Original Article
BRCA1 Mutations in a Population-Based Sample of Young Women with Breast Cancer
N Engl J Med 1996; 334:137-142January 18, 1996
- Abstract
Background
Inherited mutations in the BRCA1 gene are associated with a high risk of breast and ovarian cancer in some families. However, little is known about the contribution of BRCA1 mutations to breast cancer in the general population. We analyzed DNA samples from women enrolled in a population-based study of early-onset breast cancer to assess the spectrum and frequency of germ-line BRCA1 mutations in young women with breast cancer.
Methods
We studied 80 women in whom breast cancer was diagnosed before the age of 35, and who were not selected on the basis of family history. Genomic DNA was studied for BRCA1 mutations by analysis involving single-strand conformation polymorphisms and with allele-specific assays. Alterations were defined by DNA sequencing.
Results
Germ-line BRCA1 mutations were identified in 6 of the 80 women. Four additional rare sequence variants of unknown functional importance were also identified. Two of the mutations and three of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only one of the rare variants was identified in a reference population of 73 unrelated subjects.
Conclusions
Alterations in BRCA1 were identified in approximately 10 percent of this cohort of young women with breast cancer. The risk of harboring a mutation was not limited to women with family histories of breast or ovarian cancer. These results represent a minimal estimate of the frequency of BRCA1 mutations in this population. Comprehensive methods of identifying BRCA1 mutations and understanding their importance will be needed before testing of women in the general population can be undertaken.
Media in This Article
Figure 1
Strategy Used to Screen for BRCA1 Mutations.Figure 2
Three BRCA1 Mutations Identified by Single-Strand Conformation Polymorphism Analysis.Article Activity
- Article
Genetic, hormonal, and environmental factors each have a role in the etiology of breast cancer,1-5 which is the most common malignant condition and the second most common cause of cancer-related death among American women.6 Inherited mutations in p53,7 BRCA1, 8 and BRCA2 9 are known to confer a predisposition to breast cancer, and heterozygotes for mutations in the ataxia–telangiectasia gene may also be at increased risk for breast cancer.10 Nevertheless, quantitative information regarding the contribution of inheritance to the overall incidence of breast cancer in the population has been largely inferential.3
The identification and cloning of the BRCA1 gene offer an opportunity to define further the role of genetic factors in breast cancer. BRCA1 was mapped to chromosome 17q by linkage analysis of large families that included multiple women with breast cancer, many of whom had an unusually early age of onset of the disease.8 The pattern of breast-cancer cases in families whose disease is linked to the BRCA1 region is most consistent with an autosomal dominant mode of inheritance and high levels of penetrance, thus fitting the predictions of genetic epidemiologic analyses.2,3 Studies have also demonstrated clustering of cases of ovarian cancer in some of these families.11 Women in selected high-risk families who harbor a BRCA1 mutation appear to have at least an 80 percent lifetime risk of breast cancer, as well as a substantial risk of ovarian cancer.12 In addition, obligate carriers of mutant BRCA1 alleles may have an increased risk of both prostate and colon cancers.13,14
The BRCA1 gene is encoded by 5592 nucleotides distributed over a genomic region of approximately 100 kb.15 The 22 coding exons of the gene encode a protein of 1863 amino acids. The protein contains a putative RING finger (zinc-binding) domain near the amino terminal, suggesting that BRCA1 may regulate transcription. One recent study suggests that BRCA1 may inhibit the growth of breast epithelial cells.16
A recent collaborative survey describing 80 germ-line mutations summarizes the spectrum and frequency of BRCA1 mutations identified to date, primarily in high-risk families.17 All classes of mutations are represented — missense mutations, nonsense mutations, deletions, insertions, and intronic mutations. Over 75 percent of the reported mutations result in the production of a truncated protein. Mutations occur throughout the coding sequence, although several common mutations have been found in multiple unrelated families.17-20 There remain a few families whose disease is linked to the BRCA1 region in which mutations have not yet been found,18-20 implying the existence of mutations in regulatory sequences.
Molecular studies of germ-line BRCA1 mutations have focused to date on women from high-risk families. Although family studies have proved invaluable for mapping and cloning of the gene, observations in such families regarding the nature and penetrance of BRCA1 mutations may not reflect the full spectrum of alterations present in the general population. Epidemiologic studies suggest that mutations in highly penetrant dominant genes such as BRCA1 may account for a substantial proportion of very-early-onset breast cancer in the general population,3 although this prediction has not been directly tested at the molecular level. In order to test this hypothesis, we analyzed DNA samples from women who were enrolled in a population-based study of early-onset breast cancer. We assessed the frequency and type of BRCA1 mutations in women who were given a diagnosis of breast cancer before the age of 35 and who were not selected on the basis of family history.
Methods
Patient Population
The 80 patients in the study were a subgroup of women from a large population-based study of early-onset breast cancer.21 All white women born after 1944 who were given a diagnosis of a first invasive or in situ breast cancer between January 1, 1983, and April 30, 1990, and were residents of King, Pierce, or Snohomish County in Washington State were eligible for the original study. The patients were identified through the Cancer Surveillance System of western Washington, a population-based cancer registry that participates in the Surveillance, Epidemiology, and End Results Program.
Of the 1011 women eligible to participate in the original population-based study, 845 (84 percent) were successfully interviewed; 747 of these women had invasive breast cancer, and 98 had carcinoma in situ. Information regarding potential risk factors for breast cancer was obtained through a structured face-to-face interview. Information on family history (up to the date of diagnosis of the patient's breast cancer) was elicited by asking each patient to identify all first- and second-degree female blood relatives. For each relative identified, the interviewer then asked the year of birth, vital status, year of death (if applicable), history and type of cancer (if any), and the laterality of the cancer if it was breast cancer.
In 1991, blood samples were obtained from 439 of the 845 interviewed women (52 percent); 141 others died before blood samples could be taken, 82 could not be located, 143 were not approached, and 40 refused to give a blood sample. Of the 214 women in whom breast cancer was diagnosed before the age of 35, 80 provided blood samples that were available for this analysis. Genomic DNA was prepared either directly from blood samples or from lymphoblastoid lines immortalized with Epstein–Barr virus.22
Renewed contact and follow-up of previously interviewed women were initiated in order to obtain updated information on their female relatives and cancer histories of their male relatives. As of August 29, 1995, updated information had been obtained from 73 of the 80 subjects included in the study (91 percent).
Analysis of Single-Strand Conformation Polymorphisms
Forty-eight primer pairs19,23 were used to amplify the BRCA1 coding sequence, intron–exon boundaries, and the promoter region from genomic DNA of each of the 80 study subjects. The reaction mixtures used for the polymerase chain reaction (PCR) and the conditions of the analysis involving single-strand conformation polymorphisms (SSCP) have been described previously.19
To characterize the frequency in the general population of each rare allele identified in study patients, we used DNA samples from a reference population of 73 unrelated subjects provided by the Centre d'Etude du Polymorphisme Humain (CEPH). These subjects are the maternal and paternal grandparents of the CEPH families, and their samples are routinely used in genetic-mapping studies. Although these subjects were not part of any population-based study and there is therefore little information on them regarding epidemiologic risk factors, they are not suspected of having any inherited predisposition to malignant conditions.
Screening with Allele-Specific Oligonucleotides
Hybridization assays were performed with oligonucleotide probes corresponding to mutations in exon segments 2, 11Pi, 20, and splice-donor and splice-acceptor sites in intron 5.23 Genomic DNA from all 80 patients was amplified with the primers for the corresponding exon segment. The PCR products were then denatured and applied to a Genescreen nylon filter with a 96-well dot blot apparatus. Hybridization with mutant or normal oligonucleotides was performed as previously described.23 All mutations were confirmed by forward and reverse (bidirectional) sequencing of the PCR product.
DNA Sequencing
For each variant pattern identified by SSCP analysis, the putative mutant allele was eluted from the gel and fragments were reamplified with the original primer pair. In each case the corresponding fragment of DNA was also amplified for direct sequencing with 100 ng of genomic DNA as the template. All PCR products were bidirectionally sequenced with the Applied Biosystems Taq DyeDeoxy terminator cycle-sequencing kit according to the manufacturer's instructions. Samples were analyzed with an Applied Biosystems 373A sequencer.
Results
Patients' Characteristics
Table 1Table 1
Characteristics of 214 Women in Whom Breast Cancer Was Diagnosed before the Age of 35 and of the Subgroup of 80 Women Tested for BRCA1 Mutations. summarizes the characteristics of all 214 women from the population-based study in whom breast cancer was diagnosed before the age of 35 and of the subgroup of 80 women for whom DNA samples were available for analysis of BRCA1 mutations. The family histories of the subgroup were similar to those of the group as a whole. The subgroup had a higher proportion of women with in situ carcinoma than the group as a whole (19 percent vs. 11 percent), and the women in the subgroup were more likely to have survived their breast cancer (94 percent vs. 77 percent). These differences in the stage of cancer and survival presumably reflect the lag between diagnosis and the drawing of blood from women whose cancer was diagnosed early in the course of the study. One recent report suggests that the survival of women with breast cancer who harbor mutant BRCA1 alleles may be longer than that of unselected women with breast cancer.24 If this observation is correct, it is possible that our sample of 80 women may have a bias that slightly overestimates the proportion of cases that involve BRCA1. Characterization of Alterations in the Germ-Line BRCA1 Sequence
Figure 1Figure 1
Strategy Used to Screen for BRCA1 Mutations. shows the strategy we used to screen for mutations in the germ-line BRCA1 sequence. The alterations we found fall into three categories: definite mutations, each of which either has been associated with breast cancer in previous studies of high-risk families or is predicted to result in protein truncation; rare sequence variants of unknown functional consequence; and polymorphisms that are common in the general population, irrespective of breast-cancer status. Each category is discussed separately below.Definite BRCA1 Mutations
The six definite BRCA1 mutations identified in the study population and the characteristics of the women in whom such mutations were found are shown in Table 2Table 2
Definite BRCA1 Mutations Identified in Six Women with Early-Onset Breast Cancer..Four of the mutations result in premature termination codons and, hence, a truncated protein product (Patients 7, 51, 70, and 72 in Table 2). Three of these four mutations have been described previously in families whose disease is linked to the BRCA1 region.17 The nonsense mutation in exon 12 (Patient 70 in Table 2) is novel but qualitatively similar to others already described. The aberrant pattern produced by this mutation on SSCP analysis is shown in Figure 2AFigure 2
Three BRCA1 Mutations Identified by Single-Strand Conformation Polymorphism Analysis., Figure 2B, and Figure 2C.One missense mutation and one large intronic insertion were also identified. The change from cysteine to glycine at amino acid 61 within the zinc-binding motif of the BRCA1 protein (Patient 29 in Table 2 and Figure 2A, Figure 2B, and Figure 2C) has been reported in at least two high-risk families17 and has been seen as a somatic mutation in an ovarian tumor.25 The insertion of 12 base pairs (bp) in intron 20 in Patient 30, who had a history of breast and cervical cancer, represents a tandem reduplication of the sequence 5'GTNTTCCACTCC3' that begins 48 bp downstream of the 3' boundary of exon 20. This variant is easily detected by SSCP analysis (Figure 2A, Figure 2B, and Figure 2C) and was not present in any of the 73 subjects in the control population. This mutation has also been identified in a woman with both breast and ovarian cancer who had five maternal relatives with breast cancer.26 This alteration may affect RNA processing, but RNA was not available to test the effect of the mutation.
The family histories of the six women with BRCA1 mutations are diverse; four of them reported family histories of breast or ovarian cancer. Of the two others, Patient 70 had a paternal aunt and a paternal grandmother with unidentified malignant conditions but had no sisters or maternal aunts, and Patient 30 had no sisters but had two maternal and five paternal aunts, none of whom had a history of cancer (Table 2).
Rare BRCA1 Sequence Variants
Four rare BRCA1 sequence variants were identified (Table 3Table 3
Rare BRCA1 Sequence Variants Identified by Analysis of Single-Strand Conformation Polymorphisms in Four Women with Early-Onset Breast Cancer.). Such rare variants occur very infrequently in the general population and have not yet been associated with breast cancer in high-risk families. They may confer amino acid changes on the BRCA1 protein or have the potential to alter RNA processing, but the functional consequence of these changes remains unknown.Two of the rare sequence variants are single-base substitutions, each producing an amino acid change. The missense change in exon 2 results in the substitution of threonine for methionine at amino acid 18 (Patient 76 in Table 3), which may affect the conformation of the protein, since a polar hydrophilic residue replaces a residue that is nonpolar and hydrophobic. This alteration was not seen in any of the 73 subjects in the reference population, nor has it been identified in high-risk families. In contrast, the A-to-G missense change at nucleotide 4158 (Patient 37 in Table 3) was also found in one person in the control group. This substitution has been seen previously in a patient with an insertion elsewhere in the gene,17 suggesting that it represents a rare neutral polymorphism rather than a true mutation.
The other two rare sequence variants were found in noncoding regions, and neither was found in the control group. The single-base substitution in exon 4 found in Patient 65 is unlikely to be of functional consequence, given its location within this noncoding exon. The C-to-G change 1088 bp upstream of the site of the initiation of BRCA1 transcription (Patient 71 in Table 3) is notable because it lies within exon 1B of another gene, 1A1-3B, which encodes a putative B-box coiled-coil protein.27 Fewer than 300 bp separate the first exons of BRCA1 and 1A1-3B, raising the possibility of coordinate regulation of the expression of these two genes.28
Common Polymorphisms
Eight common polymorphisms of BRCA1 were identified in the patient population, corresponding to sequence changes in exons 11 (five polymorphisms) and 16 and introns 8 and 16 (data not shown). All alterations within the coding sequences were single-base substitutions, and each polymorphism had an allele frequency of at least 7.5 percent in the study population. These sequence alterations, which have been noted by other investigators in control subjects and patients, are not associated with the penetrant phenotypes seen in families whose disease is linked to the BRCA1 region.17-19
Discussion
The identification of six BRCA1 mutations, as well as several sequence variants with potential functional importance, in this cohort of 80 young women with breast cancer supports the prediction that the BRCA1 gene has a moderate role in the pathogenesis of breast cancer in this age group.3 The technical limitations of the available assays may result in a slight underestimate of the true frequency of BRCA1 mutations in this cohort. For instance, the sensitivity of SSCP analysis, which was the cornerstone of our screening strategy, is approximately 70 to 80 percent under the assay conditions we used.29,30 In addition, some noncoding mutations affecting gene expression or RNA processing may not have been detected because complementary DNA was not available for screening. Several of the rare sequence variants we identified may be associated with an increased likelihood of cancer, but we cannot consider them to be definite mutations on the basis of sequence information alone. Such uncertainties illustrate some of the current difficulties in interpreting the results of sequence-based screening for mutations, particularly outside the context of studies of families whose disease is linked to the BRCA1 region. Nevertheless, the results of family studies in which methods and reagents similar to ours were used suggest that the bulk of BRCA1 mutations in this patient population should have been detected.15,17-20
Five of the six mutations we identified have been seen previously in high-risk families and include three of the most common mutations identified to date (those in Patients 29, 51, and 72).17,26 We did not detect the 2-bp deletion in exon 2 (185delAG) that has been seen in multiple families of Ashkenazi Jewish descent and is estimated to occur at a frequency of approximately 1 percent in this population.31 The absence of this mutation in our study population is not surprising, given that Jewish women constituted only 1.2 percent of the study subjects who were under 35 years of age in the original population-based study.
One of the most important findings of this study is that BRCA1 mutations are not limited to women with strong family histories of breast or ovarian cancer (or both). The distribution of mutations among the study subjects according to the family history of breast and ovarian cancer is shown in Table 4Table 4
Distribution of BRCA1 Mutations and Rare Sequence Variants According to the Family History of Breast and Ovarian Cancer among 80 Women with Early-Onset Breast Cancer.. The absence of correlation between the family history and the genetic risk attributable to BRCA1 may reflect variations in family structure, incompletely penetrant alleles, the potential influence of additional modifier genes, and differences in patient recall. These observations illustrate the difficulty of making predictions about the presence or absence of BRCA1 mutations on the basis of a woman's family history.Our results illustrate several of the technical and scientific reasons why screening for BRCA1 mutations is relevant but cannot yet be applied to the general population. Similar conclusions are drawn in the accompanying paper by FitzGerald and coworkers, who used different strategies to screen young women from the population at large for BRCA1 mutations.32 Using currently available mutation assays, including direct DNA sequencing, we are not yet able to detect all alleles that increase the likelihood of disease, nor can we interpret their meaning. In addition, our data suggest that family history is not a good indicator of which women carry mutant BRCA1 alleles. Further insight into the structure and function of the BRCA1 gene and its protein product will facilitate the development of more comprehensive mutation-detection strategies and improve the interpretation of alterations in the sequence of the gene. Large population-based screening studies are needed to establish the frequency, importance, and penetrance of the broad spectrum of variations in the sequence of BRCA1 observed in both affected and unaffected women in the general population. Only then will it be possible to offer reliable results and meaningful counseling to women who choose to have such testing.
Note added in proof: We have recently identified the C-to-T single-base change at nucleotide 49 of exon 4 in 6 of 145 randomly selected men residing in the same geographic area as the 80 women included in this study, suggesting that the variant represents a neutral polymorphism.
Supported by a contract (NO1 CN 05230) with the National Cancer Institute and by grants (R01 CA63705 to Dr. Ostrander and R01 CA41416, R01 CA63697, and R01 CA 59736 to Drs. Daling and Malone) from the National Cancer Institute. Dr. Langston is the recipient of a Physician Scientist Award (K11 HD00936) from the National Institutes of Health. Dr. Ostrander is the recipient of an American Cancer Society Junior Faculty Award (JFRA-558).
We are indebted to the women who participated in the study; to Mary-Claire King and Lori Friedman for providing information on oligonucleotide sequences; to Leigh Francisco for technical assistance with DNA sequencing; and to Eileen Bryant, Brenda Sandmaier, and Jeanne Anderson for thoughtful comments on the manuscript.
Source Information
From the Divisions of Clinical Research (A.A.L., J.D.T., E.A.O.) and Public Health Sciences (K.E.M., J.R.D.), Fred Hutchinson Cancer Research Center; and the Department of Epidemiology, University of Washington (J.R.D.) — both in Seattle.
Address reprint requests to Dr. Ostrander at the Fred Hutchinson Cancer Research Center, 1124 Columbia St., Seattle, WA 98104.
- References
References
1
Newman B ,Austin MA ,Lee M ,King M-C . Inheritance of breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A 1988;85:3044-3048
CrossRef | Web of Science | Medline2
Claus EB ,Risch N ,Thompson WD . Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 1991;48:232-242
Web of Science | Medline3
Buell P . Changing incidence of breast cancer in Japanese-American women. J Natl Cancer Inst 1973;51:1479-1483
Web of Science | Medline4
Brinton LA ,Hoover R ,Fraumeni JF Jr . Reproductive factors in the aetiology of breast cancer. Br J Cancer 1983;47:757-762
CrossRef | Web of Science | Medline5
Kelsey JL ,Horn-Ross PL . Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev 1993;15:7-16
Web of Science | Medline6
Cancer facts & figures — 1995. Atlanta: American Cancer Society, 1995:10-1.
7
Malkin D ,Li FP ,Strong LC , et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250:1233-1238
CrossRef | Web of Science | Medline8
Hall JM ,Lee MK ,Newman B , et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684-1689
CrossRef | Web of Science | Medline9
Wooster R ,Neuhausen SL ,Mangion J , et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994;265:2088-2090
CrossRef | Web of Science | Medline10
Swift M ,Reitnauer PJ ,Morrell D ,Chase CL . Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 1987;316:1289-1294
Full Text | Web of Science | Medline11
Narod SA ,Feunteun J ,Lynch HT , et al. Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 1991;338:82-83
CrossRef | Web of Science | Medline12
Easton DF, Bishop DT, Ford D, Crockford GP, Breast Cancer Linkage Consortium
Web of Science | Medline13
Arason A ,Barkardottir RB ,Egilsson V . Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer. Am J Hum Genet 1993;52:711-717
Web of Science | Medline14
Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE, Breast Cancer Linkage Consortium
CrossRef | Web of Science | Medline15
Miki Y ,Swensen J ,Shattuck-Eidens D , et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71
CrossRef | Web of Science | Medline16
Thompson ME ,Jensen RA ,Obermiller PS ,Page DL ,Holt JT . Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 1995;9:444-450
CrossRef | Web of Science | Medline17
Shattuck-Eidens D ,McClure M ,Simard J , et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene: implications for presymptomatic testing and screening. JAMA 1995;273:535-541
CrossRef | Web of Science | Medline18
Castilla LH ,Couch FJ ,Erdos MR , et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet 1994;8:387-391
CrossRef | Web of Science | Medline19
Friedman LS ,Ostermeyer EA ,Szabo CI , et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet 1994;8:399-404
CrossRef | Web of Science | Medline20
Simard J ,Tonin P ,Durocher F , et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet 1994;8:392-398
CrossRef | Web of Science | Medline21
Daling JR ,Malone KE ,Voigt LF ,White E ,Weiss NS . Risk of breast cancer among young women: relationship to induced abortion. J Natl Cancer Inst 1994;86:1584-1592
CrossRef | Web of Science | Medline22
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. Plainview, N.Y.: Cold Spring Harbor Laboratory Press, 1989.
23
Friedman LS. Molecular genetics of human breast cancer: the search for BRCA1. (Ph.D. thesis. Berkeley: University of California, 1995.)
24
Porter DE ,Cohen BB ,Wallace MR , et al. Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12-21. Br J Surg 1994;81:1512-1515
CrossRef | Web of Science | Medline25
Merajver SD ,Pham TM ,Caduff RF , et al. Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nat Genet 1995;9:439-443
CrossRef | Web of Science | Medline26
Takahashi H ,Behbakht K ,McGovern PE , et al. Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res 1995;55:2998-3002
Web of Science | Medline27
Campbell IG ,Nicolai HM ,Foulkes WD , et al. A novel gene encoding a B-box protein within the BRCA1 region at 17q21.1. Hum Mol Genet 1994;3:589-594
CrossRef | Web of Science | Medline28
Brown MA ,Nicolai H ,Xu CF , et al. Regulation of BRCA1. Nature 1994;372:733-733
CrossRef | Web of Science | Medline29
Orita M ,Iwahana H ,Kanazawa H ,Hayashi K ,Sekiya T . Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A 1989;86:2766-2770
CrossRef | Web of Science | Medline30
Sheffield VC ,Beck JS ,Kwitek AE ,Sandstrom DW ,Stone EM . The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics 1993;16:325-332
CrossRef | Web of Science | Medline31
Struewing JP ,Abeliovich D ,Peretz T , et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 1995;11:198-200
CrossRef | Web of Science | Medline32
FitzGerald MG ,MacDonald DJ ,Krainer M , et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996;334:143-149
Full Text | Web of Science | Medline
- Citing Articles (86)
Citing Articles
1
A. Cerbinskaite, A. Mukhopadhyay, E.R. Plummer, N.J. Curtin, R.J. Edmondson. (2011) Defective homologous recombination in human cancers. Cancer Treatment Reviews
CrossRef2
Sarinah Basro, Justus P. Apffelstaedt. (2010) Breast Cancer in Young Women in a Limited-Resource Environment. World Journal of Surgery 34:7, 1427-1433
CrossRef3
Xiao-Yun Yang, Ming-Rong Xi, Kai-Xuan Yang, Hai Yu. (2009) Prognostic value of estrogen receptor and progesterone receptor status in young Chinese ovarian carcinoma patients. Gynecologic Oncology 113:1, 99-104
CrossRef4
Doo Ho Choi, Dae Yeon Cho, Min Hyuk Lee, Hee Sook Park, Sei Hyun Ahn, Byung Ho Son, Bruce G. Haffty. (2008) The CHEK2 1100delC mutation is not present in Korean patients with breast cancer cases tested for BRCA1 and BRCA2 mutation. Breast Cancer Research and Treatment 112:3, 569-573
CrossRef5
Daphne W. Bell, Sang H. Kim, Andrew K. Godwin, Taryn A. Schiripo, Patricia L. Harris, Sara M. Haserlat, Doke C.R. Wahrer, Christopher A. Haiman, Mary B. Daly, Kristin B. Niendorf, Matthew R. Smith, Dennis C. Sgroi, Judy E. Garber, Olufunmilayo I. Olopade, Loic Le Marchand, Brian E. Henderson, David Altshuler, Daniel A. Haber, Matthew L. Freedman. (2007) Genetic and functional analysis ofCHEK2 (CHK2) variants in multiethnic cohorts. International Journal of Cancer 121:12, 2661-2667
CrossRef6
Inbal Weiss-Salz, Susan Harlap, Yehiel Friedlander, Luna Kaduri, Efrat Levy-Lahad, Rivka Yanetz, Lisa Deutsch, Hagit Hochner, Ora Paltiel. (2007) Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years. European Journal of Cancer Prevention 16:6, 549-554
CrossRef7
M Loizidou, Y Marcou, V Anastasiadou, R Newbold, A Hadjisavvas, K Kyriacou. (2007) Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus. Clinical Genetics 71:2, 165-170
CrossRef8
Asako Koike, Toshihisa Takagi. (2007) Knowledge discovery based on an implicit and explicit conceptual network. Journal of the American Society for Information Science and Technology 58:1, 51-65
CrossRef9
Karen L. Brown, Robin Hutchison, Randi E. Zinberg, Margaret M. McGovern. (2005) Referral and Experience with Genetic Testing Among Women with Early Onset Breast Cancer. Genetic Testing 9:4, 301-305
CrossRef10
Valerie Bonadona, Olga M. Sinilnikova, Sandrine Chopin, Antonis C. Antoniou, Hervé Mignotte, Patrice Mathevet, Alain Brémond, Alain Martin, Jean-Yves Bobin, Pascale Romestaing, Daniel Raudrant, René-Charles Rudigoz, Mélanie Léoné, Franck Chauvin, Douglas F. Easton, Gilbert M Lenoir, Christine Lasset. (2005) Contribution ofBRCA1 andBRCA2 germ-line mutations to the incidence of breast cancer in young women: Results from a prospective population-based study in France. Genes, Chromosomes and Cancer 43:4, 404-413
CrossRef11
Nikki Peters, Susan M. Domchek, Abigail Rose, Rachael Polis, Jill Stopfer, Katrina Armstrong. (2005) Knowledge, Attitudes, and Utilization of BRCA1/2 Testing among Women with Early-Onset Breast Cancer. Genetic Testing 9:1, 48-53
CrossRef12
Kathleen K. Oros, Parviz Ghadirian, Celia M.T Greenwood, Chantal Perret, Zhen Shen, Yosabeth Paredes, Suzanna L. Arcand, Anne-Marie Mes-Masson, Steven A. Narod, William D. Foulkes, Diane Provencher, Patricia N. Tonin. (2004) Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5BRCA1 andBRCA2 mutations. International Journal of Cancer 112:3, 411-419
CrossRef13
A C Antoniou, P P D Pharoah, P Smith, D F Easton. (2004) The BOADICEA model of genetic susceptibility to breast and ovarian cancer. British Journal of Cancer
CrossRef14
André Nkondjock, Parviz Ghadirian. (2004) Epidemiology of breast cancer among BRCA mutation carriers: an overview. Cancer Letters 205:1, 1-8
CrossRef15
C. M. Kendziorski, M. A. Newton, H. Lan, M. N. Gould. (2003) On parametric empirical Bayes methods for comparing multiple groups using replicated gene expression profiles. Statistics in Medicine 22:24, 3899-3914
CrossRef16
Alexander J.R Bishop, Robert H Schiestl. (2003) Role of homologous recombination in carcinogenesis. Experimental and Molecular Pathology 74:2, 94-105
CrossRef17
Elizabeth B. Claus, Meredith Stowe, Darryl Carter. (2003) Family History of Breast and Ovarian Cancer and the Risk of Breast Carcinoma in situ. Breast Cancer Research and Treatment 78:1, 7-15
CrossRef18
Norbert Arnold, Henric Peper, Katrin Bandick, Maike Kreikemeier, Doris Karow, Birgit Teegen, Walter Jonat. (2002) Establishing a control population to screen for the occurrence of nineteen unclassified variants in the BRCA1 gene by denaturing high-performance liquid chromatography. Journal of Chromatography B 782:1-2, 99-104
CrossRef19
Wen-Ying Lee. (2002) Applied Immunohistochemistry 10:4, 310-315
CrossRef20
Alexander Liede, Steven A. Narod. (2002) Hereditary breast and ovarian cancer in Asia: genetic epidemiology ofBRCA1 andBRCA2. Human Mutation 20:6, 413-424
CrossRef21
Maria Lourdes De Leon Matsuda, Alexander Liede, Elaine Kwan, Cynthia A. Mapua, Eva Maria C. Cutiongco, Alex Tan,
ke Borg, Steven A. Narod. (2002) BRCA1 andBRCA2 mutations among breast cancer patients from the Philippines. International Journal of Cancer 98:4, 596-603
CrossRef22
Kristen M. Shannon, Marcie L. Lubratovich, Dianne M. Finkelstein, Barbara L. Smith, Simon N. Powell, Michael V. Seiden. (2002) Model-based predictions of BRCA1/2 mutation status in breast carcinoma patients treated at an academic medical center. Cancer 94:2, 305-313
CrossRef23
Jon F. Kerner, Jeanne S. Mandelblatt, Rebecca A. Silliman, John J. Lynch, Ruby Senie, Caryn Cohen, Yi-Ting Hwang. (2001) Screening mammography and breast cancer treatment patterns in older women. Breast Cancer Research and Treatment 69:1, 81-91
CrossRef24
K. A. Phillips. (2001) Current perspectives on BRCA1- and BRCA2-associated breast cancers. Internal Medicine Journal 31:6, 349-356
CrossRef25
N. Loman, O. Johannsson, U. Kristoffersson, H. Olsson, A. Borg. (2001) Family History of Breast and Ovarian Cancers and BRCA1 and BRCA2 Mutations in a Population-Based Series of Early-Onset Breast Cancer. JNCI Journal of the National Cancer Institute 93:16, 1215-1223
CrossRef26
Sharon N. Teraoka, Kathleen E. Malone, David R. Doody, Nicola M. Suter, Elaine A. Ostrander, Janet R. Daling, Patrick Concannon. (2001) Increased frequency ofATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer 92:3, 479-487
CrossRef27
Patricia N. Tonin, Chantal Perret, Julie A. Lambert, Anne-Jos
CrossRef28
V. Sivanesaratnam. (2001) Fertility and Gynaecologic Malignancies. Journal of Obstetrics and Gynaecology Research 27:1, 1-15
CrossRef29
D.M. Eccles, D. Gareth Evans. (2000) Management of the contralateral breast in patients with hereditary breast cancer. The Breast 9:6, 301-305
CrossRef30
Christine B. Ambrosone. (2000) Oxidants and Antioxidants in Breast Cancer. Antioxidants & Redox Signaling 2:4, 903-917
CrossRef31
J. Kollias, S. Man, M. Marafie, K. Carpenter, S. Pinder, I.O. Ellis, R.W. Blamey, G. Cross, J.D. Brook. (2000) Loss of Heterozygosity in Bilateral Breast Cancer. Breast Cancer Research and Treatment 64:3, 241-251
CrossRef32
D Turchetti, L Cortesi, M Federico, C Bertoni, L Mangone, Se Ferrari, V Silingardi. (2000) BRCA1 mutations and clinicopathological features in a sample of Italian women with early-onset breast cancer. European Journal of Cancer 36:16, 2083-2089
CrossRef33
I.C. Bennett, M. Gattas, B.T. Teh. (2000) The management of familial breast cancer. The Breast 9:5, 247-263
CrossRef34
Ellen T Matloff. (2000) The breast surgeon’s role in BRCA1 and BRCA2 testing. The American Journal of Surgery 180:4, 294-298
CrossRef35
Gay Hui Ho, Beng Hooi Phang, Ivy S. L. Ng, Hai Yang Law, Khee Chee Soo, Eng Hen Ng. (2000) Novel germlineBRCA1 mutations detected in women in Singapore who developed breast carcinoma before the age of 36 years. Cancer 89:4, 811-816
CrossRef36
Brita Arver, Quan Du, Jindong Chen, Liping Luo, Annika Lindblom. (2000) Hereditary breast cancer: a review. Seminars in Cancer Biology 10:4, 271-288
CrossRef37
Pierre O. Chappuis, Victoria Nethercot, William D. Foulkes. (2000) Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Seminars in Surgical Oncology 18:4, 287-295
CrossRef38
Kathleen E. Malone, Janet R. Daling, Cassandra Neal, Nicola M. Suter, Cecilia O'Brien, Kara Cushing-Haugen, Thora J. Jonasdottir, Jennifer D. Thompson, Elaine A. Ostrander. (2000) Frequency ofBRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer 88:6, 1393-1402
CrossRef39
Gail Gong, Alice S. Whittemore. (1999) Estimating genetic influence on disease from population-based case-control data: application to cancers of the breast and ovary. Statistics in Medicine 18:23, 3321-3336
CrossRef40
John F. Stratton, Deborah Thompson, Lynda Bobrow, Neha Dalal, Martin Gore, D.T. Bishop, Ian Scott, Gareth Evans, Peter Daly, Douglas F. Easton, Bruce A.J. Ponder. (1999) The Genetic Epidemiology of Early-Onset Epithelial Ovarian Cancer: A Population-Based Study. The American Journal of Human Genetics 65:6, 1725-1732
CrossRef41
R Eeles. (1999) Screening for hereditary cancer and genetic testing, epitomised by breast cancer. European Journal of Cancer 35:14, 1954-1962
CrossRef42
Susan L. Neuhausen. (1999) Ethnic differences in cancer risk resulting from genetic variation. Cancer 86:S11, 2575-2582
CrossRef43
Andrew Berchuck, Joellen M. Schildkraut, Jeffrey R. Marks, P. Andrew Futreal. (1999) Managing hereditary ovarian cancer risk. Cancer 86:S11, 2517-2524
CrossRef44
Susan L. Neuhausen. (1999) Ethnic differences in cancer risk resulting from genetic variation. Cancer 86:S8, 1755-1762
CrossRef45
Andrew Berchuck, Joellen M. Schildkraut, Jeffrey R. Marks, P. Andrew Futreal. (1999) Managing hereditary ovarian cancer risk. Cancer 86:S8, 1697-1704
CrossRef46
Ian C. Bennett, Michael Gattas, Bin Tean Teh. (1999) THE GENETIC BASIS OF BREAST CANCER AND ITS CLINICAL IMPLICATIONS. ANZ Journal of Surgery 69:2, 95-105
CrossRef47
Nazneen Rahman, Michael R. Stratton. (1998) THE GENETICS OF BREAST CANCER SUSCEPTIBILITY. Annual Review of Genetics 32:1, 95-121
CrossRef48
Jane E. Armes, A. J. Matthew Egan, Melissa C. Southey, Gillian S. Dite, Margaret R. E. McCredie, Graham G. Giles, John L. Hopper, Deon J. Venter. (1998) The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations. Cancer 83:11, 2335-2345
CrossRef49
Mary K. Anglin. (1998) Dismantling the master's house: Cancer activists, discourses of prevention, and environmental justice. Identities 5:2, 183-217
CrossRef50
Jacqueline Taylor, Margarita Lymboura, Paul E. Pace, Roger P. A'hern, Anil J. Desai, Sami Shousha, R. Charles Coombes, Simak Ali. (1998) An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers. International Journal of Cancer 79:4, 334-342
CrossRef51
Giske Ursin, Ronald K. Ross, Jane Sullivan-Halley, Rosemarie Hanisch, Brian Henderson, Leslie Bernstein. (1998) Use of oral contraceptives and risk of breast cancer in young women. Breast Cancer Research and Treatment 50:2, 175-184
CrossRef52
Rita Chakrabarti, Eri S. Srivatsan, Thomas F. Wood, Patricia J. Eubanks, Sam A. Ebrahimi, Richard A. Gatti, Edward Passaro, Mark P. Sawicki. (1998) Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13. Genes, Chromosomes and Cancer 22:2, 130-137
CrossRef53
Therese Sørlie, Tone Ikdahl Andersen, Ida Bukholm, Anne-Lise Børresen-Dale. (1998) Mutation screening of BRCA1 using PTT and LOH analysis at 17q21 in breast carcinomas from familial and non-familial cases. Breast Cancer Research and Treatment 48:3, 259-264
CrossRef54
ANDREW BERCHUCK, MICHAEL CARNEY, JONATHAN M. LANCASTER, JEFFREY MARKS, ANDREW P. FUTREAL. (1998) Familial Breast-Ovarian Cancer Syndromes. Clinical Obstetrics and Gynecology 41:1, 157-166
CrossRef55
Jill Greenman, Shehla Mohammed, David Ellis, Sally Watts, Gillian Scott, Louise Izatt, Diana Barnes, Ellen Solomon, Shirley Hodgson, Christopher Mathew. (1998) Identification of missense and truncating mutations in theBRCA1 gene in sporadic and familial breast and ovarian cancer. Genes, Chromosomes and Cancer 21:3, 244-249
CrossRef56
LEE-MAY CHEN, BETH Y. KARLAN. (1998) Early Detection and Risk Reduction for Familial Gynecologic Cancers. Clinical Obstetrics and Gynecology 41:1, 200-214
CrossRef57
Leif W. Ellisen, MD, PhD, Daniel A. Haber, MD, PhD. (1998) HEREDITARY BREAST CANCER. Annual Review of Medicine 49:1, 425-436
CrossRef58
A Osorio, M Robledo, J Albertos, O Dı́ez, C Alonso, M Baiget, J Benı́tez. (1998) Molecular analysis of the six most recurrent mutations in the BRCA1 gene in 87 Spanish breast/ovarian cancer families. Cancer Letters 123:2, 153-158
CrossRef59
Anne Joutel, Katayoun Vahedi, Christophe Corpechot, Alain Troesch, Hugues Chabriat, Céline Vayssière, Corinne Cruaud, Jacqueline Maciazek, Jean Weissenbach, Marie-Germaine Bousser, Jean-François Bach, Elisabeth Tournier-Lasserve. (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. The Lancet 350:9090, 1511-1515
CrossRef60
A. D. K. Hill, J. M. Doyle, E. W. McDermott, N. J. O'Higgins. (1997) Hereditary breast cancer. British Journal of Surgery 84:10, 1334-1339
CrossRef61
A. Ravaioli, D. Canuti, L. Gianni, F. Desiderio, M. Scarpellini, M. Nicolini, C. Fava, S. Bartolini, F. Monti, L. Bernardi, R. Pozzuoli, F. Barbanti, A. Manzo, P. Pivi. (1997) Prognostic factors in hereditary and sporadic breast cancers: analysis of an Italian series of 602 patients. The Breast 6:5, 275-280
CrossRef62
Pascal Bonnier, Sylvie Romain, Jean Marie Dilhuydy, Françoise Bonichon, Jean Pierre Julien, Colette Charpin, Christiane Lejeune, Pierre Marie Martin, Lucien Piana, . (1997) Influence of pregnancy on the outcome of breast cancer: A case-control study. International Journal of Cancer 72:5, 720-727
CrossRef63
A. Luz. (1997) Abschätzung des Krebsrisikos durch genetische Analyse?. Strahlentherapie und Onkologie 173:9, 444-456
CrossRef64
L. R. Cavalli, L. M. B. Cavaliéri, L. A. Ribeiro, I. J. Cavalli, R. Silveira, S. R. Rogatto. (1997) Cytogenetic Evaluation of 20 Primary Breast Carcinomas. Hereditas 126:3, 261-268
CrossRef65
John D. Burczak, Francis E. Wilkinson, David J. Robbins. (1997) Impact of genomics on diagnostic medicine. Drug Development Research 41:3-4, 193-204
CrossRef66
Struewing, Jeffery P., Hartge, Patricia, Wacholder, Sholom, Baker, Sonya M., Berlin, Martha, McAdams, Mary, Timmerman, Michelle M., Brody, Lawrence C., Tucker, Margaret A., . (1997) The Risk of Cancer Associated with Specific Mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine 336:20, 1401-1408
Full Text67
Couch, Fergus J., DeShano, Michelle L., Blackwood, M. Anne, Calzone, Kathleen, Stopfer, Jill, Campeau, Lisa, Ganguly, Arupa, Rebbeck, Timothy, Weber, Barbara L., Jablon, Lisa, Cobleigh, Melody A., Hoskins, Kent, Garber, Judy E., . (1997) BRCA1 Mutations in Women Attending Clinics That Evaluate the Risk of Breast Cancer. New England Journal of Medicine 336:20, 1409-1415
Full Text68
Krainer, Michael, Silva-Arrieta, Sandra, FitzGerald, Michael G., Shimada, Akira, Ishioka, Chikashi, Kanamaru, Ryunosuke, MacDonald, Deborah J., Unsal, Hilal, Finkelstein, Dianne M., Bowcock, Anne, Isselbacher, Kurt J., Haber, Daniel A., . (1997) Differential Contributions of BRCA1 and BRCA2 to Early-Onset Breast Cancer. New England Journal of Medicine 336:20, 1416-1422
Full Text69
Mary K. Anglin. (1997) Working from the inside out: Implications of breast cancer activism for biomedical policies and practices. Social Science & Medicine 44:9, 1403-1415
CrossRef70
Anne M. Bowcock. (1997) Breast Cancer Genes. The Breast Journal 3:s1, 1-6
CrossRef71
Stratton, John F., Gayther, Simon A., Russell, Paul, Dearden, Jo, Gore, Martin, Blake, Peter, Easton, Doug, Ponder, Bruce A.J., . (1997) Contribution of BRCA1 Mutations to Ovarian Cancer. New England Journal of Medicine 336:16, 1125-1130
Full Text72
Masashi Takano, Hiroshi Aida, Ikunosuke Tsuneki, Koichi Takakuwa, Isao Hasegawa, Hajime Tanaka, Masaaki Saito, Shoji Tsuji, Takahiko Sonoda, Masayuki Hatae, Jui-Tung Chen, Katsuyuki Takahashi, Kazuo Hasegawa, Nagayasu Toyoda, Noriyasu Saito, Michiaki Yakushiji, Tsutomu Araki, Kenichi Tanaka. (1997) Mutational Analysis of BRCA1 Gene in Ovarian and Breast-ovarian Cancer Families in Japan. Cancer Science 88:4, 407-413
CrossRef73
A GARVIN. (1997) BRCA1 mutations found in archived early onset breast tumours. European Journal of Cancer 33:4, 683-686
CrossRef74
James L. Mulshine, Jun Zhou, Anthony M. Treston, Eva Szabo, Melvyn S. Tockman, Frank Cuttitta. (1997) NEW APPROACHES TO THE INTEGRATED MANAGEMENT OF EARLY LUNG CANCER. Hematology/Oncology Clinics of North America 11:2, 235-252
CrossRef75
Dieter Niederacher, Frauke Picard, Claudia van Roeyen, Han-Xiang An, Hans Georg Bender, Matthias Wilhelm Beckmann. (1997) Patterns of allelic loss on chromosome 17 in sporadic breast carcinomas detected by fluorescent-labeled microsatellite analysis. Genes, Chromosomes and Cancer 18:3, 181-192
CrossRef76
SUSAN L. NEUHAUSEN, ELAINE A. OSTRANDER. (1997) Mutation Testing of Early-Onset Breast Cancer Genes BRCA1 and BRCA2. Genetic Testing 1:2, 75-83
CrossRef77
LISA S. PARKER, RACHEL ANKENY MAJESKE. (1996) Standards of Care and Ethical Concerns in Genetic Testing and Screening. Clinical Obstetrics and Gynecology 39:4, 873-884
CrossRef78
Klaus Grade, Burkhard Jandrig, Siegfried Scherneck. (1996) BRCA1 mutation update and analysis. Journal of Cancer Research and Clinical Oncology 122:11, 702-706
CrossRef79
Saraswatl Sukumar, Katherine McKenzie. (1996) Breast cancer prevention strategies for the twentieth century. Molecular Medicine Today 2:11, 453-459
CrossRef80
Elizabeth B. Claus, Joellen M. Schildkraut, W. Douglas Thompson, Neil J. Risch. (1996) The genetic attributable risk of breast and ovarian cancer. Cancer 77:11, 2318-2324
CrossRef81
(1996) Breast Cancer and BRCA1 Mutations. New England Journal of Medicine 334:18, 1197-1200
Full Text82
Susan Neuhausen, Teresa Gilewski, Larry Norton, Thao Tran, Peter McGuire, Jeff Swensen, Heather Hampel, Patrick Borgen, Karen Brown, Mark Skolnick, Donna Shattuck-Eidens, Suresh Jhanwar, David Goldgar, Kenneth Offit. (1996) Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nature Genetics 13:1, 126-128
CrossRef83
JefferyP. Struewing, RobertE. Tarone, LawrenceC. Brody, FrederickP. Li, JohnD. Boice. (1996) BRCA1 mutations in young women with breast cancer. The Lancet 347:9013, 1493
CrossRef84
AlexM. Garvin, Heinz Mueller, Serenella Eppenberger-Castori, U.R.S. Eppenberger, RodneyJ. Scott. (1996) Informed consent and BRCA1 mutation detection in archived breast tumour specimens. The Lancet 347:9009, 1189
CrossRef85
Collins, Francis S., . (1996) BRCA1 — Lots of Mutations, Lots of Dilemmas. New England Journal of Medicine 334:3, 186-188
Full Text86
Fergus J. Couch, Barbara L. Weber, . (1996) Mutations and Polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Human Mutation 8:1, 8-18
CrossRef
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