:1677–1679

    Article  PubMed  CAS  Google Scholar 

  17. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281:1674–1677

    Article  PubMed  CAS  Google Scholar 

  18. Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ (2000) Ataxia telangiectasia-mutated phosphorylates CHK2 in vivo and in vitro. Proc Natl Acad Sci USA 97:10389–10394

    Article  PubMed  CAS  Google Scholar 

  19. Mazars R, Spinardi L, BenCheikh M, Simony-Lafontaine J, Jeanteur P, Theillet C (1992) p53 mutations occur in aggressive breast cancer. Cancer Res 52:3918–3923

    PubMed  CAS  Google Scholar 

  20. Greenblatt MS, Chappuis PO, Bond JP, Hamel N, Foulkes WD (2001) TP53 mutations in breast cancer associated with BRCA1 or BRCA2 germline mutations: distinctive spectrum and structural distribution. Cancer Res 61:4092–4097

    PubMed  CAS  Google Scholar 

  21. Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR, CHEK2-Breast Cancer Consortium (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59

    Article  PubMed  CAS  Google Scholar 

  22. Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432–438

    Article  PubMed  CAS  Google Scholar 

  23. Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT (1986) The incidence and gene frequency of ataxia–telangiectasia in the United States. Am J Hum Genet 39:573–583

    PubMed  CAS  Google Scholar 

  24. Lahiri DK, Nurnberger J (1991) A rapid non-enzymatic method for the preparation of the HMW DNA from blood for RFLP studies. Nucleic Acids Res 19:5444

    Article  PubMed  CAS  Google Scholar 

  25. Castellví-Bel S, Sheikhavandi S, Telatar M, Tai L-Q, Hwang M, Wang Z, Yang Z, Cheng R, Gatti RA (1999) New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy. Hum Mutat 14:156–162

    Article  PubMed  Google Scholar 

  26. Sandoval N, Platzer M, Rosenthal A, Dork T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D (1999) Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet 8:69–79

    Article  PubMed  CAS  Google Scholar 

  27. Swofford DL, Selander RB, BIOSYS (1981) A Fortran program for the comprehensive analysis of electrophoretic data in population genetics and systematics. J Hered 72:281–287

  28. Nei M (1972) Genetic distance between populations. Am Nat 106:283–292

    Article  Google Scholar 

  29. Nei M (1978) Estimation of average heterozygosity and genetic distance from a small number of individuals. Genetics 89:583–590

    PubMed  CAS  Google Scholar 

  30. Wright S (1978) Variability within and among natural populations. In: Evolution and the genetics of populations, vol. 4. University of Chicago Press, Chicago, p 628

  31. Rogers JS (1991) A comparison of the suitability of the Rogers, Modified Rogers, Manhatten, Cavalli-Sforza and Edwards distances for inferring phylogenetic trees from allele frequencies. Syst Zool 40:63–73

    Article  Google Scholar 

  32. Atencio DP, Iannuzzi CM, Green S, Stock RG, Bernstein JL, Rosenstein BS (2001) Screening breast cancer patients for ATM mutations and polymorphisms by using denaturing high-performance liquid chromatography. Environ Mol Mutagen 38:200–208

    Article  PubMed  CAS  Google Scholar 

  33. GeneCard for protein-coding ATM GC11P107599. http://www.genecards.org. Cited 27 Oct 2006

  34. Vorechovsky I, Luo L, Lindblom A, Negrini M, Webster AD, Croce CM, Hammarstrom L (1996) ATM mutations in cancer families. Cancer Res 56:4130–4133

    PubMed  CAS  Google Scholar 

  35. Izatt L, Greenman J, Hodgson S, Ellis D, Watts S, Scott G, Jacobs C, Liebmann R, Zvelebil MJ, Mathew C, Solomon E (1999) Identification of germline missense mutations and rare allelic variants in the ATM gene in early-onset breast cancer. Genes Chromosomes Cancer 26:286–294

    Article  PubMed  CAS  Google Scholar 

  36. Dork T, Bendix R, Bremer M, Rades D, Klopper K, Nicke M, Skawran B, Hector A, Yamini P, Steinmann D, Weise S, Stuhrmann M, Karstens JH (2001) Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61:7608–7615

    PubMed  CAS  Google Scholar 

  37. Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Nieminen P, Winqvist R (2005) Association of common ATM polymorphism with bilateral breast cancer. Int J Cancer 116:69–72

    Article  PubMed  CAS  Google Scholar 

  38. Stredrick DL, Garcia-Closas M, Pineda MA, Bhatti P, Alexander BH, Doody MM, Lissowska J, Peplonska B, Brinton LA, Chanock SJ, Struewing JP, Sigurdson AJ (2006) The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer. Hum Mutat 27:538–544

    Article  PubMed  CAS  Google Scholar 

  39. Thorstenson YR, Shen P, Tusher VG, Wayne TL, Davis RW, Chu G, Oefner PJ (2001) Global analysis of ATM polymorphism reveals significant functional constraint. Am J Hum Genet 69:396–412

    Article  PubMed  CAS  Google Scholar 

  40. Spurdle AB, Hopper JL, Chen X, McCredie MR, Giles GG, Newman B, Chenevix-Trench G, Khanna K (2002) No evidence for association of ataxia–telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer. Breast Cancer Res 4:R15. DOI 10.1186/bcr534

  41. Sommer SS, Buzin CH, Jung M, Zheng J, Liu Q, Jeong SJ, Moulds J, Nguyen VQ, Feng J, Bennett WP, Dritschilo A (2002) Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls. Cancer Genet Cytogenet 134:25–32

    Article  PubMed  CAS  Google Scholar 

  42. Gatti RA, Tward A, Concannon P (1999) Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 68:419–423

    Article  PubMed  CAS  Google Scholar 

  43. Langholz B, Bernstein JL, Bernstein L, Olsen JH, Borresen-Dale AL, Rosenstein BS, Gatti RA, The WECARE Study Collaborative Group, Concannon P (2006) On the proposed association of the ATM variants 5557G>A and IVS38-8T>C and bilateral breast cancer. Int J Cancer 119:724–725

    Article  PubMed  CAS  Google Scholar 

  44. Fairbrother WG, Yeh RF, Sharp PA, Burge CB (2002) Predictive identification of exonic splicing enhancers in human genes. Science 297:1007–1013. http://genes.mit.edu/burgelab/rescue-ese

    Google Scholar 

  45. Thorstenson YR, Roxas A, Kroiss R, Jenkins MA, Yu KM, Bachrich T, Muhr D, Wayne TL, Chu G, Davis RW, Wagner TM, Oefner PJ (2003) Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63:3325–3333

    PubMed  CAS  Google Scholar 

  46. Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402. http://www.expasy.org. Cited 12 Jan 2007

    Google Scholar 

  47. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, Scott C, Pupo GM, Dork T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK (2002) Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94(3):205–215

    PubMed  Google Scholar 

  48. Broeks A, Urbanus JH, de Knijff P, Devilee P, Nicke M, Klopper K, Dork T, Floore AN, van’t Veer LJ (2003) IVS10-6T>G, an ancient ATM germline mutation linked with breast cancer. Hum Mutat 21:521–528

    Article  PubMed  CAS  Google Scholar 

  49. Bernstein JL, Bernstein L, Thompson WD, Lynch CF, Malone KE, Teitelbaum SL, Olsen JH, Anton-Culver H, Boice JD, Rosenstein BS, Borresen-Dale AL, Gatti RA, Concannon P, Haile RW, WECARE Study Collaborative Group (2003) ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer. Br J Cancer 89:1513–1516

    Article  PubMed  CAS  Google Scholar 

  50. Bernstein JL, Teraoka S, Southey MC, Jenkins MA, Andrulis IL, Knight JA, John EM, Lapinski R, Wolitzer AL, Whittemore AS, West D, Seminara D, Olson ER, Spurdle AB, Chenevix-Trench G, Giles GG, Hopper JL, Concannon P (2006) Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family. Hum Mutat 27:1122–1128

    Article  PubMed  CAS  Google Scholar 

  51. Torroni A, Schurr TG, Cabell MF, Brown MD, Neel JV, Larsen M, Smith DG, Vullo CM, Wallace DC (1993) Asian affinities and continental radiation of the four founding native American mtDNAs. Am J Hum Genet 53:563–590

    PubMed  CAS  Google Scholar 

  52. Joslyn SA, Foote ML, Nasseri K, Coughlin SS, Howe HL (2005) Racial and ethnic disparities in breast cancer rates by age: NAACCR Breast Cancer Project. Breast Cancer Res Treat 92:97–105

    Article  PubMed  Google Scholar 

  53. Cifuentes L, Valenzuela CY, Cruz-Coke R, Armanet L, Lyng C, Harb Z (1988) Genetic characterization of the hospital population of Santiago, Chile. Rev Med Chil 116:28–33

    PubMed  CAS  Google Scholar 

  54. Rocco P, Morales C, Moraga M, Miquel JF, Nervi F, Llop E, Carvallo P, Rothhammer F (2002) Genetic composition of the Chilean population: analysis of mitochondrial DNA polymorphism. Rev Med Chil 130:125–131

    PubMed  Google Scholar 

  55. International HapMap Project. http://www.hapmap.org. Cited 17 Jan 2007

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Acknowledgments

We are grateful to all family members who contributed to this study. We also thank Nancy Lamig and Pamela Alarcón for their valuable assistance with patients. This work was supported by a grant Fondecyt 1040779.

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Authors and Affiliations

  1. Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile

    Teresa Tapia, Alejandro Sanchez, Maricarmen Vallejos, Carolina Alvarez, Susan Smalley & Pilar Carvallo

  2. Programa de Genética, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile

    Mauricio Moraga

  3. Centro de Cáncer, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Mauricio Camus & Manuel Alvarez

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  1. Teresa Tapia
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Correspondence to Pilar Carvallo.

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Tapia, T., Sanchez, A., Vallejos, M. et al. ATM allelic variants associated to hereditary breast cancer in 94 Chilean women: susceptibility or ethnic influences?. Breast Cancer Res Treat 107, 281–288 (2008). https://doi.org/10.1007/s10549-007-9544-5

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