Originally published as JCO Early Release 10.1200/JCO.2005.03.3126 on June 26 2006

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Effect of Chest X-Rays on the Risk of Breast Cancer Among BRCA1/2 Mutation Carriers in the International BRCA1/2 Carrier Cohort Study: A Report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators’ Group

Nadine Andrieu, Douglas F. Easton, Jenny Chang-Claude, Matti A. Rookus, Richard Brohet, Elisabeth Cardis, Antonis C. Antoniou, Teresa Wagner, Jacques Simard, Gareth Evans, Susan Peock, Jean-Pierre Fricker, Catherine Nogues, Laura Van't Veer, Flora E. Van Leeuwen, David E. Goldgar

From L'Institut National de la Santé et de la Recherche Médicale Emi00-06 et Service de Biostatistique de l'Institut Curie, Paris; International Agency for Research on Cancer, Lyon; Centre Paul Strauss, Strasbourg; Centre René Huguenin, Saint Cloud, France; Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge; Department of Genetics, St Mary's Hospital, Manchester, United Kingdom; Division of Clinical Epidemiology, German Cancer Research Center, Heidelberg, Germany; Departments of Epidemiology and Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Senology, Medical University of Vienna and Private Trust for Breast Health, Vienna, Austria; Laboratoire de Génomique des Cancers, Laval University, Québec City, Québec, Canada; and Department of Medical Informatics, University of Utah, Salt Lake City, UT; and the Gene Etude Prospective Sein Ovaire (GENEPSO), Gen en Omgeving studie van de werkgroep Hereditiair Borstkanker Onderzoek Nederland (GEO-HEBON), and the International BRCA1/2 Carrier Cohort Study (IBCCS) Collaborators’ Group

Address reprint requests to David E. Goldgar, Department of Dermatology, University of Utah School of Medicine, 30 N. Medical Dr, Salt Lake City, UT 84132; e-mail: david.goldgar{at}hsc.utah.edu

	ABSTRACT

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PURPOSE: Women who carry germline mutations in the BRCA1 and BRCA2 genes are at greatly increased risk of breast cancer (BC). Numerous studies have shown that moderate to high doses of ionizing radiation are a risk factor for BC. Because of the role of the BRCA proteins in DNA repair, we hypothesized that BRCA carriers might be more sensitive to ionizing radiation than women in the general population.

PATIENTS AND METHODS: A retrospective cohort study of 1,601 female BRCA1/2 carriers was performed. Risk of breast cancer from exposure to chest x-rays, as assessed by questionnaire data, was analyzed using a weighted Cox proportional hazards model.

RESULTS: In this cohort, any reported exposure to chest x-rays was associated with an increased risk of BC (hazard ratio [HR] = 1.54; P = .007). This risk was increased in carrier women aged 40 years and younger (HR = 1.97; P < .001) and in women born after 1949 (HR = 2.56; P < .001), particularly those exposed only before the age of 20 years (HR = 4.64; P < .001).

CONCLUSION: In our series of BRCA carriers, we detected a relatively large effect on BC risk with a level of radiation exposure that is at least an order of magnitude lower than in previously studied medical radiation–exposed cohorts. Although part of this increase may be attributable to recall bias, the observed patterns of risk in terms of age at exposure and attained age are consistent with those found in previous studies. If confirmed, the results have important implications for the use of x-ray imaging in young BRCA1/2 carriers.

	INTRODUCTION

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Exposure to ionizing radiation has been shown to be associated with a significant, but at low doses, usually modest increase in breast cancer (BC) risk (reviewed recently in Ronckers et al¹). Epidemiologic studies of atomic bomb survivors, such as the Life Span Study, and of medically irradiated populations show increased risks of female BC, with relative risks ranging from 1.0 to 4.3 per Gy.^2-11 Most of the information about patterns of risk over time comes from studies of populations who received relatively moderate to high doses of radiation to the breast. The relative risks of BC for women exposed to external doses of ionizing radiation in childhood and adolescence are substantially higher than the risks for women exposed as adults.^3-9 Results of a recent combined analysis of data from atomic bomb survivors and seven medically exposed cohorts³ indicate clearly that, although radiation exposure at any age increases BC risk, the relative and absolute excess risks tend to decrease with increasing age at exposure.^3,5,7 The increased risk of BC starts to be observed 10 to 15 years after exposure, with relative risks decreasing as a function of attained age after reaching a peak, usually between age 30 and 40 years.^3,5,7 A study of children exposed repeatedly to x-rays for monitoring of the curvature of the spine for scoliosis has suggested that adolescence, when breast tissue is developing, is a vulnerable time for carcinogenic exposures.¹¹ However, little, if any, data are available on the risks because of routine, occasional x-rays in the general population.

The discovery of the BRCA1 and BRCA2 genes has facilitated the identification of a cohort of individuals at particularly high risk of this disease, with risks of BC estimated to be 65% and 45% by age 70 years for BRCA1 and BRCA2 mutation carriers, respectively.¹² Identification of genetic or lifestyle factors that modify the risks conferred by BRCA mutations could allow more precise counseling of the individual woman at risk; identification of avoidable modifiers of the genetic risk could provide at-risk women with a means of lowering their BC risk.

Accumulating evidence suggests a role for the BRCA proteins in various processes of DNA repair, including repair of double-strand breaks by homologous recombination.^13,14 Although these mechanisms have been primarily studied in BRCA nullizygous cells, there is now evidence that DNA damage repair in cells heterozygous for BRCA mutations is impaired. Indeed, studies have demonstrated a reduced fidelity of double-strand break end-joining in BRCA^+/– compared with controls,¹⁵ and an increased radiosensitivity and high level of micronuclei formation were observed in BRCA1-positive and -negative and BRCA2-positive and -negative lymphoblasts and lymphocytes.^16,17 We hypothesized that the presence of mutations in these genes could enhance the radiation-associated increase in BC risk in young women after exposure to ionizing radiation. To our knowledge, this is the first epidemiologic study to examine the effects of exposure to low doses (< 0.1 Gy) of ionizing radiation in this group of high-risk women.

	PATIENTS AND METHODS

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Study Group
The International BRCA1/2 Carrier Cohort Study (IBCCS) was initiated in 1997 as a collaborative European prospective study of women carrying a deleterious mutation in BRCA1 or BRCA2. To be eligible for the IBCCS, the women must be carriers of a disease-predisposing mutation in either BRCA1 or BRCA2, be older than age 18 years, and have been counseled as to their mutation status. Details of the design and rationale of the study can be found elsewhere.¹⁸

The present retrospective analyses were based on a sample of 1,601 women with proven BRCA1 (n = 1,187, 74%) or BRCA2 (n = 414, 26%) mutations who were recruited onto the IBCCS study during the period of 1997 to 2002. These women were recruited at European centers, with the exception of 88 patients from Québec, Canada. Approximately two thirds of the women (1,064 of 1,601 women) were participants in large ongoing national studies of BRCA carriers in the United Kingdom and Ireland (Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers [EMBRACE]), Netherlands (Gen en omgeving studie van de werkgroep hereditiair borstkanker onderzoek Nederland [GEO-HEBON]), and France (Gene Etude Prospective Sein Ovaire [GENEPSO]). A standardized questionnaire was administered to each participant, primarily by mail (approximately 85% of participants). The research protocol was approved by the relevant ethics committees, and all participants provided written informed consent.

Exposure to chest x-rays (not including mammograms, which were assessed in a subsequent part of the questionnaire) was assessed first as ever or never. For participants who indicated such exposure, more specific information was requested relating to the number of such x-rays received before age 20 and after age 20 years (zero, one to four, or five x-rays in each of the two age periods). These two variables were combined to create a measure related to age at exposure (before age 20 years only; after age 20 years only; and one or more x-rays in both periods) and another measure related to level of x-ray exposure (at least one period with a maximum of four x-rays and no period with five or more x-rays; and at least one period with five or more x-rays). In the EMBRACE study, participants reported the total number of x-rays they had undergone but did not provide information about age periods; thus, the data from the United Kingdom and Ireland could only be included in the analysis of ever versus never x-ray exposure and are excluded from the more detailed analyses of exposure.

Statistical Methods
The data presented here were analyzed using a modified Cox proportional hazards model. Although standard Cox regression provides a valid test of the association between a risk factor and BC, it may not give an unbiased estimate of the hazard ratio (HR) because the participants in this study were taken from high-risk families qualifying for genetic testing. Thus, the disease status of the individuals may have affected the likelihood of ascertainment, leading to an oversampling of affected individuals. To correct for this potential bias, the Cox regression analyses were performed using a weighted Cox regression approach,¹⁹ where individuals are weighted according to gene, age group, and birth cohort (< 1950 or 1950) such that the observed BC incidence rates in the study sample are consistent with established BC risk estimates for BRCA1 and BRCA2 carriers.¹² This approach leads to estimates that are close to unbiased but with some loss of power compared with the standard unweighted approach. There was a total of 65,675 individual person-years of observation, each corresponding to a single year of observation time starting at birth. All analyses were stratified by the participants' year of birth (< 1940, 1940 to 1949, 1950 to 1959, 1960) and four country groupings roughly delineated along geographic lines, except for Québec (group 1: Austria, Belgium, Germany, Holland, and Hungary; group 2: Iceland, Denmark, and Sweden; group 3: France, Spain, Italy, and Québec; and group 4: United Kingdom and Ireland). Because only parity and oophorectomy were significantly related to BC in our data, the analyses were adjusted for these factors (parity: 0, 1, 2, 3, or 4+; oophorectomy: yes or no) as time-dependent covariates. Because the data set included multiple members of the same families, all analyses were performed using robust variance estimators clustering on family membership to account for familial correlations in the risk factors.²⁰ Missing values were coded as an additional level to include as many participants as possible for the adjustment factors. Of the 65,675 person-years, 55,673 (85%) contributed data to the analysis of ever or never exposure, and 36,046 (55%) were available for inclusion in the analysis of the more detailed exposures.

To better exclude potential survival bias resulting from some women being interviewed a long time after their BC diagnosis, a second set of analyses was performed on individuals diagnosed or censored within the 5 years before or at their interview, with follow-up being counted only during this 5-year period and with a new set of weights calculated only for this period. This incident cohort contained a total of 969 participants (295 affected; mean age at diagnosis, 43.3 years) and 4,070 total person-years. All statistical analyses were performed using the STATA version 8 statistical package (Stata Corp, College Station, TX).

	RESULTS

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Characteristics of the entire and incident cohorts are listed in Table 1. Eight hundred seventy-nine women had been diagnosed with BC at the time of their interview; however, only 853 of these women were considered as affected in this analysis because 26 patients were diagnosed with BC after a previous cancer (mostly ovarian). The remaining 748 women were censored at age at diagnosis with ovarian cancer (n = 122), age at diagnosis of another cancer (n = 16), the age at which they underwent prophylactic bilateral mastectomy (n = 31), or age at interview (n = 579). The average age at censoring for the 748 participants without BC was 41.4 years, which is similar to the age at diagnosis of the patients, although the age at interview was substantially older for the BC patients, reflecting the pattern of genetic testing among participants.

	DISCUSSION

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However, these results must be interpreted with caution because the magnitude of the observed effect is likely to be affected by differential recall of x-ray exposure between affected and unaffected women, and it will be important to confirm these results in prospective studies that avoid such biases. However, it is unlikely that recall bias entirely explains the observed increase; we found no risk associated with another exposure, alcohol consumption at age 20 years, that might also be subject to such recall bias (HR = 1.06; 95% CI, 0.8 to 1.3), and we see no effect of chest x-ray exposure in comparing women with ovarian cancer (n = 124) with unaffected women (HR = 1.26; 95% CI, 0.8 to 2.1). Furthermore, although the accuracy of the self-reported assessment of past diagnostic exposures could not be checked in our study, it is noteworthy that at least three studies have examined this issue by comparing self-assessment to medical records.^21-23 All three reports show that, although there was a certain amount of disagreement between medical records and interview exposure measures, this misclassification was largely nondifferential between patients and controls.

Finally, the apparent relationships with increasing numbers of x-rays and age at exposure and the consistency of the results in both the whole and incident cohorts also lend credibility to the finding of an increased BC risk after low doses of radiation in BRCA mutation carriers. Indeed, despite the crude measures of exposure as assayed in our questionnaire, the pattern of risks observed in our study is consistent with what is known about the effects of radiation on BC in other exposed populations. In this study, x-ray exposure before age 20 years was associated with a higher risk than a similar exposure after age 20 years, and in general, a higher number of x-rays was associated with a higher BC risk. Surprisingly, women exposed during both age periods were at an intermediate risk, and because this is biologically implausible, further studies are needed to clarify this effect. We also found that the relative risk was greater in the period up to age 40 years, particularly in women only exposed before age 20 years; this pattern is consistent with the reports on atomic bomb survivors^5,7 and data observed in patients irradiated as treatment for Hodgkin's disease.²⁴ Moreover, when finer age groups are considered, we see a clear pattern, with estimated HRs of 2.26, 1.72, 1.36, and 1.04 for the risk periods of less than 36, 36 to 40, 41 to 50, and more than 50 years old, respectively. We also observed a strong effect of birth cohort, with no significant increased BC risk observed for women born before 1950. It should also be noted that it is only in the recent birth cohorts that substantial numbers of women report having no x-rays; half of the women who reported having had no x-rays were born in 1960 or later.

On the basis of the large increased risk of early-onset BC in the Life Span Study cohort and in cohorts of HD survivors, it has been postulated that the excess cases of BC in these groups may be occurring in a small genetically susceptible subset of the entire exposed population.^1,24 Given the role of BRCA1 and BRCA2 in DNA double-strand break repair, BRCA1/2 mutation carriers are strong candidates for such susceptible individuals, with even a relatively modest increase in radiation-induced damage having a substantial impact on BC risk. The results of this study seem to be entirely consistent with this hypothesis, and at least one other study has reported an increased BC risk among women with a family history of BC after relatively low ionizing radiation exposure.²⁵ However, it should be noted that another study²⁶ tested a small series of patients diagnosed with BC after high doses of radiation for treatment of Hodgkin's disease for mutations in BRCA1 and BRCA2 and identified only a single BRCA2 germline mutation.

The results from this study raise potentially significant clinical considerations. The absolute risk of BC by age 50 years is in the order of 40% in BRCA1 carriers and 15% in BRCA2 carriers.¹² A two- to three-fold increased risk associated with exposure to chest x-rays would imply that there are subgroups of women defined by their x-ray exposure history who are at substantially higher risk and others who are at reduced risk compared with the population of carriers as a whole. If an increased risk were to be confirmed, however, these results would have implications regarding the appropriate use of medical imaging in carriers at young ages. Thus, in young members of BRCA families, a careful risk-benefit analysis is needed before deciding on a diagnostic procedure that delivers a relatively high dose of ionizing radiation exposure to the breast such as a computed tomography scan or multiple x-rays. The results presented here also raise the issue of the potential risks from mammographic screening, which is often used to screen BRCA carriers starting in their 30s. Unfortunately, the analysis of the effect of mammographic exposure on BC risk is likely to be biased in retrospective studies because of its obvious relationship to diagnosis, and accordingly, a prospective study of mutation carriers with detailed mammographic exposure history with adjustment for confounding variables (eg, family history) is a priority.

In conclusion, this study indicates a potentially important association between radiation exposure from chest x-rays and BC risk in BRCA1/2 carriers that is of greater magnitude than the association seen in the general population. Although the magnitude of this risk cannot be evaluated with any precision because of the likely effects of recall bias, the pattern of risk with age and dose is similar to that in other radiation-exposed cohorts, which provides plausibility to these findings. Nevertheless, confirmation of these results with more detailed exposure data, preferably in a prospective study, is required before definite clinical recommendations can be made.

	Appendix

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International BRCA1/2 Carrier Cohort Study Collaborating Group members include the following: Vienna, Austria: Teresa Wagner, Verena Korn, Christine Fürhauser; Odense, Denmark: Anne-Marie Gerdes; Budapest, Hungary: Edith Olah; Reykjavik, Iceland: Jorunn Eyford; Milan, Italy: Paolo Radice; Madrid, Spain: Javier Benitez, Ana Osorio; Madrid, Spain: Trinidad Caldes, Miguel de la Hoya; Szczecin, Poland: Jan Lubinski; Stockholm, Sweden: Brita Arver; Lund, Sweden: H. Olsson, Niklas Loman; Quebec, Canada: Jacques Simard; and Brussels, Belgium: Catherine Sibille.

GEO-HEBON Collaborating Centers include the following: Center for Human and Clinical Genetics, Department of Clinical Genetics, Leiden University Medical Center, Leiden: Christi van Asperen; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam: Hanne Meijers-Heijboer; Department of Clinical Genetics, Nijmegen Medical Center, Nijmegen: Nicoline Hoogerbrugge; Family Cancer Clinic, the Netherlands Cancer Institute, Amsterdam: Senno Verhoef; The Netherlands Foundation for the Detection of Hereditary Tumors: Leiden, Hans Vasen; Department of Medical Genetics, University Medical Center Utrecht, Utrecht: Margreet Ausems; Department of Clinical Genetics and Human Genetics, Vrije Universiteit University Medical Center, Amsterdam: Fred Menko; and Department of Clinical Genetics, Maastricht University Medical Center, Maastricht: Encarna Gomez-Garcia.

EMBRACE Collaborating Centers include the following: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook; North of Scotland Regional Genetics Service, Aberdeen: Neva Haites, Helen Gregory; Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison; West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown; South West Regional Genetics Service, Bristol: Alan Donaldson; East Anglian Regional Genetics Service, Cambridge: Joan Paterson; Medical Genetics Services for Wales, Cardiff: Jonathon Gray; St James's Hospital and National Centre for Medical Genetics, Dublin: Peter Daly, David Barton; South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteus, Michael Steel; Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Julia Rankin; West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday; South East Thames Regional Genetics Service, London: Louise Izatt, Gabriella Pichert; North West Thames Regional Genetics Service, Harrow: Huw Dorkins; Leicestershire Clinical Genetics Service, Leicester: Richard Trembath; Yorkshire Regional Genetics Service, Leeds: Tim Bishop, Carol Chu; Merseyside and Cheshire Clinical Genetics Service, Liverpool: Ian Ellis; Manchester Regional Genetics Service, Manchester: Gareth Evans, Fiona Lalloo, Andrew Shenton; North East Thames Regional Genetics Service, London: James Mackay, Anne Robinson; Nottingham Centre for Medical Genetics, Nottingham: Susan Ritchie, Sandy Raeburn; Northern Clinical Genetics Service, Newcastle: Fiona Douglas, John Burn; Oxford Regional Genetics Service, Oxford: Sarah Durell; Department of Cancer Genetics, Royal Marsden Hospital: Ros Eeles; North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell; South West Thames Regional Genetics Service, London: Shirley Hodgson; and Wessex Clinical Genetics Service, Southampton: Diana Eccles, Anneke Lucassen.

GENEPSO Collaborating Centers include the following: Coordinating Centre, Centre René Hugenin, Saint Cloud: Catherine Noguès, Emmanuelle Fourme, Rosette Lidereau, Denise Stevens; Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars; Institut Gustave Roussy, Villejuif: Agnès Chompret; Centre René Huguenin, Saint Cloud: Catherine Noguès; Centre Paul Strauss, Strasbourg: Jean-Pierre Fricker; Centre François Baclesse, Caen: Pascaline Berthet; Centre Alexis Vautrin, Vandoeuvre-les-Nancy: Elisabeth Luporsi; Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona; Centres Paul Papin, René Gauducheau, and Catherine de Sienne, Angers, Nantes: Alain Lortholary; Centre Antoine Lacassagne, Nice: Marc Frénay; Hôpital D'Enfants Centre Hospitalier Universitaire, Dijon: Laurence Faivre; Institut Paoli-Calmettes, Marseille: Hagay Sobol, François Eisinger, Laetitia Huiart; Institut Bergonié, Bordeaux: Michel Longy; Institut Jean Godinot, Reims: Tan Dat Nguyen; Institut Claudius Regaud, Toulouse: Laurence Gladieff, Rosine Guimbaud; Centre Hospitalier Georges Renon, Niort: Paul Gesta; Centre Oscar Lambret, Lille: Philippe Vennin, Claude Adenis; Hôpital Charles Nicolle, Centre Henri Becquerel, Rouen: Annie Chevrier, Annick Rossi; Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon; Hôpital Civil, Strasbourg: Jean-Marc Limacher; Centre Eugène Marquis, Rennes: Catherine Dugast; Polyclinique Courlancy, Reims: Liliane Demange; Hôpital de la Timone, Marseille: Hélène Zattara-Cannoni; Clinique Sainte Catherine, Avignon: Hélène Dreyfus; Centre Hospitalier Universitaire Arnaud Villeneuve, Montpellier: Mehrdad Noruzinia; and Centre Hospitalier Régional et Universitaire Dupuytren, Limoges: Laurence Venat-Bouvet.

Associated centers include the following: Nadine Andrieu (Institut National de la Santé et de la Recherche Médicale [INSERM] Emi00-06/Service de Biostatistique, Institut Curie, Paris), Catherine Bonaïti (INSERM U535, Villejuif), Claire Julian-Reynie (INSERM U379, Marseille), Florent de Vathaire (INSERM U605, Villejuif), and Hagay Sobol (Institut Paoli-Calmettes, INSERM E-9939, Marseille).

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Nadine Andrieu, Douglas F. Easton, Jenny Chang-Claude, Matti A. Rookus, Richard Brohet, David E. Goldgar Provision of study materials or patients: Douglas F. Easton, Jenny Chang-Claude, Richard Brohet, Teresa Wagner, Jacques Simard, Gareth Evans, Susan Peock, Jean-Pierre Fricker, Catherine Nogues Collection and assembly of data: Douglas F. Easton, Jenny Chang-Claude, Richard Brohet, Teresa Wagner, Jacques Simard, Susan Peock, Catherine Nogues, Laura Van't Veer, David E. Goldgar Data analysis and interpretation: Nadine Andrieu, Douglas F. Easton, Jenny Chang-Claude, Matti A. Rookus, Elisabeth Cardis, Antonis C. Antoniou, Flora E. Van Leeuwen, David E. Goldgar Manuscript writing: Nadine Andrieu, Douglas F. Easton, Matti A. Rookus, Elisabeth Cardis, Flora E. Van Leeuwen, David E. Goldgar Final approval of manuscript: Nadine Andrieu, Douglas F. Easton, Jenny Chang-Claude, Matti A. Rookus, Richard Brohet, Elisabeth Cardis, Teresa Wagner, Jacques Simard, Flora E. Van Leeuwen, David E. Goldgar

 

	NOTES

 
Supported by Grants No. SI2.328176 and SPC.2002482 from the European Commission (International BRCA1/2 Carrier Cohort Study); Cancer Research UK and The British Council (Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers [EMBRACE]); Fondation de France and Ligue Nationale Contre le Cancer (GENEPSO); Dutch Cancer Society Grant No. NKI98-1854 (GEO-HEBON); and the Interdisciplinary Health Research International Team on Breast Cancer Susceptibility (INHERIT) project of the Canadian Institutes of Health Research.

The funding sources providing support for the International BRCA1/2 Carrier Cohort Study had no role in the design, data collection, and analysis of the data described in this article and had no role in the writing of the article and the decision to submit the paper for publication.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted June 29, 2005; accepted January 24, 2006.

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