Two highly penetrant genes involved in hereditary breast and/or ovarian cancer syndromes, BRCA1 and BRCA2, have been identified (1,2). Mutations in these genes occur throughout their coding sequences, making large-scale testing for mutations challenging. It is, therefore, not surprising that only a few studies have reported estimates of the mutation frequencies among unselected breast cancer patients. Usually, only a few hundred patients have been analyzed in each study, with mutation frequencies ranging from 3.3% to 5.7% for BRCA1 (35). The largest studies of BRCA1 and BRCA2 mutations have been carried out in isolated populations, such as the Icelanders or Ashkenazi Jews (6), where individual, highly recurrent founder mutations account for the majority of all mutations (7,8). Results derived from such populations may, however, be biased by the specific nature of these mutations.

In whole-gene mutation screening performed by two independent groups (911) on 188 breast and breast–ovarian cancer families in Finland, 11 mutations accounted for the vast majority (84%) of all detected BRCA1 and BRCA2 mutations. Besides these recurrent BRCA1 and BRCA2 founder mutations, eight other mutations have been identified only once in the Finnish population [(912); Vahteristo P, Eerola H, Tamminen A, Blomqvist C, Nevanlinna H: unpublished observations]. The 11 known mutations provide a unique, rapid way to analyze the impact of BRCA1 and BRCA2 mutations at the population level, without a bias toward any individual founder mutation.

We collected blood samples from 1035 consecutive, newly diagnosed breast cancer patients treated at the Departments of Oncology at the Helsinki University Central Hospital, Finland (n = 627) from April 1997 through March 1998, and at the Tampere University Hospital, Finland (n = 408), from January 1997 through May 1999. These cohorts cover 82% (87% in Helsinki and 75% in Tampere) of all breast cancer patients who visited the clinics during the study period. The two university hospitals accrue patients from a large, geographically defined region covering a large part of southern Finland and account for about 30% of all breast cancer patients diagnosed in Finland. Because of the recent migration patterns within Finland, the patients diagnosed in Tampere and, particularly, those diagnosed in Helsinki have their ancestral origins throughout Finland. Written, informed consent was obtained from the patients. The patients were asked to fill out a questionnaire on breast, ovarian, and other cancers in their family. Only patients reporting breast and/or ovarian cancers in first- or second-degree relatives were considered to have a family history of the disease. The study did not alter treatment protocols or patient management, and those patients with a strong family history of breast or ovarian cancer were referred to genetic counseling and possible BRCA1 and BRCA2 mutation screening, regardless of the results of this study. The mean age at diagnosis was 56.2 years in Helsinki and 58.9 years in Tampere, which is comparable to the average age of diagnosis of breast cancer in Finland (13). The study has been approved by the Ethical Committees of the Departments of Oncology and Obstetrics and Gynecology, Helsinki University Central Hospital and Tampere University Hospital, and appropriate permissions were obtained from the Ministry of Social Affairs and Health in Finland.

All 11 BRCA1 and eight BRCA2 mutations found previously in the Finnish population were screened in the 1035 patient samples. Detection of the mutations was performed by use of allele-specific oligonucleotide hybridization or by restriction fragment length polymorphism analysis. The results were confirmed by direct sequencing by use of an ABI PRISM 310 Genetic Analyzer (The Perkin-Elmer Corp., Foster City, CA).

Statistical analyses of differences in dichotomous variables were done by Fisher's exact test (Statistical Package for Social Sciences, Chicago, IL; version 8.0 for Windows). All P values are two-sided. Confidence intervals (CIs) for proportions are based on exact CIs based on the binomial distribution.

The frequency of the BRCA1 and BRCA2 mutations in unselected Finnish breast cancer patients was 1.8% (Table 1), which is much lower than the reported prevalence of BRCA1 and BRCA2 founder mutations in unselected Icelandic (7.7%–10.4%) (1416) and Ashkenazi (11.7%) (17) breast cancer patients. In contrast, a recent, large retrospective study of early-onset breast cancer case subjects (<36 years) in England by Peto et al. (18) estimated a similar frequency for both BRCA1 and BRCA2 mutations (2.8%) as obtained in this study. This figure was based on correction for assuming a 63% mutation detection sensitivity, as well as extrapolation of findings from early-onset breast cancer to the total breast cancer population assuming high penetrance for the mutations. The frequency of 1.8% reported in this study obviously also represents an underestimate, since only the 19 mutations identified previously in the Finnish population were studied. However, we believe that the result is well representative of the BRCA1 and BRCA2 mutation burden because the 11 founder mutations account for a major fraction of all mutations in these genes in Finnish breast cancer famillies (911). Nine of the 11 founder mutations were detected in this independent population-based study and accounted for 17 of the 19 mutations. In addition, one mutation seen previously only once was found here in two patients.

Screening of all breast cancer patients for BRCA1 and BRCA2 mutations remains clinically and ethically unjustified (19,20) because of the unknown psychologic and social consequences of the testing or the unknown efficacy of the surveillance or preventive methods in mutation carriers with no family history of breast or ovarian cancer. Furthermore, because of the low frequency of mutations among all case subjects, the cost-effectiveness of the screening would be very low. Identifying phenotypic clues that would predict the likelihood of finding BRCA1 and BRCA2 mutations is, therefore, important. Fewer than 4% of all unselected breast cancer patients reported a family history of ovarian cancer. However, almost one half of all mutations (42%) were found in this small group (Tables 1 and 2). Family history of ovarian cancer strongly suggested the presence of both BRCA1 (three of four BRCA1 mutation carriers detected in this subgroup) and BRCA2 (five of 15 BRCA2 mutations detected) mutations. Another strong predictor of mutations was early age at diagnosis of breast cancer. Patients diagnosed under 40 years of age had eight times higher mutation frequency as compared with those 40 years old or older (9.9% versus 1.2%; P<.0005). The age at diagnosis can, however, be affected by family history of the disease due to increased awareness leading to early surveillance and detection.

Overall, family history of site-specific breast cancer was not a strong indicator of BRCA1 and BRCA2 mutations. However, patients with two or more relatives affected with breast cancer and no ovarian cancer in the family had a 4.9% prevalence of mutations, and four of the 19 mutation carriers (21%) were found in this subgroup.

Collectively, these three criteria (ovarian cancer family history, early age at diagnosis of breast cancer, and family history of two or more breast cancers) would have distinguished 15 mutation carriers in a subset of 181 patients (8.3%). This number should be compared with the presence of 19 mutations in the entire series of 1035 patients (1.8% mutation carriers). Furthermore, the prevalence of BRCA1 or BRCA2 mutations was very low (four [0.5%] of 854) in breast cancer patients who do not belong to the above-mentioned subgroup. The results illustrate that BRCA1 and BRCA2 mutation screening is not warranted in the general breast cancer population and substantiate the suggested strict criteria for BRCA1 testing in breast cancer (4,21,22).

Table 1.

Number of BRCA1 and BRCA2 mutations in distinct groups of breast cancer patients characterized by family history of breast and/or ovarian cancers*

  No. with mutation    
Family history (No. of affected relatives in addition to index case subject) No. of case subjects tested BRCA1 BRCA2 BRCA1 or BRCA2 95% CI Two-sided P compared with the group with no family history 
*CI = confidence interval. 
None 677 0.6 0.2–1.5  
256 1.6 0.4–4.0 .23 
 Breast cancer 236 1.3 0.3–3.7 .38 
 Ovarian cancer 20 5.0 0.1–24.9 .14 
78 7.7 2.9–16.0 <.0005 
 Breast cancer only 67 6.0 1.7–14.6 .003 
 Breast and ovarian cancers 11 18.2 2.3–51.8 .003 
≥3 24 20.8 7.1–42.2 <.0005 
 Breast cancer only 15 0–21.8 1.0 
 Breast and ovarian cancers 55.6 21.2–86.3 <.0005 
  Total 1035 15 19 1.8 1.1–2.9   
  No. with mutation    
Family history (No. of affected relatives in addition to index case subject) No. of case subjects tested BRCA1 BRCA2 BRCA1 or BRCA2 95% CI Two-sided P compared with the group with no family history 
*CI = confidence interval. 
None 677 0.6 0.2–1.5  
256 1.6 0.4–4.0 .23 
 Breast cancer 236 1.3 0.3–3.7 .38 
 Ovarian cancer 20 5.0 0.1–24.9 .14 
78 7.7 2.9–16.0 <.0005 
 Breast cancer only 67 6.0 1.7–14.6 .003 
 Breast and ovarian cancers 11 18.2 2.3–51.8 .003 
≥3 24 20.8 7.1–42.2 <.0005 
 Breast cancer only 15 0–21.8 1.0 
 Breast and ovarian cancers 55.6 21.2–86.3 <.0005 
  Total 1035 15 19 1.8 1.1–2.9   
Table 2.

Clinical characteristics of the mutation carriers found in the study*

Patient No. Mutation Type of mutation Age at diagnosis, y No. of 1st- and 2nd-degree relatives with brca (age at diagnosis, y) No. of 1st- and 2nd-degree relatives with ovca (age at diagnosis, y) Other cancer cases in the family ovca (n = 40)† brca <40y (n = 71)† >2 brca cases, no ovca cases (n = 82)† 
*n.k. = not known; ovca = ovarian cancer; brca = breast cancer. The 19 mutation carriers identified in this study characterized by mutation and age at diagnosis. Also, the number of family members affected with either breast or ovarian cancer and their age at diagnosis of cancer are shown. The table demonstrates that nearly 80% of all mutation carriers have either a relative diagnosed with ovarian cancer, an age at diagnosis of breast cancer under 40 years, or an extensive family history of breast cancer. 
†n = 181 for patient fulfilling any of the three criteria. 
‡Index case subject diagnosed with breast cancer at age 59 years and with ovarian cancer at age 60 years. 
§Bilateral breast cancer. 
S4 BRCA1, ex13, 4446C>T Nonsense 48 2 (30, 40) 3 (45, 45, 68) Stomach × 2, lung   
P321 BRCA1, ex20, 5370C>T Nonsense 71 3 (46, 55, 55) 1 (50) Pancreas × 2   
K3 BRCA2, ex9, 999del5 Frameshift 47 4 (27, 33, 59, n.k.) 1 (65)  ×   
P360 BRCA2, ex18, 8555T>G Nonsense 59 1 (50) Index (60)‡   ×   
K506 BRCA1, ex11, 3604delA Frameshift 29 1 (34) 1 (50) Brain × ×  
464 BRCA2, ex15, 7708C>T Nonsense 36 5 (34, 42, 45, 61, 95) 1 (47) Prostate, cervix, bladder × ×  
P013 BRCA2, ex15, 7708C>T Nonsense 37 4 (34/40,§ 34, 38, 54) 1 (46)  × ×  
P179 BRCA2, ex15, 7708C>T Nonsense 32 1 (49) 1 (n.k.) Colon × 2, pancreas, brain × ×  
K382 BRCA1, ex12, 4216(-2)A>G Splice site 39     ×  
P566 BRCA2, ex11, 5797G>T Nonsense 30 1 (58)  Lung  ×  
P625 BRCA2, ex15, 7708C>T Nonsense 34 1 (55)  Esophagus, lung  ×  
K82 BRCA2, ex9, 999del5 Frameshift 57 2 (52, 59)  Esophagus, lung, stomach   × 
P563 BRCA2, ex15, 7708C>T Nonsense 61 2 (38, 43)  Gastric, cervix   × 
K179 BRCA2, ex11, 6503delTT Frameshift 56 2 (71, n.k.)  Prostate colon   × 
K79 BRCA2, ex24, 9346(-2)A>G Splice site 50 2 (33, 65)  Thyroid   × 
P067 BRCA2, ex11, 5797G>T Nonsense 50 1 (n.k.)  Melanoma    
K106 BRCA2, ex24, 9346(-2)A>G Splice site 56       
P342 BRCA2, ex24, 9346(-2)A>G Splice site 71       
K323 BRCA2, ex24, 9346(-2)A>G Splice site 73       
       8/19 (42%) 7/19 (37%) 4/19 (21%)  
Patient No. Mutation Type of mutation Age at diagnosis, y No. of 1st- and 2nd-degree relatives with brca (age at diagnosis, y) No. of 1st- and 2nd-degree relatives with ovca (age at diagnosis, y) Other cancer cases in the family ovca (n = 40)† brca <40y (n = 71)† >2 brca cases, no ovca cases (n = 82)† 
*n.k. = not known; ovca = ovarian cancer; brca = breast cancer. The 19 mutation carriers identified in this study characterized by mutation and age at diagnosis. Also, the number of family members affected with either breast or ovarian cancer and their age at diagnosis of cancer are shown. The table demonstrates that nearly 80% of all mutation carriers have either a relative diagnosed with ovarian cancer, an age at diagnosis of breast cancer under 40 years, or an extensive family history of breast cancer. 
†n = 181 for patient fulfilling any of the three criteria. 
‡Index case subject diagnosed with breast cancer at age 59 years and with ovarian cancer at age 60 years. 
§Bilateral breast cancer. 
S4 BRCA1, ex13, 4446C>T Nonsense 48 2 (30, 40) 3 (45, 45, 68) Stomach × 2, lung   
P321 BRCA1, ex20, 5370C>T Nonsense 71 3 (46, 55, 55) 1 (50) Pancreas × 2   
K3 BRCA2, ex9, 999del5 Frameshift 47 4 (27, 33, 59, n.k.) 1 (65)  ×   
P360 BRCA2, ex18, 8555T>G Nonsense 59 1 (50) Index (60)‡   ×   
K506 BRCA1, ex11, 3604delA Frameshift 29 1 (34) 1 (50) Brain × ×  
464 BRCA2, ex15, 7708C>T Nonsense 36 5 (34, 42, 45, 61, 95) 1 (47) Prostate, cervix, bladder × ×  
P013 BRCA2, ex15, 7708C>T Nonsense 37 4 (34/40,§ 34, 38, 54) 1 (46)  × ×  
P179 BRCA2, ex15, 7708C>T Nonsense 32 1 (49) 1 (n.k.) Colon × 2, pancreas, brain × ×  
K382 BRCA1, ex12, 4216(-2)A>G Splice site 39     ×  
P566 BRCA2, ex11, 5797G>T Nonsense 30 1 (58)  Lung  ×  
P625 BRCA2, ex15, 7708C>T Nonsense 34 1 (55)  Esophagus, lung  ×  
K82 BRCA2, ex9, 999del5 Frameshift 57 2 (52, 59)  Esophagus, lung, stomach   × 
P563 BRCA2, ex15, 7708C>T Nonsense 61 2 (38, 43)  Gastric, cervix   × 
K179 BRCA2, ex11, 6503delTT Frameshift 56 2 (71, n.k.)  Prostate colon   × 
K79 BRCA2, ex24, 9346(-2)A>G Splice site 50 2 (33, 65)  Thyroid   × 
P067 BRCA2, ex11, 5797G>T Nonsense 50 1 (n.k.)  Melanoma    
K106 BRCA2, ex24, 9346(-2)A>G Splice site 56       
P342 BRCA2, ex24, 9346(-2)A>G Splice site 71       
K323 BRCA2, ex24, 9346(-2)A>G Splice site 73       
       8/19 (42%) 7/19 (37%) 4/19 (21%)  
K. Syrjäkoski and P. Vahteristo as well as T. Kainu and H. Nevanlinna contributed equally to this work.
Supported by the Academy of Finland, The Sigrid Juselius Foundation, The Nordic Cancer Union, The Finnish Cancer Society, The Clinical Research Fund of Helsinki University Central Hospital, The Research Fund of Tampere University Hospital, and The Pirkanmaa Cancer Society.

We thank Minna Merikivi, Päivi Virtanen, and Kristiina Selkee for their help in patient contacts and sample collection and Kati Rouhento for her technical assistance. We also acknowledge the patients participating in this study.

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