|Home | About | Journals | Submit | Contact Us | Français|
We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer–specific death, and risk of a second breast cancer in women with a first breast cancer.
From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer–specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.
CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor–positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer–specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor–positive first breast cancer only.
Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer–specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.
Breast cancer is the most common cancer among women. Treatment and clinical management of breast cancer has improved considerably during the last few decades, but breast cancer remains a potentially fatal disease, partly because the prognostication at diagnosis is still insufficient. Thus, there is need to identify biomarkers associated with poor prognosis and to adjust surveillance in women at risk accordingly.
CHEK2*1100delC is a founder mutation carried by 0.5% to 1.6% of individuals of Northern and Eastern European descent.1,2 It is inherited from the parents and present in the germline DNA, is not a tumor marker, and encodes a truncated CHEK2 protein. In the cell nucleus, normal CHEK2 is activated in response to DNA double-strand breakage, and this protein controls cell cycle, DNA repair, and apoptosis.3,4 Individuals heterozygous for CHEK2*1100delC have a two- to three-fold increased risk of breast cancer.1,2,5–9 However, it is unknown whether CHEK2*1100delC heterozygous women with breast cancer differ in their prognosis from noncarriers.
Here we examined the overall risk of early death, risk of breast cancer–specific death, and risk of a second breast cancer in CHEK2*1100delC heterozygotes and noncarriers in 25,571 white women of Northern and Eastern European descent who had breast cancer by using data from 22 studies conducted in 12 countries (Appendix Table A1, online only). We also re-estimated the risk of (first) breast cancer in 25,571 breast cancer cases and 30,056 controls.
From the studies participating in the Breast Cancer Association Consortium, we included women who had been tested for CHEK2*1100delC, including noncarriers or heterozygotes for CHEK2* 1100delC (Appendix Table A1; Appendix Fig A1, online only). The majority of the samples were genotyped in a single, prospective experiment by using a standard assay (see Table A1, Genotyping, online only). Women of self-reported non-European ancestry were excluded. Women with a first invasive breast cancer were eligible for inclusion if information was available on death, breast cancer–specific death, or diagnosis of a second breast cancer during follow-up. Second breast cancer was defined as a contralateral breast cancer. Only 14 CHEK2*1100delC homozygotes were identified, and these were excluded a priori from all analyses. For this study, we included 25,571 women for whom there was available information on early death, for 24,345 women on breast cancer–specific death, and for 25,094 on diagnosis of a second breast cancer (Appendix Fig A1).
For the case-control analysis, each participating study included controls from the same population as previously described (Appendix Table A1). The 22 participating studies included 30,056 controls.
Participants from 21 of the 22 studies were genotyped by using the same TaqMan-based assay.10 A 162-bp fragment flanking the CHEK2*1100delC mutation was amplified by polymerase chain reaction by using forward primer 5′-GGCAGACTATGTTAATCTTTTTATTTT ATGG-3′ and reverse primer 5′-CAAGAACTTCAGGCGCCAAGT-3′. CHEK2*1100delC carrier status was detected by using the following probes: wild-type allele 5′-VIC-TTTAGATTACTGATTTTGGGC-3′ and mutated allele 5′-FAM-TTAGATTATGATTTTGGGCAC-3′. A positive, negative, and nontemplate control were included in each run. In the majority of studies, heterozygote status was validated by using sequencing.9–11 Of all participants available for genotyping, 98.6% were successfully genotyped.
We used the statistical software STATA (STATA/SE for Windows, version 12.1; STATA, College Station, TX). We used the χ2 test for categorical characteristics and Kruskal-Wallis one-way analysis of variance for continuous characteristics to test for differences in epidemiologic and tumor characteristics between CHEK2*1100delC heterozygotes and noncarriers.
We plotted cumulative incidences of early death, breast cancer–specific death, and second breast cancer as a function of time after the first breast cancer diagnosis and tested for differences between CHEK2*1100delC heterozygotes and noncarriers by using log-rank statistics. For breast cancer–specific death and second breast cancer, any death was considered as a competing event when plotting the cumulative incidence curves by using the Fine-Gray method. The women were observed from time of diagnosis of the first breast cancer. However, most studies included prevalent cases, and time under observation began from the date of blood sampling (left truncation). This provides a valid test of association and, provided the proportional hazards assumption is not violated, an unbiased estimate of the hazard ratio.12 Follow-up ended at the end point of interest, death, or end of follow-up, whichever came first. We used Cox proportional hazard regression to calculate hazard ratios with 95% CIs for early death, breast cancer–specific death, and a second breast cancer. The proportional hazard assumption was assessed visually by plotting ln(−ln(survival)) versus ln(age). Hazard ratios for early death and breast cancer–specific death were stratified by study and were adjusted for epidemiologic and tumor characteristics: age at and year of diagnosis, family history (positive, negative, missing), body mass index (< 18.5, 18.5 to 24.9, 25.0 to 29.9, ≥ 30.0 kg/m2, missing), menopausal status (premenopausal, postmenopausal, missing), tumor size (< 20, 20-50, > 50 cm, missing), lymph node status (positive, negative, missing), tumor differentiation grade (good, moderate, poor, missing), progesterone receptor status (positive, negative, missing), and human epidermal growth factor receptor 2 status (positive, negative, missing). In overall survival analyses, we adjusted for the changes in risk over time by estrogen receptor status13 by modeling the effect of estrogen receptor status (positive, negative, missing) to change as a function of years of follow-up. In the multifactorially adjusted regression models, participants with missing information were assigned a missing value category. We tested for interactions between CHEK2*1100delC and epidemiologic and tumor characteristics by using a likelihood ratio test, excluding women for whom the relevant information was missing. Hazard ratio for a second breast cancer was stratified by study and adjusted for age at and year of diagnosis of the first breast cancer, study, and family history.
We used logistic regression to calculate odds ratios with 95% CIs of a first breast cancer by CHEK2*1100delC heterozygosity for each individual study, for all studies overall, separated by estrogen receptor status, adjusting for age at diagnosis of cases and age at ascertainment of controls on a continuous scale. We tested for heterogeneity across all studies and across estrogen receptor status by using the metan command.
All studies were approved by their institutional review committees, and written informed consent was obtained from all participants.
Among 25,571 women with invasive breast cancer, 459 (1.8%) were CHEK2*1100delC heterozygous and 25,112 (98.2%) were noncarriers (Table 1). Over a median follow-up period of 6.6 years, we observed 124 (27%) deaths, 100 (22%) breast cancer–specific deaths, and 40 (9%) second breast cancers among CHEK2*1100delC heterozygotes; corresponding numbers among noncarriers were 4,864 (19%), 2,732 (11%), and 607 (2%), respectively. At the time of diagnosis, heterozygotes versus noncarriers were on average 4 years younger (P < .001), more often had a positive family history (P < .001), were more likely to be premenopausal (P < .001), and had a higher frequency of estrogen receptor–positive (P < .001) and progesterone receptor–positive (P = .01) tumors. We observed no differences in year of diagnosis, body mass index, tumor size, lymph node status, tumor grade, or human epidermal growth factor receptor 2 status between heterozygotes and noncarriers. Although the amount of missing data was substantial, the frequency of missing information was similar for most characteristics between CHEK2*1100delC heterozygotes and noncarriers.
The hazards of early death and breast cancer–specific death by estrogen receptor status were not proportional over time. Within each estrogen receptor stratum, however, the hazards by CHEK2*1100delC carrier status were proportional; hence, subsequent analyses of these end points were performed separated by estrogen receptor status. There was no evidence for interaction between CHEK2*1100delC carrier status and estrogen receptor status on the risk of early death (P = .39) or on breast cancer–specific death (P = .28) when we excluded women with missing information on estrogen receptor status.
Cumulative incidence and risk of early death, overall and separated by estrogen receptor status, following a first breast cancer by CHEK2*1100delC carrier status is shown in Figure 1. Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygotes had increased incidence of early death compared with noncarriers (log-rank test P = .004) with a multifactorially adjusted hazard ratio of 1.43 (95% CI, 1.12 to 1.82). Among women with estrogen receptor–negative breast cancer, incidence of early death was similar for CHEK2*1100delC heterozygotes and noncarriers (log-rank test P = .84) with a multifactorially adjusted hazard ratio of 0.95 (95% CI, 0.52 to 1.74).
In women with estrogen receptor–positive tumors, we observed no interactions for risk of early death between CHEK2*1100delC carrier status and age at and year of diagnosis, family history, menopausal status, tumor size, lymph node status, tumor grade, or progesterone receptor status; we observed borderline significant interactions with body mass index (P = .02), lymph node status (P = .05), and human epidermal growth factor receptor 2 status (P = .05; Table 2); however, if these P values for tests of interaction were corrected for 10 parallel tests by using the Bonferroni method, none were significant (required P value = .05/10 = .005).
Cumulative incidence and risk of breast cancer–specific death, overall and separated by estrogen receptor status, following a first breast cancer by CHEK2*1100delC carrier status is shown in Figure 2. Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygotes had increased risk of breast cancer–specific death compared with noncarriers (log-rank test P < .001) with a multifactorially adjusted hazard ratio of 1.63 (95% CI, 1.24 to 2.15). Among women with estrogen receptor–negative breast cancer, risk of breast cancer–specific death was similar for CHEK2*1100delC heterozygotes and noncarriers (log-rank test P = .71) with a multifactorially adjusted hazard ratio of 1.09 (95% CI, 0.56 to 2.14).
Cumulative incidence and risk of second breast cancer, overall and separated by estrogen receptor status, following a first breast cancer by CHEK2*1100delC carrier status is shown in Figure 3. Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygotes had an increased risk of second breast cancer compared with noncarriers (log-rank test P < .001) with a multifactorially adjusted hazard ratio of 3.52 (95% CI, 2.35 to 5.27). We observed no second breast cancers among CHEK2*1100delC heterozygous women with estrogen receptor–negative first breast cancer; however, the cumulative incidence did not differ between CHEK2*1100delC heterozygous and noncarriers (log-rank P = .29). A test for interaction between CHEK2*1100delC and estrogen receptor status on risk of second breast cancer was not possible.
We estimated the odds ratio of a first breast cancer for CHEK2*1100delC heterozygotes versus noncarriers in 25,571 cases and 30,056 controls (Fig 4). Age-adjusted odds ratio of breast cancer for heterozygotes versus noncarriers was 3.01 (95% CI, 2.53 to 3.58) for all studies combined; the test for heterogeneity of estimates across studies gave P = .06. In analyses separated by estrogen receptor status, the corresponding odds ratios were 3.47 (95% CI, 2.87 to 4.18) for estrogen receptor–positive and 1.54 (95% CI, 1.09 to 2.17) for estrogen receptor–negative breast cancer; these two estimates were different (P < .001).
In 25,571 white women of European ancestry with a first breast cancer that was estrogen receptor–positive who were observed for a median of 6.6 years, we found that CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer–specific death, and a 3.5-fold risk of a second breast cancer. The poorer survival in CHEK2*1100delC heterozygotes has been suggested previously,14,15 but this study provides much stronger evidence for this association and demonstrates that it is restricted to estrogen receptor–positive disease.11,16,17 We also obtained an estimate for the relative risk of breast cancer in CHEK2*1100delC heterozygotes similar to that estimated previously.1,2,5–9 This is one of the few examples of a genetic factor influencing long-term prognosis documented in an extensive series of women with breast cancer, and it raises the possibility that other genetic factors influencing breast cancer prognosis could be identified, given sufficiently large, well-conducted studies.
The 2.8-fold risk of a second breast cancer in all CHEK2* 1100delC heterozygous versus noncarrier women was similar to the estimated odds ratios of a first breast cancer in a previous meta-analysis1 and the odds ratio found in this study. This finding is supported by other smaller studies of selected patients with breast cancer. The increased risk of second breast cancer is believed to be largely a result of inherited susceptibility, and this result is consistent with the model that CHEK2*1100delC combines with other risk factors to confer increased susceptibility.11,16–18
Strengths of this study include the large sample size and the participation of 22 centers in 12 countries. Moreover, the large majority of genotypes were generated in a single experiment by using one single assay, minimizing the possibility for bias as a result of differential genotyping by disease status. Furthermore, the long duration of follow-up and the detailed records on a second breast cancer and death allowed us to observe the associations between CHEK2*1100delC carrier status and these end points beyond the usually reported 5 years after diagnosis of a first breast cancer.
One factor limiting the clinical application of our finding is that CHEK2*1100delC appears to be confined to white individuals of Northern or Eastern European origin, and our findings are therefore unlikely to be directly applicable to populations with other origins. Other inactivating CHEK2 mutations have been reported in other populations, but further studies would be required to confirm whether these are also associated with a poor prognosis. In addition, 65% of the women were missing human epidermal growth factor receptor 2 status, 25% to 30% estrogen receptor status, 40% to 45% lymph node status, 25% tumor size, and 60% to 70% family history, all characteristics known to be associated with survival. Importantly, however, the frequency of the missing information was similar between CHEK2*1100delC heterozygotes and noncarriers for most of these characteristics, as expected, given that CHEK2*1100delC was unknown to the woman and her physician when the information was collected and that germline genotypes are distributed at random during meiosis and therefore typically are not confounded by lifestyle or treatment.19,20 Therefore, although the amount of missing data has limited our statistical power in some analyses, we do not believe that it reflects inherent biases likely to distort our results. Another important limitation of the study is the absence of treatment information. It is therefore theoretically possible that the reason for the lack of a significant survival difference in the estrogen receptor–negative group in CHEK2*1100delC heterozygotes versus noncarriers is that whatever negative prognostic impact heterozygosity has, it is overcome by the administration of chemotherapy specific for this group. However, any choice of therapy was blinded to CHEK2*1100delC status. Finally, the number of second breast cancers is small, which might indicate insufficient ascertainment but may also indicate that the number is unlikely to have been inflated by recurrences registered as second breast cancers.
These results raise the question of whether CHEK2*1100delC testing should be offered to white women of Northern or Eastern European descent with an estrogen receptor–positive first breast cancer. The high risk of a second breast cancer is comparable to that at which women with a strong family history of breast cancer would be offered prophylactic surgery. However, this observational study cannot provide a specific recommendation on whether prophylactic surgery is warranted. Prolonged duration of antiestrogen therapy might be warranted, particularly since it may result in a substantial reduction in the risk of second cancer. Furthermore, in CHEK2*1100delC heterozygous versus noncarrier women, the risk of an estrogen receptor–positive breast cancer was three-fold for both the first and second breast cancer, although the effect was less pronounced for estrogen receptor–negative breast cancer. This finding is supported by an earlier study14 and could have implications for prevention of breast cancer in CHEK2*1100delC heterozygous women. An analysis of treatment subgroups and CHEK2*1100delC status would hopefully provide insight into the mechanism, and therefore potentially affect clinical use of CHEK2*1100delC mutation testing. It would also have been of interest to know whether the estrogen receptor–positive breast cancers of CHEK2*1100delC heterozygotes were highly proliferative since women with these breast cancers have a relatively poor prognosis despite their tumors being estrogen receptor–positive. Although the test of interaction between tumor grade and CHEK2*1100delC status was insignificant for the women with estrogen receptor–positive breast cancers, the highest hazard ratios for early death were found for the well-differentiated tumors. Further studies should focus on the mechanism(s) behind the present observations and hopefully will provide sufficient evidence to guide prophylaxis and treatment of CHEK2*1100delC heterozygous women.
In conclusion, approximately one in 50 women with breast cancer is CHEK2*1100delC heterozygous, and testing for this mutation can identify women at increased risk of early death or breast cancer–specific death and of developing a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.
We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out, in particular: Copenhagen General Population Study (CGPS) acknowledges its participants and team; Helsinki Breast Cancer Study (HEBCS) acknowledges Kristiina Aittomäki, MD, Dario Greco, PhD, and Irja Erkkilä, RN, for their help with the patient data and samples; Amsterdam Breast Cancer Study (ABCS) acknowledges Frans Hogervorst, Senno Verhoef, and contributors of the BOSOM study (Breast Cancer Outcome Study of Mutation Carriers); Singapore and Sweden Breast Cancer Study (SASBAC) acknowledges all the patients who participated; Ontario Familial Breast Cancer Registry (OFBCR) acknowledges Teresa Selander and Nayana Weerasooriya from Cancer Care for their contributions to the study as well as the study participants; Leuven Multidisciplinary Breast Centre (LMBC) acknowledges Gilian Peuteman, Dominiek Smeets, and Kathleen Corthouts; Rotterdam Breast Cancer Study (RBCS) acknowledges Ans van den Ouweland, Jannet Blom, Petra Bos, Ellen Crepin, Annette Heemskerk-Gerritsen, Elisabeth Huijskens, and Anja Nieuwlaat; Sheffield Breast Cancer Study SBCS acknowledges Sue Higham, Helen Cramp, and Dan Connley; Breast Cancer Study of the University Clinic of Heidelberg (BSUCH) acknowledges Peter Bugert, Mannheim, for providing the control DNA samples; Mayo Clinic Breast Cancer Study (MCBCS) acknowledges Zachary Fredericksen, Catherine Erding, Matthew Kosel, and Kristen Stevens for assistance in coordination; Kuopio Breast Cancer Project (KBCP) acknowledges Eija Myöhänen and Helena Kemiläinen; and Hannover Breast Cancer Study (HABCS) acknowledges Michael Bremer, Johann H. Karstens, Hans Christiansen, and Peter Hillemanns.
Copenhagen General Population Study (CGPS) was supported by Herlev Hospital, the Danish Medical Research Council, Chief Physician Johan Boserup and Lise Boserup's Fund; Study of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) was supported by Grant No. C490/A10124 from Cancer Research UK; Breast Cancer Association Consortium was supported by Grant No. C1287/A12014 from Cancer Research UK, by the European Commission Seventh Framework Program HEALTH-2007-2.4.1-11 as a part of Collaborative Oncologic Gene-Environment Study, and by EU European Cooperation in Science and Technology office BM0606; Helsinki Breast Cancer Study (HEBCS) was supported by the Helsinki University Central Hospital Research Fund, Grant No. 132473 from the Academy of Finland, and by the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation; Amsterdam Breast Cancer Study (ABCS) was supported by Grants No. NKI 2001-2423 and NKI 2007-3839 from the Dutch Cancer Society and by the Dutch National Genomics Initiative; Singapore and Sweden Breast Cancer Study (SASBAC) was supported by the Agency for Science, Technology and Research, by Grant No. R01 CA 104021 from the National Institute of Health, by Märit and Hans Rausing's Initiative Against Breast Cancer, and by the Susan J. Komen Foundation; Ontario Familial Breast Cancer Registry (OFBCR) was supported by Grant No. RFA CA-06-503 from the National Cancer Institute, National Institutes of Health, and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and principal investigators, including Grants No. U01 CA69467 from Cancer Care Ontario and No. U01 CA69417 from Northern California Cancer Center, and by the University of Melbourne; Leiden University Medical Centre Breast Cancer Study (ORIGO) was supported by Grants No. UL1997-1505 from the Dutch Cancer Society and No. BBMRI-NL CP16 from the Biobanking and Biomolecular Resources Research Infrastructure; University of California at Irvine Breast Cancer Study (UCIBCS) was supported by Grants No. R01 CA 58860 from the National Cancer Institute and No. LVSF-44528 from the Lon V. Smith Foundation; Leuven Multidisciplinary Breast Centre (LMBC) was supported by Grants No. 232-2008 and No. 196-2010 from Stichting tegen Kanker; Rotterdam Breast Cancer Study (RBCS) was supported by Grants No. DDHK 2004-3124 and No. DDHK 2009-4318 from the Dutch Cancer Society; Sheffield Breast Cancer Study (SBCS) was supported by Yorkshire Cancer Research and the Breast Cancer Campaign; Melbourne Collaborative Cohort Study (MCCS) was supported by Australian National Health and Medical Research Council Grants No. 209057, 251553, and 504711, and infrastructure was provided by the Cancer Council Victoria; Breast Cancer Study of the University Clinic of Heidelberg (BSUCH) was supported by the Dietmar-Hopp Foundation, the Helmholtz Society, and the German Cancer Research Center; Karolinska Breast Cancer Study (KARBAC) was supported by the Swedish Cancer Society, the Stockholm Cancer Society, and the Gustav V Jubilee Foundation; Mayo Clinic Breast Cancer Study (MCBCS) was supported by Grant No. CA122340 from the National Institutes of Health (NIH) and No. CA116201 from the NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer; Kuopio Breast Cancer Project (KBCP) was supported by grants from special Government Funding (EVO) of Kuopio University Hospital, and by the Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and strategic funding from the University of Eastern Finland; Norwegian Breast Cancer Study (NBCS) was supported by Grants No. 193387/V50 (A.L.B.D. and V.N.K.) from the Norwegian Research Council and No. 181600/V11 from Functional Genomics Program (V.N.K.); Northern California Breast Cancer Family Registry (NC-BCFR) was supported by Grant No. RFA CA-06-503 from the National Cancer Institute, National Institutes of Health, and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and principal investigators, including Grant No. U01 CA69417 from the Cancer Prevention Institute of California; Hannover Breast Cancer Study (HABCS) was supported by Rudolf Bartling Foundation and a stipend from Hannelore Munke (N.B.).
|Study Acronym||Study Name||Country||Study Design||Cases||Controls||Genotyping Method||Reference|
|ABCFS||Australian Breast Cancer Family Study||Australia||Population-based case-control study||1,242||673||TaqMan||Dite et al: J Natl Cancer Inst 95:448-457, 2003|
|ABCS||Amsterdam Breast Cancer Study||The Netherlands||Hospital-based consecutive cases, and (ABCS-F; Amsterdam Breast Cancer Study-Familial) all non-BRCA1/BRCA2 breast cancer cases from the family cancer clinic of the Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis tested from 1995 to 2009; all ages and diagnosed with breast cancer from 1965 to 2008; population-based controls||2,134||989||TaqMan||Schmidt et al,11 Adank et al10|
|BBCC||Bavarian Breast Cancer Cases and Controls||Germany||Hospital-based cases; population-based controls||763||765||TaqMan||Fasching et al: Breast Cancer Res Treat 112:89-98, 2007; Schrauder et al: J Cancer Res Clin Oncol 134:873-882, 2008|
|BSUCH||Breast Cancer Study of the University Clinic of Heidelberg||Germany||Hospital-based cases; healthy blood donator controls||469||939||TaqMan||Yang et al: Breast Cancer Res Treat 127:549-554, 2011|
|CGPS||Copenhagen General Population Study||Denmark||Population-based||2,246||6,229||TaqMan||Bojesen et al: Br J Cancer 93:167-171, 2005; Weischer et al9|
|HABCS||Hannover Breast Cancer Study||Germany||Hospital-based case-control study||144||996||TaqMan||Dörk et al: Cancer Res 61:7608-7615, 2001|
|HEBCS||Helsinki Breast Cancer Study||Finland||Hospital-based case-control study plus additional familial cases||2,231||1,102||TaqMan||Kilpivaara et al: Int J Cancer 113:575-580, 2005; Fagerholm et al: Nat Genet 40:844-853, 2008|
|KARBAC||Karolinska Breast Cancer Study||Sweden||Population- and hospital-based cases; geographically matched controls||465||866||TaqMan||Lindblom et al: Breast Cancer Res Treat 24:159-165, 1992; Margolin et al: Genet Test 8:127-132, 2004|
|KBCP||Kuopio Breast Cancer Project||Finland||Population-based case-control study||409||446||TaqMan||Hartikainen et al: Cancer Epidemiol Biomarkers Prev 14:75-80, 2005; Hartikainen et al: Clin Cancer Res 12:1454-1462, 2006|
|LMBC||Leuven Multidisciplinary Breast Centre||Belgium||Hospital-based case-control study||740||945||TaqMan||Neven et al: J Clin Oncol 26:1768-1769, 2008; De Maeyer et al: J Clin Oncol 26:335-336, 2008|
|MCBCS||Mayo Clinic Breast Cancer Study||United States||Hospital-based case-control study||464||1,133||TaqMan||Olson et al: Cancer Epidemiol Biomarkers Prev 16:623-625, 2007|
|MCCS||Melbourne Collaborative Cohort Study||Australia||Prospective cohort study||655||380||TaqMan||Giles et al: IARC Sci Publ 156:69-70, 2002|
|NBCS||Norwegian Breast Cancer Study||Norway||Hospital-based case-control study||332||1,899||TaqMan||Nordgard et al: Genes Chromosomes Cancer 47:680-696, 2008|
|NC-BCFR||Northern California Breast Cancer Family Registry||United States||Population-based familial case-control study||250||154||TaqMan||John et al: Breast Cancer Res 6:R375-R389, 2004|
|OFBCR||Ontario Familial Breast Cancer Registry||Canada||Population-based familial case-control study||1,064||328||TaqMan||John et al: Breast Cancer Res 6:R375-R389, 2004|
|ORIGO||Leiden University Medical Centre Breast Cancer Study||The Netherlands||Hospital-based case-control study, Rotterdam area||844||86||Oligohybridization assay||de Bock et al14|
|PBCS||National Cancer Institute Polish Breast Cancer Study||Poland||Population-based case-control study||1,496||2,264||TaqMan||García-Closas et al: Hum Genet 119:376-388, 2006|
|RBCS||Rotterdam Breast Cancer Study||The Netherlands||Hospital based case-control study, Rotterdam area||680||797||TaqMan||Meijers-Heijboer et al,6 Easton et al: Nature 447, 1087-1093, 2007|
|SASBAC||Singapore and Sweden Breast Cancer Study||Sweden||Population-based case-control study||1,164||1,358||TaqMan||Wedrén et al: Breast Cancer Res 6:R437-R449, 2004|
|SBCS||Sheffield Breast Cancer Study||United Kingdom||Hospital-based case-control study||658||988||TaqMan||MacPherson et al: J Natl Cancer Inst 96:1866-1869, 2004; Rafii et al: Hum Mol Genet 11:1433-1438, 2002|
|SEARCH||Study of Epidemiology and Risk Factors in Cancer Heredity||United Kingdom||Population-based case-control study||6,378||7,197||TaqMan||Lesueur et al: Hum Mol Genet 14:2349-2356, 2005|
|UCIBCS||University of California at Irvine Breast Cancer Study||United States||Population-based case-control study||743||518||TaqMan||Anton-Culver et al: Eur J Cancer 36:1200-1208, 2000; Ziogas et al: Cancer Epidemiol Biomarkers Prev 9:103-111, 2000|
The funding organizations had no role in the design or conduct of the study, or in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
The author(s) indicated no potential conflicts of interest.
Conception and design: Maren Weischer, Børge G. Nordestgaard, Stig E. Bojesen
Financial support: Børge G. Nordestgaard, Paul Pharoah, Per Hall, Douglas F. Easton
Administrative support: Manjeet K. Bolla, Qin Wang, Douglas F. Easton
Provision of study materials or patients: All authors
Collection and assembly of data: All authors
Data analysis and interpretation: Maren Weischer, Børge G. Nordestgaard, Paul Pharoah, Douglas F. Easton, Marjanka K. Schmidt, Stig E. Bojesen
Manuscript writing: All authors
Final approval of manuscript: All authors