The Influence of Common Polymorphisms on Breast Cancer

Part of the Cancer Treatment and Research book series (CTAR, volume 155)


Breast cancer is one of the most frequently diagnosed cancers in the Western world and a significant cause of mortality worldwide. A small proportion of cases are accounted for by high-penetrance monogenic predisposition genes; however, this explains only a small fraction (less than 5%) of all breast cancers. Increasingly with advances in molecular technology and the development of large research consortia, the locations and identities of many low-penetrance genetic variants are being discovered. However, each variant has a very small effect similar to or smaller than many of the known environmental risk factors. It is therefore unlikely that these variants will be appropriate for predictive genetic testing, although they may identify novel pathways and genes which provide new insights and targets for therapeutic intervention. The future challenges will be identifying causal variants and determining how these low-penetrance alleles interact with each other and with environmental factors in order to usefully implement them in the practice of clinical medicine. Furthermore, it is clear that breast cancer comes in many forms with the tumour pathology and immunohistochemical profile already being used routinely as prognostic indicators and to inform treatment decisions. However, these indicators of prognosis are imperfect; two apparently identical tumours may have very different outcomes in different individuals. Inherited genetic variants may well be one of the other factors that need to be taken into account in assessing prognosis and planning treatment.


Breast Cancer Oral Contraceptive Pill Male Breast Cancer Common Genetic Variant Wellcome Trust Case Control Consortium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Claus EB, Risch N, Thompson WD (1991) Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 48(2):232–242PubMedGoogle Scholar
  2. 2.
    Hartman M, Hall P, Edgren G et al (2008) Breast cancer onset in twins and women with bilateral disease. J Clin Oncol 26(25):4086–4091PubMedCrossRefGoogle Scholar
  3. 3.
    Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40(1):17–22PubMedCrossRefGoogle Scholar
  4. 4.
    Antoniou AC, Hardy R, Walker L et al (2008) Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J Med Genet 45(7):425–431PubMedCrossRefGoogle Scholar
  5. 5.
    Ford D, Easton DF, Stratton M 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(3):676–689PubMedCrossRefGoogle Scholar
  6. 6.
    Antoniou AC, Spurdle AB, Sinilnikova OM et al (2008) Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82(4):937–948PubMedCrossRefGoogle Scholar
  7. 7.
    Wiseman RA (2004) Breast cancer: critical data analysis concludes that estrogens are not the cause, however lifestyle changes can alter risk rapidly. J Clin Epidemiol 57(8):766–772PubMedCrossRefGoogle Scholar
  8. 8.
    Ziegler RG, Hoover RN, Pike MC et al (1993) Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 85(22):1819–1827PubMedCrossRefGoogle Scholar
  9. 9.
    Pakkiri P, Lakhani SR, Smart CE (2009) Current and future approach to the pathologist’s assessment for targeted therapy in breast cancer. Pathology 41(1):89–99PubMedCrossRefGoogle Scholar
  10. 10.
    Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham prognostic index in primary breast cancer. Breast Cancer Res Treat 22:207–219PubMedCrossRefGoogle Scholar
  11. 11.
    Schmidt M, Victor A, Bratzel D et al (2008) Long-term outcome prediction by clinicopathological risk classification algorithms in node-negative breast cancer – comparison between Adjuvant! St Gallen, and a novel risk algorithm used in the prospective randomized Node-Negative-Breast Cancer-3 (NNBC-3) trial. Ann Oncol 20(2):258–264PubMedCrossRefGoogle Scholar
  12. 12.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672PubMedCrossRefGoogle Scholar
  13. 13.
    Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874PubMedCrossRefGoogle Scholar
  14. 14.
    Wessels LF, van Welsem T, Hart AA, van’t Veer LJ, Reinders MJ, Nederlof PM (2002) Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 62(23):7110–7117PubMedGoogle Scholar
  15. 15.
    Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRefGoogle Scholar
  16. 16.
    Anderson WF, Rosenberg PS, Menashe I, Mitani A, Pfeiffer RM (2008) Age-related crossover in breast cancer incidence rates between black and white ethnic groups. J Natl Cancer Inst 100(24):1804–1814PubMedCrossRefGoogle Scholar
  17. 17.
    Bowen RL, Duffy SW, Ryan DA, Hart IR, Jones JL (2008) Early onset of breast cancer in a group of British black women. Br J Cancer 98(2):277–281PubMedCrossRefGoogle Scholar
  18. 18.
    Anderson WF, Chu KC, Chang S, Sherman ME (2004) Comparison of age-specific incidence rate patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomarkers Prev 13(7):1128–1135PubMedGoogle Scholar
  19. 19.
    Walker RA, Lees E, Webb MB, Dearing SJ (1996) Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer 74(11):1796–1800PubMedCrossRefGoogle Scholar
  20. 20.
    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(14):5175–5180PubMedCrossRefGoogle Scholar
  21. 21.
    Sobin LH (2003) TNM, sixth edition: new developments in general concepts and rules. Semin Surg Oncol 21:19–22PubMedCrossRefGoogle Scholar
  22. 22.
    Veronesi U, Salvadori B, Luini A et al (1995) Breast-conservation is a safe method in patients with small cancer of the breast – long-term results of 3 randomized trials on 1,973 patients. Eur J Cancer 31A(10):1574–1579PubMedCrossRefGoogle Scholar
  23. 23.
    Throckmorton AD, Esserman LJ (2009) When informed, all women do not prefer breast conservation. J Clin Oncol 27(4):484–486PubMedCrossRefGoogle Scholar
  24. 24.
    Gui GP, Joubert DJ, Reichert R et al (2005) Continued axillary sampling is unnecessary and provides no further information to sentinel node biopsy in staging breast cancer. Eur J Surg Oncol 31(7):707–714PubMedCrossRefGoogle Scholar
  25. 25.
    Piccart-Gebhart MJ (2004) New stars in the sky of treatment for early breast cancer. N Engl J Med 350(11):1140–1142PubMedCrossRefGoogle Scholar
  26. 26.
    Clarke M (2006) Meta-analyses of adjuvant therapies for women with early breast cancer: the Early Breast Cancer Trialists’ Collaborative Group overview. Ann Oncol 17(Supplement 10):x59–x62PubMedCrossRefGoogle Scholar
  27. 27.
    Untch M, Gelber RD, Jackisch C et al (2008) Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol 19(6):1090–1096PubMedCrossRefGoogle Scholar
  28. 28.
    Collaborative Group on Hormonal Factors in Breast Cancer (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389–1399CrossRefGoogle Scholar
  29. 29.
    Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31(1):33–36PubMedCrossRefGoogle Scholar
  30. 30.
    Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093PubMedCrossRefGoogle Scholar
  31. 31.
    Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11(2):103–105PubMedCrossRefGoogle Scholar
  32. 32.
    Lalloo F, Varley J, Moran A et al (2006) BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 42(8):1143–1150PubMedCrossRefGoogle Scholar
  33. 33.
    Bonadona V, Sinilnikova OM, Chopin S et al (2005) Contribution of BRCA1 and BRCA2 germ-line mutations to the incidence of breast cancer in young women: results from a prospective population-based study in France. Genes Chromosomes Cancer 43(4):404–413PubMedCrossRefGoogle Scholar
  34. 34.
    Anderson WF, Chen BE, Brinton LA, Devesa SS (2007) Qualitative age interactions (or effect modification) suggest different cancer pathways for early-onset and late-onset breast cancers. Cancer Causes Control 18(10):1187–1198PubMedCrossRefGoogle Scholar
  35. 35.
    Eccles D, Marlow A, Royle G, Collins A, Morton NE (1994) Genetic epidemiology of early onset breast cancer. J Med Genet 31(12):944–949PubMedCrossRefGoogle Scholar
  36. 36.
    Li FP, Fraumeni JFJ (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71(4):747–752PubMedGoogle Scholar
  37. 37.
    Li FP, Fraumeni JF Jr, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362PubMedGoogle Scholar
  38. 38.
    Malkin D, Li FP, Strong LC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250(4985):1233–1238PubMedCrossRefGoogle Scholar
  39. 39.
    Hall JM, Lee MK, Newman B et al (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250(4988):1684–1689PubMedCrossRefGoogle Scholar
  40. 40.
    Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266(5182):66–71PubMedCrossRefGoogle Scholar
  41. 41.
    Wooster R, Neuhausen SL, Mangion J et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265(5181):2088–2090PubMedCrossRefGoogle Scholar
  42. 42.
    Wooster R, Bignell G, Lancaster J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378(6559):789–792PubMedCrossRefGoogle Scholar
  43. 43.
    Smith P, McGuffog L, Easton DF et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45(7):646–655PubMedCrossRefGoogle Scholar
  44. 44.
    Rosa-Rosa JM, Pita G, Urioste M et al (2009) Genome-wide linkage scan reveals three putative breast-cancer-susceptibility loci. Am J Hum Genet 84(2):115–122PubMedCrossRefGoogle Scholar
  45. 45.
    Renwick A, Thompson D, Seal S et al (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873–875PubMedCrossRefGoogle Scholar
  46. 46.
    Rahman N, Seal S, Thompson D et al (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167PubMedCrossRefGoogle Scholar
  47. 47.
    Seal S, Thompson D, Renwick A et al (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38(11):1239–1241PubMedCrossRefGoogle Scholar
  48. 48.
    Hunter DJ, Kraft P, Jacobs KB et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39(7):870–874PubMedCrossRefGoogle Scholar
  49. 49.
    Stacey SN, Manolescu A, Sulem P et al (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40(6):703–706PubMedCrossRefGoogle Scholar
  50. 50.
    Gold B, Kirchhoff T, Stefanov S et al (2008) Genome-wide association study provides evidence for a breast cancer risk locus at 6q22-33. Proc Natl Acad Sci USA 105(11):4340–4345PubMedCrossRefGoogle Scholar
  51. 51.
    Argos M, Kibriya MG, Jasmine F et al (2008) Genomewide scan for loss of heterozygosity and chromosomal amplification in breast carcinoma using single-nucleotide polymorphism arrays. Cancer Genet Cytogenet 182(2):69–74PubMedCrossRefGoogle Scholar
  52. 52.
    Newport M, Sirugo G, Lyons E et al (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39(11):1329–1337PubMedCrossRefGoogle Scholar
  53. 53.
    Kibriya MG, Jasmine F, Argos M et al (2009) A pilot genome-wide association study of early-onset breast cancer. Breast Cancer Res Treat 114(3):463–477PubMedCrossRefGoogle Scholar
  54. 54.
    Zheng W, Long JR, Gao YT et al (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41(3):324–328PubMedCrossRefGoogle Scholar
  55. 55.
    Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273(5281):1516–1517PubMedCrossRefGoogle Scholar
  56. 56.
    Abd El-Rehim DM, Pinder SE, Paish CE et al (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203(2):661–671PubMedCrossRefGoogle Scholar
  57. 57.
    Makretsov NA, Huntsman DG, Nielsen TO et al (2004) Hierarchical clustering analysis of tissue microarray immunostaining data identifies prognostically significant groups of breast carcinoma. Clin Cancer Res 10(18 Pt 1):6143–6151PubMedCrossRefGoogle Scholar
  58. 58.
    Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423PubMedCrossRefGoogle Scholar
  59. 59.
    Turner NC, Reis-Filho JS, Russell AM et al (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26(14):2126–2132PubMedCrossRefGoogle Scholar
  60. 60.
    Lakhani SR (1999) The pathology of familial breast cancer: morphological aspects. Breast Cancer Res 1(1):31–35PubMedCrossRefGoogle Scholar
  61. 61.
    Lakhani SR, Van D V, Jacquemier J et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318PubMedCrossRefGoogle Scholar
  62. 62.
    Palacios J, Honrado E, Osorio A et al (2005) Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat 90(1):5–14PubMedCrossRefGoogle Scholar
  63. 63.
    Hedenfalk IA, Ringner M, Trent JM, Borg A (2002) Gene expression in inherited breast cancer. Adv Cancer Res 84:1–34PubMedCrossRefGoogle Scholar
  64. 64.
    Jonsson G, Naylor TL, Vallon-Christersson J et al (2005) Distinct genomic profiles in hereditary breast tumors identified by array-based comparative genomic hybridization. Cancer Res 65(17):7612–7621PubMedGoogle Scholar
  65. 65.
    The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678Google Scholar
  66. 66.
    Stacey SN, Manolescu A, Sulem P et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39(7):865–869PubMedCrossRefGoogle Scholar
  67. 67.
    Kibriya MG, Jasmine F, Argos M et al (2009) A pilot genome-wide association study of early-onset breast cancer. Breast Cancer Res Treat 114(3):463–477Google Scholar
  68. 68.
    Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S et al (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39(3):352–358Google Scholar
  69. 69.
    Garcia-Closas M, Hall P, Nevanlinna H et al (2008) Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 4(4):e1000054PubMedCrossRefGoogle Scholar
  70. 70.
    Amos CI (2007) Successful design and conduct of genome-wide association studies. Hum Mol Genet 16(R2):R220–R225PubMedCrossRefGoogle Scholar
  71. 71.
    Ozanne EM, Braithwaite D, Sepucha K, Moore D, Esserman L, Belkora J (2009) Sensitivity to input variability of the adjuvant! Online breast cancer prognostic model. J Clin Oncol 27(2):214–219PubMedCrossRefGoogle Scholar
  72. 72.
    Bueno-de-Mesquita JM, van Harten WH, Retel VP et al (2007) Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol 8(12):1079–1087PubMedCrossRefGoogle Scholar
  73. 73.
    Hartman M, Lindstrom L, Dickman PW, Adami HO, Hall P, Czene K (2007) Is breast cancer prognosis inherited? Breast Cancer Res 9(3):R39PubMedCrossRefGoogle Scholar
  74. 74.
    Tapper W, Hammond V, Gerty S et al (2008) The influence of genetic variation in thirty selected genes on the clinical characteristics of early onset breast cancer. Breast Cancer Res 10(6):R108PubMedCrossRefGoogle Scholar
  75. 75.
    Liu ZL, He B, Fang F, Tang CY, Zou LP (2008) Genetic polymorphisms of MC2R gene associated with responsiveness to adrenocorticotropic hormone therapy in infantile spasms. Chinese Med J 121(17):1627–1632Google Scholar
  76. 76.
    Schroth W, Antoniadou L, Fritz P et al (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25(33):5187–5193PubMedCrossRefGoogle Scholar
  77. 77.
    Okishiro M, Taguchi T, Kim SJ, Shimazu K, Tamaki Y, Noguchi S (2009) Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer 115(5):952–961PubMedCrossRefGoogle Scholar
  78. 78.
    Fagerholm R, Hofstetter B, Tommiska J et al (2008) NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 40(7):844–853PubMedCrossRefGoogle Scholar
  79. 79.
    Hsieh SM, Lintell NA, Hunter KW (2006) Germline polymorphisms are potential metastasis risk and prognosis markers in breast cancer. Breast Dis 26:157–162PubMedGoogle Scholar
  80. 80.
    Crawford NPS, Alsarraj J, Lukes L et al (2008) Bromodomain 4 activation predicts breast cancer survival. Proc Natl Acad Sci USA 105(17):6380–6385PubMedCrossRefGoogle Scholar
  81. 81.
    Park YG, Zhao XH, Lesueur F et al (2005) Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat Genet 37(10):1055–1062PubMedCrossRefGoogle Scholar
  82. 82.
    Smid M, Wang Y, Klijn JG et al (2006) Genes associated with breast cancer metastatic to bone. J Clin Oncol 24(15):2261–2267PubMedCrossRefGoogle Scholar
  83. 83.
    Gail MH (2008) Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 100(14):1037–1041PubMedCrossRefGoogle Scholar
  84. 84.
    Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358(26):2796–2803PubMedCrossRefGoogle Scholar
  85. 85.
    Ueda H, Howson JM, Esposito L et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423(6939):506–511PubMedCrossRefGoogle Scholar
  86. 86.
    Gibbs RA, Belmont JW, Hardenbol P et al (2003) The international HapMap project. Nature 426(6968):789–796CrossRefGoogle Scholar
  87. 87.
    Bowen RL, Stebbing J, Jones LJ (2006) A review of the ethnic differences in breast cancer. Pharmacogenomics 7(6):935–942PubMedCrossRefGoogle Scholar
  88. 88.
    Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Human Genetics and Cancer Sciences Divisions, School of MedicineUniversity of Southampton, Southampton University Hospitals NHS TrustSouthamptonUK

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