Abstract
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.
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References
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):232–242
Hartman M, Hall P, Edgren G et al (2008) Breast cancer onset in twins and women with bilateral disease. J Clin Oncol 26(25):4086–4091
Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40(1):17–22
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):425–431
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):676–689
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):937–948
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):766–772
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):1819–1827
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):89–99
Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham prognostic index in primary breast cancer. Breast Cancer Res Treat 22:207–219
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):258–264
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):1659–1672
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 98:10869–10874
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):7110–7117
Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752
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):1804–1814
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):277–281
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):1128–1135
Walker RA, Lees E, Webb MB, Dearing SJ (1996) Breast carcinomas occurring in young women (<35 years) are different. Br J Cancer 74(11):1796–1800
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):5175–5180
Sobin LH (2003) TNM, sixth edition: new developments in general concepts and rules. Semin Surg Oncol 21:19–22
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):1574–1579
Throckmorton AD, Esserman LJ (2009) When informed, all women do not prefer breast conservation. J Clin Oncol 27(4):484–486
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):707–714
Piccart-Gebhart MJ (2004) New stars in the sky of treatment for early breast cancer. N Engl J Med 350(11):1140–1142
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–x62
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):1090–1096
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):1389–1399
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):33–36
Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093
Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11(2):103–105
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):1143–1150
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):404–413
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):1187–1198
Eccles D, Marlow A, Royle G, Collins A, Morton NE (1994) Genetic epidemiology of early onset breast cancer. J Med Genet 31(12):944–949
Li FP, Fraumeni JFJ (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71(4):747–752
Li FP, Fraumeni JF Jr, Mulvihill JJ et al (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48(18):5358–5362
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):1233–1238
Hall JM, Lee MK, Newman B et al (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250(4988):1684–1689
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):66–71
Wooster R, Neuhausen SL, Mangion J et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265(5181):2088–2090
Wooster R, Bignell G, Lancaster J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378(6559):789–792
Smith P, McGuffog L, Easton DF et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45(7):646–655
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):115–122
Renwick A, Thompson D, Seal S et al (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873–875
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):165–167
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):1239–1241
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):870–874
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):703–706
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):4340–4345
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):69–74
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):1329–1337
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):463–477
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):324–328
Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273(5281):1516–1517
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):661–671
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):6143–6151
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 100:8418–8423
Turner NC, Reis-Filho JS, Russell AM et al (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26(14):2126–2132
Lakhani SR (1999) The pathology of familial breast cancer: morphological aspects. Breast Cancer Res 1(1):31–35
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):2310–2318
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):5–14
Hedenfalk IA, Ringner M, Trent JM, Borg A (2002) Gene expression in inherited breast cancer. Adv Cancer Res 84:1–34
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):7612–7621
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 447:661–678
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):865–869
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):463–477
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):352–358
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):e1000054
Amos CI (2007) Successful design and conduct of genome-wide association studies. Hum Mol Genet 16(R2):R220–R225
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):214–219
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):1079–1087
Hartman M, Lindstrom L, Dickman PW, Adami HO, Hall P, Czene K (2007) Is breast cancer prognosis inherited? Breast Cancer Res 9(3):R39
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):R108
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):1627–1632
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):5187–5193
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):952–961
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):844–853
Hsieh SM, Lintell NA, Hunter KW (2006) Germline polymorphisms are potential metastasis risk and prognosis markers in breast cancer. Breast Dis 26:157–162
Crawford NPS, Alsarraj J, Lukes L et al (2008) Bromodomain 4 activation predicts breast cancer survival. Proc Natl Acad Sci USA 105(17):6380–6385
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):1055–1062
Smid M, Wang Y, Klijn JG et al (2006) Genes associated with breast cancer metastatic to bone. J Clin Oncol 24(15):2261–2267
Gail MH (2008) Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast cancer risk. J Natl Cancer Inst 100(14):1037–1041
Pharoah PD, Antoniou AC, Easton DF, Ponder BA (2008) Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med 358(26):2796–2803
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):506–511
Gibbs RA, Belmont JW, Hardenbol P et al (2003) The international HapMap project. Nature 426(6968):789–796
Bowen RL, Stebbing J, Jones LJ (2006) A review of the ethnic differences in breast cancer. Pharmacogenomics 7(6):935–942
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):559–575
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Eccles, D., Tapper, W. (2010). The Influence of Common Polymorphisms on Breast Cancer. In: Pasche, B. (eds) Cancer Genetics. Cancer Treatment and Research, vol 155. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-6033-7_2
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DOI: https://doi.org/10.1007/978-1-4419-6033-7_2
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