Human Molecular Genetics, 2001, Vol. 10, No. 7 715-720
© 2001 Oxford University Press
‘Other’ breast cancer susceptibility genes: searching for more holy grail
Department of Medicine, University of Pennsylvania School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA 19104, USA
Received 10 January 2001 ; Revised and Accepted 26 January 2001.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONTHE SEARCH FOR BRCA3LOW PENETRANCE GENESSUMMARYREFERENCES |
|---|
While germline mutations in BRCA1 and BRCA2 account for most, if not all families with autosomal dominant transmission of susceptibility to both breast and ovarian cancer, it has become clear that together these genes only account for a small proportion of hereditary site-specific breast cancer susceptibility. However, difficulties due to genetic heterogeneity, reduced penetrance and perhaps gene mutation frequency complicate ongoing efforts to identify additional susceptibility genes. Therefore, multiple approaches are being used to identify additional high and low penetrance genes. Families with three or more breast cancer cases are being used in traditional linkage studies, which are expected to yield only moderate or high penetrance susceptibility genes. Breast cancer case-control studies are being used to look for genetic variants or polymorphisms that confer an increased risk of breast cancer in a wide variety of cellular pathways, ranging from the detoxification of environmental carcinogens to steroid hormone metabolism, DNA damage repair and immune surveillance, an approach useful primarily to identify low penetrance susceptibililty genes. However, neither approach has yielded convincing results to date. A third approach, using BRCA1 and BRCA2 mutation carriers to identify genes that are associated with modification of breast cancer risk has met with some limited success, perhaps because effects on breast cancer risk in BRCA1 and BRCA2 mutation carriers are more readily detected in smaller studies, given the much higher number of events in these cohorts at very high risk of breast cancer. Clearly, hereditary breast cancer susceptibility is a complex phenomenon, in which multiple genes may play a role. It will be necessary to use all of these approaches, as well as more comprehensive genomic studies, to identify additional breast cancer-related genes.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR BRCA3LOW PENETRANCE GENESSUMMARYREFERENCES |
|---|
In the 6 years since the discovery of BRCA1 and BRCA2, it has become clear that mutations in BRCA1 and BRCA2 account for only a fraction of inherited susceptibility to breast cancer. While essentially all families with apparent autosomal dominant inheritance of susceptibility to both breast and ovarian cancer are accounted for by mutations in BRCA1 and BRCA2, even among those families with four or more cases of early onset breast cancer (<60 years), 67% showed no convincing evidence of linkage to BRCA1 or BRCA2 in a large study by the Breast Cancer Linkage Consortium (BCLC) (1). Smaller mutation based studies have provided additional supportive evidence that the majority of families with site-specific breast cancer are not accounted for by germline mutations in BRCA1 and BRCA2, (Fig. 1) (2–5). Additionally, a large case-control study using PCR-based mutation analysis to identify BRCA1 and BRCA2-associated families using probands with breast cancer diagnosed before the age of 45 found only 16% of the excess breast cancer risk to sisters and mothers of the cases was attributable to mutations in these two genes (6). Finally, Claus et al. (7) reported that family history remains a predictive factor for breast cancer risk in women without detectable coding region mutations BRCA1 and BRCA2. The cumulative evidence from all of these studies suggests strongly that there are moderate or high penetrance genes in addition to BRCA1 and BRCA2 that contribute to heritable susceptibility to breast cancer. In this review, we provide an update on the search for additional moderate or high penetrance genes, an example of a class of genetic variants that may be associated with a modest increase in breast cancer risk, and an overview of genetic variants that may modify breast cancer risk associated with germline mutations in BRCA1 and BRCA2.
|
|
THE SEARCH FOR BRCA3 |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR BRCA3LOW PENETRANCE GENESSUMMARYREFERENCES |
|---|
Several genomic regions have been suggested as candidate loci for additional breast cancer susceptibility genes, but none has been supported in confirmatory studies. PTEN germline mutations, which confer predisposition to thyroid and breast cancer, as well as benign hamartomatous lesions (Cowden syndrome), have been evaluated in light of this. Analysis of 56 families (three or more cases <60 years of age) did not show evidence of linkage between breast cancer and genetic markers in the region of PTEN (10q23) (8). Chromosome 8p also has been proposed as a locus for a breast cancer susceptibility gene based on studies documenting allelic loss in this region in sporadic breast cancers (9,10). Initial linkage studies evaluating 8p were performed using 11 families—one family had a multipoint LOD score of 2.32, but only three of the remaining families had positive LOD scores, all <0.6 (9). In a larger series of 38 site-specific breast cancer families (three or more cases <60 years of age) no evidence of linkage was found on 8p, suggesting that if a breast cancer susceptibility gene exists at this locus, it accounts for a very small proportion of familial site-specific breast cancer (11).
Recently, it has been suggested that a breast cancer susceptibility gene may be located on 13q21 (12). Using comparative genomic hybridization (CGH) on 61 tumors from 37 families, (at least three breast cancers, no age criteria, no germline mutations by PCR-based methods in BRCA1 or BRCA2), the most common somatic alteration was loss of 13q21–31, which was thought to be an early event in tumorigenesis using hierarchical branching algorithms. These CGH findings were followed up with targeted linkage analysis in 77 breast cancer families, in which BRCA1 and BRCA2 mutations were excluded. An overall maximum two-point LOD score of 2.76 at D13S1308 was observed, with a peak three-point heterogeneity LOD (HLOD) of 3.46 (
= 0.65). However, markers immediately adjacent to the positive HLOD gave lower HLOD scores of 1.5. Preliminary studies from the BRCA3 Linkage Consortium using 100 families (at least three breast cancers <60 years of age, site-specific disease, no BRCA1 or BRCA2 mutations by both mutational and linkage analyses) do not support 13q21–31 as a locus for a moderate or high penetrance breast cancer susceptibility gene (M. Stratton, unpublished data).
The search for BRCA3 is difficult for several reasons. First, in the search for BRCA1 and BRCA2, the associations between ovarian cancer (BRCA1 and BRCA2) and male breast cancer (BRCA2) were recognized before either gene was isolated, allowing for targeted ascertainment of families with a high prior probability of linkage to the respective candidate regions. As no such phenotype has been associated with mutations in the putative BRCA3 gene(s), families entered into current studies are selected only for early age of breast cancer diagnosis and the absence of ovarian and male breast cancer. Additionally, BRCA3 mutations may be associated with lower breast cancer penetrance than BRCA1 and BRCA2, and, if so, sporadic differentiating from hereditary cancers becomes a serious problem. Finally, multiple additional genes, each responsible for small numbers of families may exist and limit the power of traditional linkage analyses. Thus investigators searching for BRCA3 share many of the problems faced by those searching for hereditary prostate cancer genes (reviewed in 13). Larger family sets are needed to move this effort forward and to increase statistical power in the face of significant heterogeneity.
|
LOW PENETRANCE GENES |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR BRCA3LOW PENETRANCE GENESSUMMARYREFERENCES |
|---|
Low penetrance genes are, in this instance, defined as genes in which subtle sequence variants or polymorphisms may be associated with a small to moderate increased relative risk for breast cancer. Such variants are relatively common in the population and as such may confer a much higher attributable risk in the general population than rare mutations in high penetrance cancer susceptibility genes such as BRCA1 and BRCA2. Thus variants in low penetrance genes presumably explain a greater proportion of breast cancers than germline mutations in BRCA1 and BRCA2, estimated at
3% in a US population-based series (14). An example of how variants in hypothetical low penetrance genes could explain more breast cancer risk than mutations in a high penetrance gene is illustrated in Table 1.
|
Candidate low penetrance gene products are usually chosen on the basis of biological plausibility, in that alterations in their protein sequence, and therefore function, could affect a pathway involved in carcinogenesis, however subtle the change. A wide variety of cellular pathways, ranging from the detoxification of environmental carcinogens to steroid hormone metabolism, DNA damage repair and immune surveillance have been hypothesized as candidates for biologically plausible candidate genes. We have reviewed the DNA damage response pathway as an example.
DNA damage response pathway genes
The capacity of cells to repair DNA damage is at least in part, genetically determined. Twin studies support a genetic component in DNA repair capacity, and an increased frequency of individuals with reduced repair capacity among relatives of patients with cancer has been described (15–17). The latter type of study highlights the association between DNA damage response pathway defects and cancer susceptibility. Not only are multiple heritable cancer susceptibility syndromes due to germline mutations in genes involved in DNA damage response, such as hereditary non-polyposis colorectal cancer (HNPCC), breast and ovarian cancer, ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS), but also a reduced ability to repair DNA appears to increase cancer risk in case-control association studies. This reduced capacity to repair DNA is associated with an increased odds ratios for cancer ranging from 1.6 to as much as 10 in multiple studies (16–21). Cellular radiosensitivity, a measure of DNA damage response capacity, has been directly associated with breast cancer susceptibility and may be a heritable trait, with a limited number of genes contributing to the phenotype (21–23). For genes within the multiple DNA damage response pathways, both heterozygosity for germline mutations in genes that cause autosomal recessive cancer susceptibility syndromes and common variants in genes that cause autosomal dominant cancer susceptibility syndromes may be low penetrance risk factors for breast cancer.
ATM. Individuals homozygous for germline mutations in ATM have AT, an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasias, radiation hypersensitivity and an increased incidence of malignancy (24). AT homozygotes have cancer risks 60–180 times greater than the general population including non-Hodgkins lymphoma (nearly 100% lifetime risk) and breast and ovarian cancer (25). Heterozygosity for germline mutations in ATM was initally hypothesized by Swift (26) to confer an increased breast cancer risk, a finding that could be particularly significant given that ATM heterozygotes represent up to 7% of the general population, and that screening mammography, a source of ionizing radiation, could theoretically increase the penetrance of such mutations. However, subsequent studies do not all support the initial claim and the association remains controversial. Two approaches have been used to address this issue. First, unaffected family members of AT patients consistently have an increased risk of breast cancer, with relative risks ranging from 1.5 to 9 (27–31). The most recent study, evaluating 609 female relatives of Nordic AT patients found an increased breast cancer risk only in mothers of AT patients, and an overall relative risk of 2.4 associated with ATM heterozygosity (32).
A second approach has been to use mutational analysis to define the contribution of mutations in ATM to breast cancer risk. In the first such study of 401 women diagnosed with breast cancer under 40, ATM mutation frequency did not differ from controls (33). However, protein truncation testing (PTT) was used for mutation screening, which may have missed some mutations. Null results also were found by Izatt et al. (34) in 100 breast cancer cases under the age of 40 and by Chen et al. (35) in 100 breast cancer patients with a family history, as well as several smaller studies (36–38). Finally, in a recent study of 483 unselected Norwegian breast cancer cases (150 of whom were under the age of 55), screened for the Norwegian founder ATM mutations, no increase in prevalence over controls was found (39). However, Broeks et al. (40) did find an increased rate of ATM mutations in 82 patients diagnosed with breast cancer before the age of 45, 40% of whom had contralateral disease and all of whom had been exposed to low-dose radiation at a young age. The latter study suggests that exposure to even low-dose radiation at a young age may be an important component of breast cancer risk in the presence of an ATM mutation. Taken together, these data suggest that in the absence of additional exposures, any increased breast cancer risk due to truncating mutations in ATM is likely to be minimal, with a population attributable risk of 1–2% (32).
NBS1. Patients with NBS have an increased sensitivity to ionizing radiation and a predisposition to cancer similar to patients with AT. As such, a large case-control study of women with breast cancer diagnosed before the age of 51 was undertaken to determine whether the common Slavic founder mutation in NBS1, the gene associated with NBS, was associated with an increased susceptibility to breast cancer (41). In this study no difference in NBSI mutation frequency was seen in cases as compared to controls, suggesting that this variant does not predispose carriers to breast cancer.
BRCA1 and BRCA2. As deleterious germline mutations in BRCA1 and BRCA2 confer a greatly increased risk of breast cancer, common variants in both genes are ideal candidates for low penetrance alleles. Several common variants in BRCA1 have been studied, without any clear evidence for low penetrance susceptibility alleles. The common BRCA1 haplotypes 356Q/871P/1038E/1613S (frequency 0.57) and 356Q/871L/1038G/1613G (frequency 0.32) and the variant R356Q do not significantly differ between cases and controls (42,43). The BRCA1 variant R841W may be associated with an increase in breast cancer susceptibility based on one study of BRCA1 mutations in breast cancer cases, however, this variant is rare (<1% in US controls) and has not been rigorously evaluated in another large case-control study (44,45).
Recently, six variants in BRCA2 were studied for an association with breast cancer susceptibility. Of those variants (a-26g, N298H, N372H, T1915M, R2034C, K3326X) only one, N372H, appears to confer a small increased risk of breast cancer (46). N372H also is the only variant amino acid change in BRCA2 with an allele frequency >6%. In a joint analysis of five series of breast cancer case-control studies (3459 cases and 2805 controls), homozygosity for the 372H allele, as compared to homozygosity for the 372N allele, was associated with an OR of 1.31 [95% confidence interval (CI) 1.04–1.61]. Interestingly, the study also revealed that the N372H allele is not in Hardy–Weinberg equilibrium, with females having an excess of heterozygotes and a deficit of homozygotes, while the reverse is true in males. The authors suggest that there is sex-specific selection in utero, supporting a role for BRCA2 in human development.
TP53. Given the well-described high penetrance of germline TP53 mutations for early onset breast cancer as a component of Li–Fraumeni syndrome, sequence variants in TP53 also have been investigated as possible low penetrance cancer susceptibility alleles (47). Three polymorphisms (IVS3 16 bp tandem repeat, IVS6 +62 G
A, and Arg72Pro) (48–52) have all been extensively studied. In a meta-analysis, the Arg72Pro variant (Pro carrier OR = 1.27, P = 0.03) was associated with a small increase in breast cancer risk; the other variants have not been consistently associated with increased breast cancer risk (42).
Other genes. In addition to variants in DNA damage response genes, variants in other genes that participate in DNA damage response pathways have been studied for association with breast cancer risk on a limited basis. Microsatellite repeats associated with XRCC1, XRCC3 and XRCC5 have been evaluated in a small case-control series and an association with breast cancer was found for XRCC1 and XRCC3; however, these data need to be confirmed in larger studies (53). In general, variants in DNA damage response genes remain the focus of ongoing study in many laboratories and our understanding of how they affect breast cancer risk is still in its infancy.
BRCA1 and BRCA2 modifier genes
While, overall, germline mutations in BRCA1 and BRCA2 confer a high risk of breast cancer, a great deal of variability in cancer risk among individuals both between and within familes has been observed. In addition, the estimated lifetime risk of breast cancer for BRCA1 mutation carriers ranges from 36% in population based series to 85% in families ascertained for linkage analysis, apparently varying by population ascertainment (54–57). Furthermore, genes that affect familial breast cancer risk in the general population could presumably affect breast cancer risk in BRCA1 and BRCA2 mutation carriers. Therefore, a number of studies have evaluated variants in candidate genes, some examples of which are reviewed here, looking for modifiers of penetrance. In general, these studies have been done using increasing age at diagnosis of breast cancer as a surrogate for decreasing penetrance.
Androgen receptor. An association between age of breast cancer diagnosis in BRCA1 mutation carriers and length of the CAG repeat in exon 1 of the androgen receptor (AR) has been suggested recently (58). The AR-CAG repeat was selected for study as it modulates the activity of the AR, with alleles containing longer CAG repeat lengths having a decreased ability to activate androgen responsive genes (59), resulting in turn in increased breast epithelial cell proliferation. In this series, women with BRCA1 mutations who had at least one AR allele with more than 28, 29 or 30 CAG repeats were diagnosed with breast cancer 0.8, 1.8 and 6.3 years earlier, respectively, than women who did not carry at least one such AR allele. Recent data have shown that BRCA1 interacts physically with and is a co-activator of the AR promoter and, provide a plausible explanation for the finding that allelic variation in AR affects breast cancer penetrance in BRCA1 mutation carriers (60).
Progesterone receptor. Preliminary data suggest that the PROGINS variant of the progesterone receptor, in which there is a 306 bp Alu insertion in intron 7, may be associated with an increased risk (OR 2.4) of ovarian cancer in BRCA1 and BRCA2 mutation carriers who have never used oral contraceptives (61). There are two transcribed isoforms of the progesterone receptor (HPR-A and HPR-B) that use alternate initiation sites. The PROGINS variant of HPR-A isoform has been demonstrated to increase transcriptional activity and stability, and may repress estrogen receptor activation and transcriptional activity of the HPR-B isoform more effectively than the wild-type (62). In breast cancer case-control studies, there is evidence that carriers of PROGINS are at decreased risk of breast cancer (42,62).
AIB1. AIB1 is a member of the SRC-1 family of transcriptional co-activators that interact with steroid hormones to enhance estrogen-dependent transcription. AIB1 has been found to be amplified in 10% and over-expressed in 64% of 105 breast tumors (63). The AIB1 coding region contains a variable number of glutamine residues (20–29) beginning at residue 3930. In a study of 165 breast cancer cases and 139 unaffected controls, all of whom had germline BRCA1 mutations, women with an AIB1 allele with at least 28 polyglutamine repeats were a higher breast cancer risk compared with women with shorter alleles (OR = 1.59, 95% CI 1.03–2.47 and OR = 2.85, 95% CI 1.64– 4.96, respectively) (T.R. Rebbeck, unpublished data). Breast cancer risk increased further in association with late age at first live birth and no AIB1 alleles with less than 28 or 29 repeats (OR = 4.62, 95% CI 2.02–10.56 and OR = 6.97, 95% CI 1.71–28.43, respectively). This preliminary association study suggests that expression levels of AIB1 may vary based on the number of glutamine repeats and consequently influence breast cancer penetrance.
All of these association studies suggest that variants in endocrine signaling pathway genes may affect cancer penetrance in BRCA1 and BRCA2 mutation carriers. In addition, the affect of the variants may be modulated by other hormonal and environmental exposures such as oral contraceptives and age at first live birth.
There are several explanations for why variants in genes that affect penetrance in BRCA1 and BRCA2 mutation carriers have not been consistently associated with an increased risk of sporadic breast cancer. First, it may be that these variants affect penetrance in BRCA1 and BRCA2 mutation carriers specifically, and are not low penetrance susceptibility genes in general. More likely however, given that the majority of studies evaluating hormonal risk factors in BRCA1 and BRCA2 mutation carriers have produced very similar results to general population studies, it may be that population-based studies have been underpowered, given that the associated relative risks are small. Effects on breast cancer risk in BRCA1 and BRCA2 mutation carriers may be more readily detected, given the much higher number of events in study cohorts at a very high risk of breast cancer. In fact, this study design may be hampered by a lack of age-matched unaffected controls.
|
SUMMARY |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR BRCA3LOW PENETRANCE GENESSUMMARYREFERENCES |
|---|
While the identification of BRCA1 and BRCA2 has greatly increased our understanding of breast cancer susceptibility, it is clear that additional genes remain to be identified. As reviewed here, multiple efforts, using various methodologies, such as linkage in high-risk families, association studies in large case-control studies and BRCA1 and BRCA2 mutation carriers, are underway to identify additional breast cancer susceptibility genes.
|
FOOTNOTES |
|---|
+ To whom correspondence should be addressed. Tel: +1 215 898 0247; Fax: +1 215 573 2486; Email: weberb@mail.med.upenn.edu
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONTHE SEARCH FOR BRCA3LOW PENETRANCE GENESSUMMARYREFERENCES |
|---|
1 Ford, D., Easton, D.F., Stratton, M., Narod, S., Goldgar, D., Devilee, P., Bishop, D.T., 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.[Web of Science][Medline]
2 Serova, O.M., Mazoyer, S., Puget, N., Dubois, V., Tonin, P., Shugart, Y.Y., Goldgar, D., Narod, S.A., Lynch, H.T. and Lenoir, G.M. (1997) Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am. J. Hum. Genet., 60, 486–495.[Web of Science][Medline]
3 Schubert, E.L., Lee, M.K., Mefford, H.C., Argonza, R.H., Morrow, J.E., Hull, J., Dann, J.L. and King, M.C. (1997) BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am. J. Hum. Genet., 60, 1031–1040.[Web of Science][Medline]
4 Rebbeck, T.R., Couch, F.J., Kant, J., Calzone, K., DeShano, M., Peng, Y., Chen, K., Garber, J.E. and Weber, B.L. (1996) Genetic heterogeneity in hereditary breast cancer: role of BRCA1 and BRCA2. Am. J. Hum. Genet., 59, 547–553.[Web of Science][Medline]
5 Vehmanen, P., Friedman, L.S., Eerola, H., McClure, M., Ward, B., Sarantaus, L., Kainu, T., Syrjakoski, K., Pyrhonen, S., Kallioniemi, O.P., Muhonen, T. et al. (1997) Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. Hum. Mol. Genet., 6, 2309–2315.
6 Peto, J., Collins, N., Barfoot, R., Seal, S., Warren, W., Rahman, N., Easton, D.F., Evans, C., Deacon, J. and Stratton, M.R. (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J. Natl Cancer Inst., 91, 943–949.
7 Claus, E.B., Schildkraut, J., Iversen, E.S., Jr, Berry, D. and Parmigiani, G. (1998) Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history. J. Natl Cancer Inst., 90, 1824–1829.
8 Shugart, Y.Y., Cour, C., Renard, H., Lenoir, G. and Goldgar, D. (1999) Linkage analysis of 56 multiplex families excludes the Cowden disease gene PTEN as a major contributor to familial breast cancer. J. Med. Genet., 36, 720–721.
9 Seitz, S., Rohde, K., Bender, E., Nothnagel, A., Pidde, H., Ullrich, O.-M., El-Zehairy, A., Haensch, W., Jandrig, B., Kolble K. et al. (1997) Deletion mapping and linkage analysis provide strong indication for the involvement of the human chromosome region 8p12-p22 in breast carcinogenesis. Br. J. Cancer, 76, 983–991.[Web of Science][Medline]
10 Kerangueven, F., Essioux, L. and Dib, A. (1995) Loss of heterozygosity and linkage analysis in breast carcinoma: Indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene, 10, 1023.[Web of Science][Medline]
11 Rahman, N., Teare, M.D., Seal, S., Renard, H., Mangion, J., Cour, C., Thompson, D., Shugart, Y., Eccles, D., Devilee, P. et al. (2000) Absence of evidence for a familial breast cancer susceptibility gene at chromosome 8p12-p22. Oncogene, 19, 4170–4173.[Web of Science][Medline]
12 Kainu, T., Juo, S.H., Desper, R., Schaffer, A.A., Gillanders, E., Rozenblum, E., Freas-Lutz, D., Weaver, D., Stephan, D., Bailey-Wilson, J. et al. (2000) Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc. Natl Acad. Sci. USA, 97, 9603–9608.
13 Ostrander, E.A. and Standford, J.L. (2000) Genetics of prostate cancer: too many loci, too few genes. Am. J. Hum. Genet., 67, 1367–1375.[Web of Science][Medline]
14 Newman, B., Mu, H., Butler, L.M., Millikan, R.C., Moorman, P.G. and King, M.C. (1998) Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. J. Am. Med. Assoc., 279, 915–921.
15 Pero, R.W., Johnson, D.B., Markowitz, M., Doyle, G., Lund-Pero, M., Seidegard, J., Halper, M. and Miller, D.G. (1989) DNA repair synthesis in individuals with and without a family history of cancer. Carcinogenesis, 10, 693–697.
16 Helzlsouer, K., Harris, E., Parshad, R., Fogel, S., Bigbee, W.L. and Sanford, K.K. (1995) Familial clustering of breast cancer: possible interaction between DNA repair proficiency and radiation exposure in the risk of breast cancer. Int. J. Cancer, 64, 14–17. [Web of Science][Medline]
17 Kovacs, E. and Almendral, A. (1987) Reduced DNA repair synthesis in healthy women having first degree relatives with breast cancer. Eur. J. Cancer Clin. Oncol., 23, 1051–1057.[Web of Science][Medline]
18 Grossman, L. and Wei, Q. (1994) DNA repair capacity as a biomarker of human variational responses to the environment. In Vos, J. (ed.), DNA Repair Mechanisms. R.G. Landes Co., Austin, TX, pp. 329–347.
19 Helzlsouer, K., Harris, E., Parshad, R., Perry, H.R., Price, F.M. and Sanford, K.K. (1996) DNA repair proficiency: potential susceptibility factor for breast cancer. J. Natl Cancer Inst., 88, 754–755.
20 Knight, R., Parshad, R. and Price, F. (1993) X-ray induced chromatid damage in relation to DNA repair and cancer incidence in family members. Int. J. Cancer, 54, 589–593.[Web of Science][Medline]
21 Scott, D., Spreadborough, A., Levine, E. and Roberts, S.A. (1994) Genetic predisposition in breast cancer (letter to the editor). Lancet, 344, 1444.
22 Roberts, S.A., Spreadborough, A.R., Bulman, B., Barber, J.B.P., Evans, D.G.R. and Scott, D. (1999) Heretibility of cellular radiosensitivity: A marker of low-penetrance predisposition genes in breast cancer? Am. J. Hum. Genet., 65, 784–794.[Web of Science][Medline]
23 Scott, D., Barber, J.B., Levine, E.L., Burrill, W. and Roberts, S.A. (1998) Radiation-induced micronucleus induction in lymphocytes identifies a high frequency of radiosensitive cases among breast cancer patients: a test for predisposition? Br. J. Cancer, 77, 614–620.[Web of Science][Medline]
24 Wright, J., Teraoka, S., Onengut, S., Tolun, A., Gatti, R.A., Ochs, H.D. and Concannon, P. (1996) A high frequency of distinct ATM gene mutations in ataxia-telangiectasia., 59, 839–846.
25 Morrell, D., Cromartie, E. and Swift, M. (1986) Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J. Natl Cancer Inst., 77, 89–92.
26 Swift, M., Morrell, D., Cromartie, E., Chamberlin, A.R., Skolnick, M.H. and Bishop, D.T. (1986) The incidence and gene frequency of ataxia-telangiectasia in the United States. Am. J. Hum. Genet., 39, 573–583.[Web of Science][Medline]
27 Swift, M., Reitnauer, P.J., Morrell, D. and Chase, C.L. (1987) Breast and other cancers in families with ataxia-telangiectasia. N. Engl. J. Med., 316, 1289–1294.[Abstract]
28 Swift, M., Morrell, D., Massey, R.B. and Chase, C.L. (1991) Incidence of cancer in 161 families affected by ataxia-telangiectasia. N. Engl. J. Med., 325, 1831–1836.[Abstract]
29 Easton, D.F. (1994) Cancer risks in A-T heterozygotes. Int. J. Radiat. Biol., 66, S177–S182.
30 Inskip, H.M., Kinlen, L.J., Taylor, A.M.R., Woods, C.G. and Arlett, C.F. (1999) Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. Br. J. Cancer, 79, 1304–1307.[Web of Science][Medline]
31 Janin, N., Andrieu, N., Ossian, K., Lauge, A., Croquette, M.F., Griscelli, C., Debre, M., Bressac-de-Paillerets, B., Aurias, A. and Stoppa-Lyonnet, D. (1999) Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. Br. J. Cancer, 80, 1042–1045.[Web of Science][Medline]
32 Olsen, J.H., Hanemann, J.M., Borresen-Dale, A.L., Brondum-Neilsen, K., Hammarstrom, L., Kleinerman, R., Kaarianen, H., Lonnqvist, T., Sankila, R., Seersholm, N. et al. (2001) Cancer in patients with Ataxia-telangiectasia and in their relatives in the Nordic countries. J. Natl Cancer Inst., 93, 121–127.
33 FitzGerald, M.G., Bean, J.M., Hegde, S.R., Unsal, H., MacDonald, D.J., Harkin, D.P., Finkelstein, D.M., Isselbacher, K.J. and Haber, D.A. (1997) Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet., 15, 307–310.[Web of Science][Medline]
34 Izatt, L., Greenman, J., Hodgson, S., Ellis, D., Watts, S., Scott, G., Jacobs, C., Liebmann, R., Zvelebil, M.J., Mathew, C. and 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.[Web of Science][Medline]
35 Chen, J., Birkholtz, G.G., Lindblom, P., Rubio, C. and Lindblom, A. (1998) The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res., 58, 1376–1379.
36 Vorechovsky, I., Luo, L., Lindblom, A., Negrini, M., Webster, A.D., Croce, C.M. and Hammarstrom, L. (1996) ATM mutations in cancer families. Cancer Res., 56, 4130–4133.
37 Shayeghi, M., Seal, S., Regan, J., Collins, N., Barfoot, R., Rahman, N., Ashton, A., Moohan, M., Wooster, R., Owen, R. et al. (1998) Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients. Br. J. Cancer, 78, 922–927.[Web of Science][Medline]
38 Bebb, G., Glickman, B., Gelmon, K. and Gatti, R. (1997) "AT risk" for breast cancer. Lancet, 349, 1784–1785.[Web of Science][Medline]
39 Laake, K., Vu, P., Andersen, T.I., Erikstein, B., Karesen, R., Lonning, P.E., Skovlund, E. and Borresen-Dale, A.L. (2000) Screening breast cancer patients for Norwegian ATM mutations. Br. J. Cancer, 83, 1650–1653.[Web of Science][Medline]
40 Broeks, A., Urbanus, J.H., Floore, A.N., Dahler, E.C., Klijn, J.G., Rutgers, E.J., Devilee, P., Russell, N.S., van Leeuwen, F.E. and van’t, Veer L.J. (2000) ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am. J. Hum. Genet., 66, 494–500.[Web of Science][Medline]
41 Carlomagno, F., Chang-Claude, J., Dunning, A.M. and Ponder, B.A. (1999) Determination of the frequency of the common 657Del5 Nijmegen breakage syndrome mutation in the German population: no association with risk of breast cancer. Genes Chromosomes Cancer, 25, 393–395.[Web of Science][Medline]
42 Dunning, A.M., Healey, C.S., Pharoah, P.D., Teare, M.D., Ponder, B.A. and Easton, D.F. (1999) A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol. Biomarkers Prev., 8, 843–854.
43 Durocher, F., Shattuck-Eidens, D., McClure, M., Labrie, F., Skolnick, M.H., Goldgar, D.E. and 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.
44 Barker, D.F., Almeida, E.R., Casey, G., Fain, P.R., Liao, S.Y., Masunaka, I., Noble, B., Kurosaki, T. and Anton-Culver, H. (1996) BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype. Genet. Epidemiol., 13, 595–604.[Web of Science][Medline]
45 Petersen, G.M., Parmigiani, G. and Thomas, D. (1998) Missense mutations in disease genes: a Bayesian approach to evaluate causality. Am. J. Hum. Genet., 62, 1516–1524.[Web of Science][Medline]
46 Healey, C.S., Dunning, A.M., Dawn Teare, M., Chase, D., Parker, L., Burn, J., Chang-Claude, J., Mannermaa, A., Kataja, V., Huntsman, D.G. et al. (2000) A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability. Nature Genet., 26, 362–364.[Web of Science][Medline]
47 Varley, J.M., McGown, G., Thorncroft, M., Santibanez-Koref, M.F., Kelsey, A.M., Tricker, K.J., Evans, D.G. and Birch, J.M. (1997) Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. Cancer Res., 57, 3245–3252.
48 Sjalander, A., Birgander, R., Hallmans, G., Cajander, S., Lenner, P., Athlin, L., Beckman, G. and Beckman, L. (1996) p53 polymorphisms and haplotypes in breast cancer. Carcinogenesis, 17, 1313–1316.
49 Mavridou, D., Gornall, R., Campbell, I.G. and Eccles, D.M. (1998) TP53 intron 6 polymorphism and the risk of ovarian and breast cancer. Br. J. Cancer, 77, 676–677.[Web of Science][Medline]
50 Wang-Gohrke, S., Rebbeck, T.R., Besenfelder, W., Kreienberg, R. and Runnebaum, I.B. (1998) p53 germline polymorphisms are associated with an increased risk for breast cancer in German women. Anticancer Res., 18, 2095–2099.[Web of Science][Medline]
51 Campbell, I.G., Eccles, D.M., Dunn, B., Davis, M. and Leake, V. (1996) p53 polymorphism in ovarian and breast cancer. Lancet, 347, 393–394.[Web of Science][Medline]
52 Weston, A., Pan, C.F., Ksieski, H.B., Wallenstein, S., Berkowitz, G.S., Tartter, P.I., Bleiweiss, I.J., Brower, S.T., Senie, R.T. and Wolff, M.S. (1997) p53 haplotype determination in breast cancer. Cancer Epidemiol. Biomarkers Prev., 6, 105–112.[Abstract]
53 Price, E., Bourne, S., Radbourne, P., Lawton, P.A., Lamerdin, J., Thompson, L.H. and Arrand, J.E. (1997) Rare microsatellite polymorphisms in DNA repair genes XRCC1, XRCC3 and XRCC5 associated with cancer in patients of varying radiosensitivity. Somat. Cell Mol. Genet., 23, 237–247.[Web of Science][Medline]
54 Easton, D.F., Ford, D. and Bishop, D.T. (1995) Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am. J. Hum. Genet., 56, 265–271.[Web of Science][Medline]
55 Fodor, F.H., Weston, A., Bleiweiss, I.J., McCurdy, L.D., Walsh, M.M., Tartter, P.I., Brower, S.T. and Eng, C.M. (1998) Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am. J. Hum. Genet., 63, 45–51.[Web of Science][Medline]
56 Struewing, J.P., Hartge, P., Wacholder, S., Baker, S.M., Berlin, M., McAdams, M., Timmerman, M.M., Brody, L.C. and Tucker, M.A. (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N. Engl. J. Med., 336, 1401–1408.
57 Ford, D., Easton, D.F., Bishop, D.T., Narod, S.A. and Goldgar, D.E. (1994) Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet, 343, 692–695.[Web of Science][Medline]
58 Rebbeck, T.R., Kantoff, P.W., Krithivas, K., Neuhausen, S., Blackwood, M.A., Godwin, A.K., Daly, M.B., Narod, S.A., Garber, J.E., Lynch, H.T. et al. (1999) Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am. J. Hum. Genet., 64, 1371–1377.[Web of Science][Medline]
59 Szelei, J., Jimenez, J., Soto, A.M., Luizzi, M.F. and Sonnenschein, C. (1997) Androgen-induced inhibition of proliferation in human breast cancer MCF7 cells transfected with androgen receptor. Endocrinology, 138, 1406–1412.
60 Park, J.J., Irvine, R.A., Buchanan, G., Koh, S.S., Park, J.M., Tilley, W.D., Stallcup, M.R., Press, M.F. and Coetzee, G.A. (2000) Breast cancer susceptibility gene 1 (BRCAI) is a co-activator of the androgen receptor. Cancer Res., 60, 5946–5949.
61 Runnebaum, I.B., Wang-Gohrke, S., Vesprini, D., Moslehi, R., Brunet, S., Kieback, D.G. and Narod, S.A. (2000) Progesterone receptor variant and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. AACR Proceedings 2000, 804.
62 Wang-Gohrke, S., Chang-Claude, J., Becher, H., Kieback, D.G. and Runnebaum, I.B. (2000) Progesterone receptor gene polymorphism is associated with decreased risk for breast cancer by age 50. Cancer Res., 60, 2348–2350.
63 Anzick, S.L., Kononen, J., Walker, R.L., Azorsa, D.O., Tanner, M.M., Guan, X.Y., Sauter, G., Kallioniemi, O.P., Trent, J.M. and Meltzer, P.S. (1997) AIB1, a steroid receptor co-activator amplified in breast and ovarian cancer. Science, 277, 965–968.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. D. Strome, X. Wu, M. Kimmel, and S. E. Plon Heterozygous Screen in Saccharomyces cerevisiae Identifies Dosage-Sensitive Genes That Affect Chromosome Stability Genetics, March 1, 2008; 178(3): 1193 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Blackburn, L. Z. Hill, A. L. Roberts, J. Wang, D. Aud, J. Jung, T. Nikolcheva, J. Allard, G. Peltz, C. N. Otis, et al. Genetic Mapping in Mice Identifies DMBT1 as a Candidate Modifier of Mammary Tumors and Breast Cancer Risk Am. J. Pathol., June 1, 2007; 170(6): 2030 - 2041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Howell and M. J. Rose-Zerilli Cytokine Gene Polymorphisms, Cancer Susceptibility, and Prognosis J. Nutr., January 1, 2007; 137(1): 194S - 199S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Oldenburg, K. Kroeze-Jansema, H. Meijers-Heijboer, C. J. van Asperen, N. Hoogerbrugge, I. van Leeuwen, H. F.A. Vasen, A.-M. Cleton-Jansen, J. Kraan, J. J. Houwing-Duistermaat, et al. Characterization of Familial Non-BRCA1/2 Breast Tumors by Loss of Heterozygosity and Immunophenotyping. Clin. Cancer Res., March 15, 2006; 12(6): 1693 - 1700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shaag, T. Walsh, P. Renbaum, T. Kirchhoff, K. Nafa, S. Shiovitz, J. B. Mandell, P. Welcsh, M. K. Lee, N. Ellis, et al. Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population Hum. Mol. Genet., February 15, 2005; 14(4): 555 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Heikkinen, S-M Karppinen, Y Soini, M Makinen, and R Winqvist Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility J. Med. Genet., December 1, 2003; 40(12): e131 - 131. [Full Text]
|
|
|
|
 |
|
 J. D. Haag, L. A. Shepel, B. D. Kolman, D. M. Monson, M. E. Benton, K. T. Watts, J. L. Waller, C. C. Lopez-Guajardo, D. J. Samuelson, and M. N. Gould Congenic Rats Reveal Three Independent Copenhagen Alleles within the Mcs1 Quantitative Trait Locus That Confer Resistance to Mammary Cancer Cancer Res., September 15, 2003; 63(18): 5808 - 5812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. de Jong, I. M. Nolte, E. G. E. de Vries, M. Schaapveld, J. H. Kleibeuker, E. Oosterom, J. C. Oosterwijk, A. H. van der Hout, G. van der Steege, M. Bruinenberg, et al. The HLA class III subregion is responsible for an increased breast cancer risk Hum. Mol. Genet., September 15, 2003; 12(18): 2311 - 2319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Samuelson, J. D. Haag, H. Lan, D. M. Monson, M. A. Shultz, B. D. Kolman, and M. N. Gould Physical evidence of Mcs5, a QTL controlling mammary carcinoma susceptibility, in congenic rats Carcinogenesis, September 1, 2003; 24(9): 1455 - 1460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Blackburn, J. S. Brown, S. P. Naber, C. N. Otis, J. T. Wood, and D. J. Jerry BALB/c Alleles for Prkdc and Cdkn2a Interact to Modify Tumor Susceptibility in Trp53+/- Mice Cancer Res., May 15, 2003; 63(10): 2364 - 2368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Hedenfalk, M. Ringner, A. Ben-Dor, Z. Yakhini, Y. Chen, G. Chebil, R. Ach, N. Loman, H. Olsson, P. Meltzer, et al. Molecular classification of familial non-BRCA1/BRCA2 breast cancer PNAS, March 4, 2003; 100(5): 2532 - 2537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. S. Bernstein, M. Leppert, N. Singh, M. Dean, R. A. Lewis, J. R. Lupski, R. Allikmets, and J. M. Seddon Genotype-Phenotype Analysis of ABCR Variants in Macular Degeneration Probands and Siblings Invest. Ophthalmol. Vis. Sci., February 1, 2002; 43(2): 466 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Esteller, M. F. Fraga, M. Guo, J. Garcia-Foncillas, I. Hedenfalk, A. K. Godwin, J. Trojan, C. Vaurs-Barriere, Y.-J. Bignon, S. Ramus, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis Hum. Mol. Genet., December 1, 2001; 10(26): 3001 - 3007. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||