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Use of association studies to define genetic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

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Abstract

Though much progress has been made in understanding the role of two major high-risk breast cancer (BC) susceptibility genes, BRCA1 and BRCA2, it remains unclear what causes the observed variation in risk between mutation carriers. This marked variability in individual cancer risk both between and within BRCA1 and BRCA2 mutation carrier families may be partly explained by modifier genes that influence mutation penetrance. Defining these modifiers should help refine individual cancer risk estimates and is also expected to be an efficient method to identify further BC susceptibility alleles in general. This approach is predicated on the concept that variants in genes that are low to moderate penetrance predisposition genes are likely to have a larger risk modification effect in BRCA1/2 mutation carriers. Association studies are usually used to assess the influence of variants in biologically plausible candidate loci on the penetrance of BRCA1/2 mutations (i.e., differences in age of onset or tissue-specificity of disease). Several such modifier loci, including the genes AIB1 and AR involved in hormone metabolism, and the RAD51 gene acting in DNA repair, have been proposed in the literature. A consortium of laboratories (CIMBA) has recently confirmed the RAD51 135 G/C variant as a BC risk modifier in BRCA2 mutation carriers, though not in BRCA1 carriers. This review describes molecular epidemiological efforts to evaluate the potential influence of polymorphic variants in candidate modifier genes on the risk of BC conferred by the BRCA1 and BRCA2 genes.

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Abbreviations

BC:

Breast cancer

OC:

Ovarian cancer

CIMBA:

Consortium of investigators of modifiers of BRCA1 and BRCA2

IBCCS:

International breast cancer cohort study

nt:

Nucleotides

RR:

Relative risk

HR:

Hazards ratio

95% CI:

95% Confidence intervals

P :

Probability value

SNP:

Single nucleotide polymorphism

DH:

Double heterozygote

IR:

Ionizing radiation

MEC:

Multi ethnic cohort

2df:

Two degrees of freedom

OR:

Odds ratio

IHCC:

International hereditary cancer center

Poly-Q:

multiple glutamine residues

LD:

Linkage disequilibrium

References

  1. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q et al (1994) A strong candidate for the 17q-linked breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71

    Article  PubMed  CAS  Google Scholar 

  2. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–791

    Article  PubMed  CAS  Google Scholar 

  3. Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S et al (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12:333–337

    Article  PubMed  CAS  Google Scholar 

  4. Easton DF, Ford D, Bishop DT (1995) Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast cancer linkage consortium. Am J Hum Genet 56:265–271

    PubMed  CAS  Google Scholar 

  5. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE (1994) Risks of cancer in BRCA1-mutation carriers. Breast cancer linkage consortium. Lancet 343:692–695

    Article  PubMed  CAS  Google Scholar 

  6. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet 62:676–689

    Article  PubMed  CAS  Google Scholar 

  7. Antoniou AC, Pharoah PDP, Mc Mullan G, Day NE et al (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76–83

    Article  PubMed  CAS  Google Scholar 

  8. Whittemore AS, Gong G, John EM, McGuire V, Li FP, Ostrow KL, Dicioccio R, Felberg A, West DW (2004) Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev 13:2078–83

    PubMed  CAS  Google Scholar 

  9. Neuhausen SL, Mazoyer S, Friedman L, Stratton M et al (1996) Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58:271–280

    PubMed  CAS  Google Scholar 

  10. Roa BB, Boyd AA, Volcik K, Richards CS (1996) Ashkenazi jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14:185–187

    Article  PubMed  CAS  Google Scholar 

  11. Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, Hornreich G, Lishinsky E, Shohat M, Weber BL, Beller U, Lahad A, Halle D (1997) Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet 60:1059–1067

    PubMed  CAS  Google Scholar 

  12. The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316

    Article  Google Scholar 

  13. Thompson D, Easton D, The Breast Cancer Linkage Consortium (2002) Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 11:329–336

    PubMed  CAS  Google Scholar 

  14. Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL (2002) Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Nat Cancer Inst 1:76–83

    Google Scholar 

  15. Gayther SA, Mangion J, Russell PA, Seal S et al (1997) Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15:103–105

    Article  PubMed  CAS  Google Scholar 

  16. Thompson D, Easton D, The Breast Cancer Linkage Consortium (2001) Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68:410–419

    Article  PubMed  CAS  Google Scholar 

  17. Antoniou AC, Pharoah PDP, Narod S, Risch A et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:117–1130

    Article  Google Scholar 

  18. Perrin-Vidoz L, Sinilnikova OM, Stoppa-Lyonnet D, Lenoir GM, Mazoyer S (2002) The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons. Hum Mol Genet 11:2805–2814

    Article  PubMed  CAS  Google Scholar 

  19. Ware MD, DeSilva D, Sinilnikova OM, Stoppa-Lyonnet D, Tavtigian SV, Mazoyer S (2006) Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene? Oncogene 25:323–328

    PubMed  CAS  Google Scholar 

  20. Nathanson KN, Weber BL (2001) ‘Other’ breast cancer susceptibility genes: searching for more holy grail. Hum Mol Genet 10:715–720

    Article  PubMed  CAS  Google Scholar 

  21. Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33 Suppl:238–244

    Article  PubMed  CAS  Google Scholar 

  22. Narod SA, Goldgar D, Cannon-Albright L, Weber B, Moslehi R, Ives E, Lenoir G, Lynch H (1995) Risk modifiers in carriers of BRCA1 mutations. Int J Cancer 64:394–398

    Article  PubMed  CAS  Google Scholar 

  23. Jernström H, Lerman C, Ghadirian P, Lynch HT et al (1999) Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 354:1846–1850

    Article  PubMed  Google Scholar 

  24. Rebbeck TR, Levin AM, Eisen A, Snyder C et al (1999) Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91:1475–1479

    Article  PubMed  CAS  Google Scholar 

  25. Narod SA, Sun P, Risch HA, Hereditary Ovarian Cancer Clinical Study Group (2001) Ovarian cancer, oral contraceptives, and BRCA mutations. N Engl J Med 345:1706–1707

    Article  PubMed  CAS  Google Scholar 

  26. Rebbeck TR (2002) Inherited predisposition and breast cancer: modifiers of BRCA1/2-associated breast cancer risk. Environ Mol Mutagen 39:228–234

    Article  PubMed  CAS  Google Scholar 

  27. Narod SA (2002) Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2:113–123

    Article  PubMed  Google Scholar 

  28. Nkondjock A, Ghadirian P (2004) Epidemiology of breast cancer among BRCA mutation carriers: an overview. Cancer Lett 205:1–8

    Article  PubMed  CAS  Google Scholar 

  29. Andrieu N, Goldgar DE, Easton DF, Rookus M, Brohet R, Antoniou AC, Peock S, Evans G, Eccles D et al (2006) Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 carrier cohort study (IBCCS). J Natl Cancer Inst 98:535–544

    Article  PubMed  Google Scholar 

  30. Mitchell G, Antoniou AC, Warren R, Peock S, Brown J, Davies R, Mattison J, Cook M, Warsi I, Evans DG et al (2006) Mammographic density and breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Res 66:1866–1872

    Article  PubMed  CAS  Google Scholar 

  31. Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, Giles GG, Tritchler D, Chiarelli A, Yaffe MJ et al (2002) Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 347:886–894

    Article  PubMed  Google Scholar 

  32. Andrieu N, Easton DF, Chang-Claude J et al (2006) Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators’ Group. J Clin Oncol 24:3361–3366

    Article  PubMed  CAS  Google Scholar 

  33. Lakhani SR, Jacquemier J, Sloane JP et al (1998) Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138–1145

    Article  PubMed  CAS  Google Scholar 

  34. Lakhani SR, Reis-Filho JS, Fulford L et al (2005) Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11:5175–5180

    Article  PubMed  CAS  Google Scholar 

  35. 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 

  36. Zheng L, Li S, Boyer TG, Lee WH (2000) Lessons learned from BRCA1 and BRCA2. Oncogene 19:6159–6175

    Article  PubMed  CAS  Google Scholar 

  37. Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2:171–182

    Article  Google Scholar 

  38. Powell SN, Kachnic LA (2003) Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 22:5784–5791

    Article  PubMed  CAS  Google Scholar 

  39. Nathanson KL, Shugart YY, Omaruddin R, Szabo C, Goldgar D, Rebbeck TR, Weber BL (2002) CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q. Hum Mol Genet 11:1327–1332

    Article  PubMed  CAS  Google Scholar 

  40. Colditz GA (1998) Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer risk. J Natl Cancer Inst 90:814–823

    Article  PubMed  CAS  Google Scholar 

  41. Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90:1292–1299

    Article  PubMed  CAS  Google Scholar 

  42. Rebbeck TR, Kantoff PW, Krithivas K et al (1999) Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet 64:1371–1377

    Article  PubMed  CAS  Google Scholar 

  43. Chamberlain NL, Driver ED, Miesfeld RL (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22:3181–3186

    Article  PubMed  CAS  Google Scholar 

  44. Szelei J, Jimenez J, Soto AM, Luizzi MF, Sonnenschein C (1997) Androgen-induced inhibition of proliferation in human breast cancer MCF7 cells transfected with androgen receptor. Endocrinology 138:1406–1412

    Article  PubMed  CAS  Google Scholar 

  45. Park JJ, Irvine RA, Buchanan G, Koh SS, Park JM, Tilley WD, Stallcup MR, Press MF, Coetzee GA (2000) Breast cancer susceptibility gene 1 (BRCA1) is a coactivator of the androgen receptor. Cancer Res 60:232–236

    Google Scholar 

  46. Kadouri L, Easton DF, Edwards S et al (2001) CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non carriers. Br J Cancer 85:36–40

    Article  PubMed  CAS  Google Scholar 

  47. Dagan E, Friedman E, Paperna T, Carmi N, Gershoni-Baruch R (2002) Androgen receptor CAG repeat length in Jewish Israeli women who are BRCA1/2 mutation carriers: association with breast/ovarian cancer phenotype. Eur J Hum Genet 10:724–728

    Article  PubMed  CAS  Google Scholar 

  48. Spurdle AB, Antoniou AC, Duffy DL et al (2005) The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 7:R176–R183

    Article  PubMed  CAS  Google Scholar 

  49. Anzick SL, Kononen J, Walker RL, Azorsa DO et al (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277:965–968

    Article  PubMed  CAS  Google Scholar 

  50. Bautista S, Valles H, Walker RL et al (1998) In breast cancer, amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity. Clin Cancer Res 4:2925–2929

    PubMed  CAS  Google Scholar 

  51. Shirazi SK, Bober MA, Coetzee GA (1998) Polymorphic exonic CAG microsatellites in the gene amplified in breast cancer (AIB1 gene). Clin Genet 54:102–103

    Article  PubMed  CAS  Google Scholar 

  52. Bevan CL, Hoare S, Claessens F, Heery DM, Parker MG (1999) The AF1 and AF2 domains of the androgen receptor interact with distinct regions of SRC1. Mol Cell Biol 19:8383–8392

    PubMed  CAS  Google Scholar 

  53. Rebbeck TR, Wang Y, Kantoff PW et al (2001) Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history. Cancer Res 61:5420–5424

    PubMed  CAS  Google Scholar 

  54. Kadouri L, Kote-Jarai Z, Easton DF, Hubert A, Hamoudi R, Glaser B, Abeliovich D, Peretz T, Eeles RA (2004) Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers. Int J Cancer 108:399–403

    Article  PubMed  CAS  Google Scholar 

  55. Haiman CA, Hankinson SE, Spiegelman D, Colditz GA, Willet WC, Speizer FE, Brown M, Hunter DJ (2000) Polymorphic repeat in AIB1 does not alter breast cancer risk. Breast Cancer Res 2:378–385

    Article  PubMed  CAS  Google Scholar 

  56. Wilkening S, Burwinkel B, Grzybowska E, Klaes R, Pamula J, Pekala W, Zientek H, Hemminki K, Forsti A (2005) Polyglutamine repeat length in the NCOA3 does not affect risk in familial breast cancer. Cancer Epidemiol Biomarkers Prev 14:291–292

    PubMed  CAS  Google Scholar 

  57. Hughes DJ, Ginolhac SM, Coupier I et al (2005) Breast cancer risk in BRCA1 and BRCA2 mutation carriers and polyglutamine repeat length in the AIB1 gene. Int J Cancer 117:230–233

    Article  PubMed  CAS  Google Scholar 

  58. Spurdle AB, Antoniou AC, Kelemen L et al (2006) The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 15:76–79

    Article  PubMed  CAS  Google Scholar 

  59. Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH (1996) Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet 12:191–194

    Article  PubMed  CAS  Google Scholar 

  60. Connor F, Bertwistle D, Mee PJ, Ross GM, Swift S, Grigorieva E, Tybulewicz VL, Ashworth A (1997) Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet 17:423–430

    Article  PubMed  CAS  Google Scholar 

  61. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D’Andrea AD (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–609

    Article  PubMed  CAS  Google Scholar 

  62. Offit K, Levran O, Mullaney B et al (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95:1548–1551

    PubMed  CAS  Google Scholar 

  63. Reid S, Renwick A, Seal S, Baskcomb L, Barfoot R, Jayatilake H, Pritchard-Jones K, Stratton MR, Ridolfi-Lathy A, Rahman N, Breast Cancer Susceptibility Collaboration (UK); Familial Wilms Tumour Collaboration (2005) Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet 42:147–151

    Article  PubMed  CAS  Google Scholar 

  64. Leegte B, van der Hout AH, Deffenbaugh AM et al (2005) Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. J Med Genet 42:e20

    Article  PubMed  CAS  Google Scholar 

  65. Ludwig T, Chapman DL, Papaioannou VE, Efstratiadis A (1997) Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of BRCA1, BRCA2, BRCA1/BRCA2, BRCA1/p53 and BRCA2/p53 nullizygous embryos. Genes Dev 11:1226–1241

    Article  PubMed  CAS  Google Scholar 

  66. Antoniou AC, Sinilnikova OM, Simard J et al (2007) RAD51 135G>C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies. Am J Hum Genet 81:1186–1200

    Article  PubMed  CAS  Google Scholar 

  67. Durocher F, Shattuck-Eidens D, McClure M, Labrie F, Skolnick MH, Goldgar DE, Simard J (1996) Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum Mol Genet 5:835–842

    Article  PubMed  CAS  Google Scholar 

  68. Dunning AM, Chiano M, Smith NR, Dearden J, Gore M, Oakes S, Wilson C, Stratton M, Peto J, Easton D, Clayton D, Ponder BA (1997) Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. Hum Mol Genet 6:285–289

    Article  PubMed  CAS  Google Scholar 

  69. Foray N, Randrianarison V, Marot D, Perricaudet M, Lenoir G, Feunteun J (1999) Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2. Oncogene 18:7334–7342

    Article  PubMed  CAS  Google Scholar 

  70. Rothfuss A, Schutz P, Bochum S, Volm T, Eberhardt E, Kreienberg R, Vogel W, Speit G (2000) Induced micronucleus frequencies in peripheral lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families. Cancer Res 60:390–394

    PubMed  CAS  Google Scholar 

  71. Buchholz T A, Wu X, Hussain A, Tucker SL, Mills GB, Haffty B, Bergh S, Story M, Geara FB, Brock WA (2002) Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2. Int J Cancer 97:557–561

    Article  PubMed  CAS  Google Scholar 

  72. Baldeyron C, Jacquemin E, Smith J, Jacquemont C, De Oliveira I, Gad S, Feunteun J, Stoppa-Lyonnet D, Papadopoulo D (2002) A single mutated BRCA1 allele leads to impaired fidelity of double strand break end-joining. Oncogene 21:1401–1410

    Article  PubMed  CAS  Google Scholar 

  73. Ginolhac SM, Gad S, Corbex M et al (2003) BRCA1 wild-type allele modifies risk of ovarian cancer in carriers of BRCA1 germ-line mutations. Cancer Epidemiol Biomarkers Prev 12:90–95

    PubMed  CAS  Google Scholar 

  74. Janezic SA, Ziogas A, Krumroy LM, Krasner M, Plummer SJ, Cohen P, Gildea M, Barker D, Haile R, Casey G, Anton-Culver H (1999) Germline BRCA1 alterations in a population-based series of ovarian cancer cases. Hum Mol Genet 8:889–897

    Article  PubMed  CAS  Google Scholar 

  75. Freedman ML, Penney KL, Stram DO, Le Marchand L, Hirschhorn JN, Kolonel LN, Altshuler D, Henderson BE, Haiman CA (2004) Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic cohort. Hum Mol Genet 13:2431–2441

    Article  PubMed  CAS  Google Scholar 

  76. Healey CS, Dunning AM, Teare MD (2000) A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability. Nature Genet 26:362–364

    Article  PubMed  CAS  Google Scholar 

  77. Spurdle AB, Hopper JL, Chen X et al (2002) The BRCA2 372 HH genotype is associated with risk of breast cancer in Australian women under age 60 years. Cancer Epidemiol Biomarkers Prev 11:413–416

    PubMed  CAS  Google Scholar 

  78. Sigurdson AJ, Hauptmann M, Chatterjee N et al (2004) Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes. BMC Cancer 4:9

    Article  PubMed  Google Scholar 

  79. Auranen A, Spurdle AB, Chen X et al (2003) BRCA2 Arg372His polymorphism and epithelial ovarian cancer risk. Int J Cancer 103:427–430

    Article  PubMed  CAS  Google Scholar 

  80. Ishitobi M, Miyoshi Y, Ando A et al (2003) Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis. Clin Cancer Res 9:1376–1380

    PubMed  CAS  Google Scholar 

  81. Hughes DJ, Ginolhac SM, Coupier I et al (2005) Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev 14:265–267

    PubMed  CAS  Google Scholar 

  82. Tutt A, Ashworth A (2002) The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 8:571–576

    Article  PubMed  CAS  Google Scholar 

  83. Pellegrini L, Venkitaraman A (2004) Emerging functions of BRCA2 in DNA recombination. Trends Biochem Sci 29:310–316

    Article  PubMed  CAS  Google Scholar 

  84. Yang H, Li Q, Fan J, Holloman WK, Pavletich NP (2005) The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction. Nature 433:653–657

    Article  PubMed  CAS  Google Scholar 

  85. Kuschel B, Auranen A, McBride S, Novik KL et al (2002) Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet 11:1399–1407

    Article  PubMed  CAS  Google Scholar 

  86. Levy-Lahad E, Lahad A, Eisenberg S, Dagan E et al (2001) A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci USA 98:3232–3236

    Article  PubMed  CAS  Google Scholar 

  87. Kadouri L, Kote-Jarai Z, Hubert A, Durocher F, Abeliovich D, Glaser B, Hamburger T, Eeles RA, Peretz T (2004) A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers. Br J Cancer 90:2002–2005

    Article  PubMed  CAS  Google Scholar 

  88. Wang WW, Spurdle AB, Kolachana P et al (2001) A single nucleotide polymorphism in the 5′ untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10:955–960

    PubMed  CAS  Google Scholar 

  89. Jakubowska A, Narod SA, Goldgar DE, Mierzejewski M et al (2003) Breast cancer risk reduction associated with the RAD51 polymorphism among carriers of the BRCA1 5382insC mutation in Poland. Cancer Epidemiol Biomarkers Prev 12:457–459

    PubMed  CAS  Google Scholar 

  90. Jakubowska A, Gronwald J, Menkiszak J, Garski B, Huzarski T, Byrski T, Edler L, Lubiaski J, Scott RJ, Hamann U (2007) The RAD51 135 G>C polymorphism modifies breast cancer and ovarian cancer risk in Polish BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev 16:270–275

    Article  PubMed  CAS  Google Scholar 

  91. Osorio A, Martinez-Delgado B, Pollán M et al (2006) A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers. Hum Mutat 27:242–248

    Google Scholar 

  92. Chenevix-Trench G, Milne RL, Antoniou AC, Couch FJ, Easton DF, Goldgar DE, CIMBA (2007) An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the consortium of investigators of modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9:104

    Article  PubMed  CAS  Google Scholar 

  93. Couch FJ, Sinilnikova O, Vierkant RA et al (2007) AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. Cancer Epidemiol Biomarkers Prev 16:1416–1421

    Article  PubMed  CAS  Google Scholar 

  94. Pepe C, Guidugli L, Sensi E, Aretini P, D’Andrea E, Montagna M, Manoukian S, Ottini L, Radice P, Viel A, Bevilacqua G, Caligo MA (2007) Methyl group metabolism gene polymorphisms as modifier of breast cancer risk in Italian BRCA1/2 carriers. Breast Cancer Res Treat 103:29–36

    Article  PubMed  CAS  Google Scholar 

  95. Neale B, Sham PC (2004) The future of association studies: gene-based analysis and replication. Am J Hum Genet 75:353–362

    Article  PubMed  CAS  Google Scholar 

  96. Ke X, Cardon LR (2003) Efficient selective screening of haplotype tag SNPs. Bioinformatics 19:287–288

    Article  PubMed  CAS  Google Scholar 

  97. Stram DO, Haiman CA, Kolonel LN, Henderson BE, Pike MC (2003) Choosing haplotype-tagging snps based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the multiethnic cohort study. Human Heredity 55:27–36

    Article  PubMed  Google Scholar 

  98. Cox A, Dunning AM, Garcia-Closas M et al (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39:352–358

    Article  PubMed  CAS  Google Scholar 

  99. Lin DY, Wei LJ (1989) Robust inference for the Cox proportional hazards model. J Am Stat Assn 84:1074–1078

    Article  Google Scholar 

  100. Antoniou AC, Goldgar DE, Andrieu N, Chang-Claude J, Brohet R, Rookus MA, Easton DF (2005) A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol 29:1–11

    Article  PubMed  Google Scholar 

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Acknowledgments

The author would like to warmly thank Dr Olga Sinilnikova (CLB, Lyon, France) and Dr David Goldgar (University of Utah, Salt Lake City, Utah) for helpful suggestions and advise on the text.

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  1. Department of Clinical Medicine, Trinity College Dublin, AMNCH Hospital, Dublin 24, Ireland

    David J. Hughes

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Hughes, D.J. Use of association studies to define genetic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Familial Cancer 7, 233–244 (2008). https://doi.org/10.1007/s10689-008-9181-0

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