Background
Confirmed Candidate Breast Cancer Susceptibility Genes
        CHEK2
        ATM
        BRIP1
        PALB2
        CASP8 and TGFB1
Genome-Wide Searches

Background

Mutations in BRCA1, BRCA2, and the genes involved in other rare syndromes discussed above account for less than 25% of the excess familial risk of breast cancer.[1] Despite intensive genetic linkage studies, there do not appear to be other BRCA1/BRCA2-like high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters.[2] These observations suggest that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively large number of low-penetrance genes are involved.[3] Each locus would be expected to have a relatively small effect on breast cancer risk and would not produce dramatic familial aggregation or influence patient management. However in combination with other genetic loci and/or environmental factors, particularly given how common these can be, variants of this kind might significantly alter breast cancer risk. These types of genetic variations are sometimes referred to as “polymorphisms”, meaning that the gene or locus occurs in several “forms” within the population (and more formally defined as polymorphic when at least 1% of chromosomes at a position vary from each other). Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed “disease-associated polymorphisms” or “functionally relevant polymorphisms.” This polygenic model of susceptibility is consistent with the observed patterns of familial aggregation of breast cancer.[4] Although the clinical significance and causality of associations with breast cancer are often difficult to evaluate and establish, genetic polymorphisms may account for why some women are more sensitive than others to environmental carcinogens.

Polymorphisms underlying polygenic susceptibility to breast cancer are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to “high-penetrance” variants or alleles that are typically associated with more severe phenotypes, for example those BRCA1/BRCA2 mutations leading to an autosomal dominant inheritance patterns in a family. The definition of a “moderate” risk of cancer is arbitrary, but it is usually considered to be in the range of a relative risk of 1.5–2.0. Because these types of sequence variants (also called low-penetrance genes, alleles, mutations, and polymorphisms) are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from mutations in BRCA1 and BRCA2. For example, it is estimated by segregation analysis that half of all breast cancer occurs in 12% of the population that is deemed most susceptible.[3] There are no known low-penetrance variants in BRCA1/BRCA2. The N372H variation in BRCA2, initially thought to be a low-penetrance allele, was not verified in a large combined analysis.[5]

Two strategies have been taken to identify low-penetrance polymorphisms leading to breast cancer susceptibility: candidate gene and genome-wide searches. Both involve the epidemiologic case-control study design. The candidate gene approach involves selecting genes based on their known or presumed biological function, relevance to carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and has been relatively disappointing despite some confirmed associations, as described below. It has largely been replaced by the genome-wide association studies (GWAS) in which a very large number of single nucleotide polymorphisms (SNPs) (potentially 1,000,000 or more) are chosen within the genome and tested largely without regard to their possible biological function, but instead to capture more uniformly all genetic variation throughout the genome.

CHEK2 (OMIM), a gene involved in the DNA damage repair response pathway, was initially evaluated as a potential cause of Li-Fraumeni syndrome (LFS).[6] While it does not appear to be a common cause of LFS,[7] based on numerous studies, a single polymorphism, 1100delC, appears to be a rare, low-penetrance susceptibility allele.[8-13] The deletion was present in 1.2% of the European controls, 4.2% of the European BRCA1/2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.[8] In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC mutation.[14] In both Europe and the United States (where the mutation appears to be slightly less common), additional studies, including a large prospective study,[15] have detected the mutation in 4% to 11% of familial cases of breast cancer and overall have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer[16-19]. A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among mutation carriers.[20] One study suggests the risk associated with a CHEK2 1100delC mutation was stronger in the families of probands ascertained because of bilateral breast cancer.[21] At least one study has also suggested that the mutation may be associated with both breast and colorectal cancer.[17] Although the initial report suggested that male mutation carriers were at a significantly increased risk of breast cancer,[13] several follow-up studies have failed to confirm the association.[22-25] The contribution of CHEK2 mutations to breast cancer may be dependent on the population studied. A study of 3,228 women diagnosed with breast cancer before age 51 years, and 5,496 population controls demonstrated that three founder alleles in CHEK2 contributed to 8% of early onset breast cancer in Poland.[26] Although a meta-analysis of 1100delC mutation carriers estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer,[27] the clinical applicability of this finding remains uncertain due to low mutation prevalence and lack of guidelines for clinical management.[28]

Ataxia telangiectasia (AT) (OMIM) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM mutations(OMIM).[29] More than 300 mutations in the gene have been identified to date, most of which are truncating mutations.[30] (Refer to the ATM online database for more information on AT mutations) ATM proteins have been shown to play a role in cell cycle control.[31-33] In vitro, AT cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[34]

Initial studies searching for an excess of ATM mutations among breast cancer patients provided conflicting results, perhaps due to study design and mutation testing strategies.[35-45] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated relative risk of approximately 2.0.[45,46] Despite this convincing epidemiologic association, the clinical application of testing for ATM mutations is unclear due to the wide mutational spectrum and the logistics of testing. Because the presence of a mutation could pose a risk in screening-related radiation exposure, further work is needed.

BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCT domain of BRCA1. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallellic mutations in BRIP1 are a cause of Fanconi anemia,[47-49] much like such mutations in BRCA2. Inactivating mutations of BRIP1 are associated with an increased risk of breast cancer. Over 3,000 individuals from BRCA1/BRCA2 mutation negative families were examined for BRIP1 mutations. Mutations were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = 0.003). The relative risk of breast cancer was estimated to be 2.0 (95% confidence interval (CI), 1.2-3.2, P = 0.012). Of note, in families with BRIP1 mutations and multiple cases of breast cancer, there was incomplete segregation of the mutation with breast cancer, consistent with a low penetrance allele and similar to that seen with CHEK2.[50]

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic mutations in PALB2 have also been shown to cause Fanconi anemia.[51] PALB2 mutations were found in 10 of 923 (1.1%) individuals with BRCA1 and BRCA2 mutation negative familial breast cancer, compared to none of 1084 (0%) controls (P = 0.0004). One of the ten families with a PALB2 mutation included a case of male breast cancer, raising the possibility that male breast cancer is included in the spectrum of PALB2. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 mutations in families with hereditary breast cancer.[52]

The Breast Cancer Association Consortium (BCAC) investigated single nucleotide polymorphisms identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP80 D302H and TGFB1 L10P, were associated with invasive breast cancer with relative risks of 0.88 (95% CI, 0.84-0.92) and 1.08 (95% CI, 1.04-1.11) respectively.[53]

In contrast to assessing candidate genes and/or alleles, genome wide association studies involve comparing a very large set of genetic variants spread throughout the genome. The current paradigm uses sets of 100,000 to 1,000,000 SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap project.[54,55] By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[56-58] The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. While this between-SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is the causal one.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases[59] including breast cancer.[60-62] The first and most comprehensive study involved an initial scan in familial breast cancer cases followed by replication in two large sample sets of sporadic breast cancer, the final being a collection of over 20,000 cases and 20,000 controls from the BCAC, an international group of investigators.[60] Five distinct genomic regions were identified that were within or near the FGFR2, TNRC9, MAP3K1, and LSP1 genes or at the chromosome 8q region. Subsequent genome-wide studies from the Nurses Health Study, from an Icelandic study, and from a large cohort of Ashkenazi Jewish individuals, clearly replicated the FGFR2[62,63] and TNRC9[61] loci and pointed to additional susceptibility loci at chromosomes 2q35[61] and 6q22.33.[63]

Although the statistical evidence for an association between genetic variation at these loci and breast cancer risk is overwhelming, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk, with the largest odds ratio among heterozygous carriers being 1.23 (95% CI, 1.18–1.28). More risk variants are likely to be identified. Until their individual and collective influences on cancer risk are evaluated prospectively, they are not considered clinically relevant.

References

1. Easton DF: How many more breast cancer predisposition genes are there? Breast Cancer Res 1 (1): 14-7, 1999.  [PUBMED Abstract]
   
   
2. Smith P, McGuffog L, Easton DF, et al.: A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45 (7): 646-55, 2006.  [PUBMED Abstract]
   
   
3. Pharoah PD, Antoniou A, Bobrow M, et al.: Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31 (1): 33-6, 2002.  [PUBMED Abstract]
   
   
4. Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004.  [PUBMED Abstract]
   
   
5. Breast Cancer Association Consortium: Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98 (19): 1382-96, 2006.  [PUBMED Abstract]
   
   
6. Bell DW, Varley JM, Szydlo TE, et al.: Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286 (5449): 2528-31, 1999.  [PUBMED Abstract]
   
   
7. Sodha N, Houlston RS, Bullock S, et al.: Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome. Hum Mutat 20 (6): 460-2, 2002.  [PUBMED Abstract]
   
   
8. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al.: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31 (1): 55-9, 2002.  [PUBMED Abstract]
   
   
9. Kuschel B, Auranen A, Gregory CS, et al.: Common polymorphisms in checkpoint kinase 2 are not associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 12 (8): 809-12, 2003.  [PUBMED Abstract]
   
   
10. Sodha N, Bullock S, Taylor R, et al.: CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. Br J Cancer 87 (12): 1445-8, 2002.  [PUBMED Abstract]
    
    
11. Ingvarsson S, Sigbjornsdottir BI, Huiping C, et al.: Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast Cancer Res 4 (3): R4, 2002.  [PUBMED Abstract]
    
    
12. Vahteristo P, Bartkova J, Eerola H, et al.: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71 (2): 432-8, 2002.  [PUBMED Abstract]
    
    
13. Meijers-Heijboer H, Wijnen J, Vasen H, et al.: The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72 (5): 1308-14, 2003.  [PUBMED Abstract]
    
    
14. Schmidt MK, Tollenaar RA, de Kemp SR, et al.: Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 25 (1): 64-9, 2007.  [PUBMED Abstract]
    
    
15. Weischer M, Bojesen SE, Tybjaerg-Hansen A, et al.: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25 (1): 57-63, 2007.  [PUBMED Abstract]
    
    
16. Offit K, Pierce H, Kirchhoff T, et al.: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4 (1): 1, 2003.  [PUBMED Abstract]
    
    
17. Oldenburg RA, Kroeze-Jansema K, Kraan J, et al.: The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63 (23): 8153-7, 2003.  [PUBMED Abstract]
    
    
18. Neuhausen S, Dunning A, Steele L, et al.: Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer 108 (3): 477-8, 2004.  [PUBMED Abstract]
    
    
19. Ohayon T, Gal I, Baruch RG, et al.: CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer 108 (3): 479-80, 2004.  [PUBMED Abstract]
    
    
20. CHEK2 Breast Cancer Case-Control Consortium.: CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74 (6): 1175-82, 2004.  [PUBMED Abstract]
    
    
21. Johnson N, Fletcher O, Naceur-Lombardelli C, et al.: Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study. Lancet 366 (9496): 1554-7, 2005 Oct 29-Nov 4.  [PUBMED Abstract]
    
    
22. Osorio A, Rodríguez-López R, Díez O, et al.: The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108 (1): 54-6, 2004.  [PUBMED Abstract]
    
    
23. Syrjäkoski K, Kuukasjärvi T, Auvinen A, et al.: CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108 (3): 475-6, 2004.  [PUBMED Abstract]
    
    
24. Tsou HC, Teng DH, Ping XL, et al.: The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet 61 (5): 1036-43, 1997.  [PUBMED Abstract]
    
    
25. Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12(10): 1-12, 1998. 
    
    
26. Cybulski C, Górski B, Huzarski T, et al.: CHEK2-positive breast cancers in young Polish women. Clin Cancer Res 12 (16): 4832-5, 2006.  [PUBMED Abstract]
    
    
27. Weischer M, Bojesen SE, Ellervik C, et al.: CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26 (4): 542-8, 2008.  [PUBMED Abstract]
    
    
28. Offit K, Garber JE: Time to check CHEK2 in families with breast cancer? J Clin Oncol 26 (4): 519-20, 2008.  [PUBMED Abstract]
    
    
29. Savitsky K, Bar-Shira A, Gilad S, et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268 (5218): 1749-53, 1995.  [PUBMED Abstract]
    
    
30. Telatar M, Teraoka S, Wang Z, et al.: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 62 (1): 86-97, 1998.  [PUBMED Abstract]
    
    
31. Uhrhammer N, Bay JO, Bignon YJ: Seventh International Workshop on Ataxia-Telangiectasia. Cancer Res 58 (15): 3480-5, 1998.  [PUBMED Abstract]
    
    
32. Ahmed M, Rahman N: ATM and breast cancer susceptibility. Oncogene 25 (43): 5906-11, 2006.  [PUBMED Abstract]
    
    
33. Khanna KK, Chenevix-Trench G: ATM and genome maintenance: defining its role in breast cancer susceptibility. J Mammary Gland Biol Neoplasia 9 (3): 247-62, 2004.  [PUBMED Abstract]
    
    
34. Gilad S, Chessa L, Khosravi R, et al.: Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am J Hum Genet 62 (3): 551-61, 1998.  [PUBMED Abstract]
    
    
35. FitzGerald MG, Bean JM, Hegde SR, et al.: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15 (3): 307-10, 1997.  [PUBMED Abstract]
    
    
36. Chen J, Birkholtz GG, Lindblom P, et al.: The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58 (7): 1376-9, 1998.  [PUBMED Abstract]
    
    
37. Bay JO, Grancho M, Pernin D, et al.: No evidence for constitutional ATM mutation in breast/gastric cancer families. Int J Oncol 12 (6): 1385-90, 1998.  [PUBMED Abstract]
    
    
38. Laake K, Vu P, Andersen TI, et al.: Screening breast cancer patients for Norwegian ATM mutations. Br J Cancer 83 (12): 1650-3, 2000.  [PUBMED Abstract]
    
    
39. Dörk T, Bendix R, Bremer M, et al.: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61 (20): 7608-15, 2001.  [PUBMED Abstract]
    
    
40. Teraoka SN, Malone KE, Doody DR, et al.: Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92 (3): 479-87, 2001.  [PUBMED Abstract]
    
    
41. Chenevix-Trench G, Spurdle AB, Gatei M, et al.: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94 (3): 205-15, 2002.  [PUBMED Abstract]
    
    
42. Thorstenson YR, Roxas A, Kroiss R, et al.: Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res 63 (12): 3325-33, 2003.  [PUBMED Abstract]
    
    
43. Cavaciuti E, Laugé A, Janin N, et al.: Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families. Genes Chromosomes Cancer 42 (1): 1-9, 2005.  [PUBMED Abstract]
    
    
44. Olsen JH, Hahnemann JM, Børresen-Dale AL, et al.: Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia. Br J Cancer 93 (2): 260-5, 2005.  [PUBMED Abstract]
    
    
45. Renwick A, Thompson D, Seal S, et al.: ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38 (8): 873-5, 2006.  [PUBMED Abstract]
    
    
46. Thompson D, Duedal S, Kirner J, et al.: Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97 (11): 813-22, 2005.  [PUBMED Abstract]
    
    
47. Levitus M, Waisfisz Q, Godthelp BC, et al.: The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet 37 (9): 934-5, 2005.  [PUBMED Abstract]
    
    
48. Levran O, Attwooll C, Henry RT, et al.: The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37 (9): 931-3, 2005.  [PUBMED Abstract]
    
    
49. Litman R, Peng M, Jin Z, et al.: BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8 (3): 255-65, 2005.  [PUBMED Abstract]
    
    
50. Seal S, Thompson D, Renwick A, et al.: Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38 (11): 1239-41, 2006.  [PUBMED Abstract]
    
    
51. Reid S, Schindler D, Hanenberg H, et al.: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39 (2): 162-4, 2007.  [PUBMED Abstract]
    
    
52. Rahman N, Seal S, Thompson D, et al.: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39 (2): 165-7, 2007.  [PUBMED Abstract]
    
    
53. Cox Angela, Dunning Alison, Garcia-Closas Montserrat, et al.: Nature genetics. Nat Genet 39 (5): 352-8, 2007. 
    
    
54. The International HapMap Consortium.: The International HapMap Project. Nature 426 (6968): 789-96, 2003.  [PUBMED Abstract]
    
    
55. Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005.  [PUBMED Abstract]
    
    
56. Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006.  [PUBMED Abstract]
    
    
57. Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006.  [PUBMED Abstract]
    
    
58. Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007.  [PUBMED Abstract]
    
    
59. Wellcome Trust Case Control Consortium.: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007.  [PUBMED Abstract]
    
    
60. Easton DF, Pooley KA, Dunning AM, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 (7148): 1087-93, 2007.  [PUBMED Abstract]
    
    
61. Stacey SN, Manolescu A, Sulem P, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39 (7): 865-9, 2007.  [PUBMED Abstract]
    
    
62. Hunter DJ, Kraft P, Jacobs KB, et al.: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39 (7): 870-4, 2007.  [PUBMED Abstract]
    
    
63. Gold B, Kirchhoff T, Stefanov S, et al.: Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A 105 (11): 4340-5, 2008.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >