1 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany; 2 Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden
* Correspondence to: Dr J. Lorenzo Bermejo, Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany. Tel: +49-6221-421805; Fax: +49-6221-421810; Email: j.lorenzo{at}dkfz.de
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Abstract |
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Patients and methods: The families of the Swedish Family-Cancer Database with at least three generations (N=944 723) were classified according to the criteria proposed by the German Consortium for Hereditary Breast and Ovarian Cancer for BRCA1/2 mutation testing. We calculated the proportion of women with breast cancer in the classified families and used standardised incidence ratios (SIRs) to estimate the risk of histology specific breast cancers in families with suspected BRCA1/2 mutations.
Results: Families with two breast cancers before the age of 50 years included 1.8% of the breast cancer patients; 1% of the women with breast cancer belonged to families with breast and ovarian cancers. The SIR of female breast cancer was lowest in families with male breast cancer and highest in families with two women affected by breast cancer under the age of 50 years. The SIRs of medullary breast cancer agreed with the BRCA1 mutation prevalences detected by the German Consortium for Hereditary Breast and Ovarian Cancer.
Conclusions: Most of the breast malignancies in families with male breast cancer are likely to be related to BRCA2 mutations. Non-BRCA1/2 related effects are probably involved in the strong clustering of breast cancer in families with early onset breast and ovarian cancers.
Key words: BRCA1, BRCA2, clinical criteria, mutation testing
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Introduction |
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Criteria based on a familial history of breast and ovarian cancer are the most common tool used to recommend individuals for genetic testing of BRCA1/2 germline mutations [7]. The German Consortium for Hereditary Breast and Ovarian Cancer (GCHBO) recently classified 989 individuals according to their family history of breast/ovarian cancer [8
]. Similar criteria of classification have been used by Verhoog et al. and by the National Comprehensive Cancer Network [9
, 10
]. However, only fragmentary data are available on the true population-level frequencies of families that fulfil the criteria for mutation testing [11
]. Family histories are not uniformly recorded in the clinics and they are based on patients recall, which may be inaccurate [11
]. Thus, in order to present the full scope of familial breast cancer and the needs for mutation screening services, population-based data are needed on the proportions of families with familial breast cancer, classified according to the criteria used for mutation testing, and on the clustering of breast cancer in such families.
In this study, we apply the criteria used by the GCHBO for recommending BRCA1/2 mutation testing to classify the families of the nationwide Swedish Family-Cancer Database. Our purpose is to analyse the prevalence of the classified families at the population level and to explore the aggregation of breast cancer in families eligible for mutation testing. The Swedish Family-Cancer Database offers unique possibilities for a reliable estimation of risk in the classified families since the data on family relationships and cancers are obtained from registered sources of practically complete coverage and are free from bias [12].
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Patients and methods |
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The families in the Database were identified by their founder parents. If a founder parent of the family was missing or if she had married several times, the family was excluded. Only families in the Database with at least three generations were considered in this study. Overlap between families was possible, e.g. individuals in the fourth generation belonged to four different families. The families were classified according to the clinical criteria proposed by the GCHBO, as described in Table 1. These criteria considered bilateral breast cancers as two independent cases. Breast and ovarian cancer families were those families with at least one breast cancer patient and at least one ovarian cancer patient. This study also analysed separately the families with two affected members under the age of 50 years and the families with bilateral breast cancer before the age of 50 years.
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The BRCA1/2 prevalences from the GCHBO study [8] and the average risks associated with BRCA1/2 mutations estimated by Antoniou et al. [1
] were used to calculate the cumulative risks of breast cancer attributable to BRCA1/2 mutations in families eligible for mutation testing. For example, 24% of the families with two cases of breast cancer under the age of 50 years had BRCA1 mutations and 13% of those families showed BRCA2 mutations in the GCHBO study. The average cumulative risks of breast cancer by age 70 years estimated by Antoniou et al., 65% in BRCA1 and 45% in BRCA2 mutation carriers, would result in 240.65 + 130.45 = 21.45% of the women affected with breast cancer by age 70 years in families with two cases of breast cancer before age 50 years.
The standardised incidence ratio (SIR) was used to estimate the relative risk of breast cancer in the classified families. The relative risk for women with a first-degree relative affected by breast cancer was based on women from the second generation because information on mothers and sisters was only available for those women. Follow-up started at birth, immigration date or first year of the study (1961 or 1993 for histology-specific cancers), whichever came latest. Follow-up terminated at diagnosis of cancer, death, emigration date or 31 December 2000. The SIR was calculated as the ratio of observed to expected number of cases. The expected numbers were computed from age- (5-year bands), parity- (six groups from any parturition to more than five parturitions), socioeconomic status- (six groups), age at first birth- (five groups, 5-year bands between before age of 20 and after age of 35) and residential area- (four groups) standardised incidence rates. The confidence intervals (95% CI) were calculated assuming a Poisson distribution [15]. The distribution of histology-specific breast cancers among individuals with a first-degree relative affected by breast cancer and for members of the classified families was also calculated.
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Results |
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Morbus Paget carcinomas and cystosarcomas phylloides were also analysed (results not shown). Four Morbus Paget carcinomas were found in families with breast cancer under the age of 35, five cases in families with two breast cancers, at least one of them under 50, and three Morbus Paget carcinomas occurred in families with two breast cancers diagnosed after the age of 50. Three cystosarcomas phylloides were found in families with breast cancer under the age of 35 years and two cases occurred in families with two breast cancers, at least one of them under the age of 50 years.
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Discussion |
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Many types of data indicates genetic similarity between Germans and Swedes in relation to breast/ovarian cancer incidences [18] and BRCA1/2 mutation prevalences [2
, 8
, 19
], which justify certain conclusions between the GCHBO study and this study. The cumulative risk of breast cancer has been estimated to be 0.97% by the age of 45 years, 2.8% by the age of 55 and 6.4% by the age of 65, in both Sweden and Germany [18
]. According to the same source, the estimated cumulative risk of ovarian cancer in Sweden has been 0.18% by the age of 45 years, 0.39% by the age of 55 years and 0.90% by the age of 65 years. For Germany, the corresponding estimates have been very similar: 0.15%, 0.42% and 0.80%, respectively. Moreover, the frequencies of BRCA1 (22.6%) and BRCA2 (11.3%) mutation carriers among high-risk Swedish breast cancer families, reported by Hakansson et al. [19
], are in concordance with the 21.4% BRCA1 and the 9.1% BRCA2 mutation carriers found by the GCHBO among the classified German families. Loman et al. [2
] reported percentages of mutation carriers of 7.3% (BRCA1) and 2.1% (BRCA2) among 234 Swedish breast cancer patients diagnosed before the age of 41 years, which are also in agreement with the 8.8% BRCA1 and the 4.4% BRCA2 mutation carriers found by the GCHBO among 45 German patients diagnosed before the age of 35 years. Unfortunately, no information was available about the mutation status of the 75 606 breast cancer patients included in this study.
The definition of clinical criteria for genetic testing of BRCA1/2 mutations is a challenging issue. The proportion of cases attributable to BRCA1/2 mutations is limited, even in high-risk breast or ovarian cancer families, and the percentage of BRCA1/2 mutation carriers with a familial history of breast or ovarian cancer may, on average, be less than half [3]. The inclusion of second-degree relatives, as proposed by Sibert et al. [7
], may result in improved classification criteria, but the proportion of identified BRCA1/2 mutation carriers will probably remain low. For example, among the 1008 Ashkenazi Jewish women diagnosed with cancer who were screened in a recent study, 52% of them had neither mother, sister, grandmother nor aunt with breast or ovarian cancer [20
]. In this study, 12.6% of the women with breast cancer had a first-degree relative affected by breast cancer. The criteria that were associated with the highest BRCA1/2 mutation rates in the GCHBO study permitted classification of only 1.8% (two breast cancers under age 50) and 1% (breast and ovarian cancers) of the cases of breast cancer. These data show the limited percentage of breast cancers that are ascertained by familial criteria, even if the criteria are based on relatively loose familial relationships. The criterion two breast cancers, at least one of them before age 50 covered 4.9% of the breast cancers. This criterion is also included in the Practice Guidelines in Oncology of the National Comprehensive Cancer Network as suggestive of hereditary breast/ovarian cancer syndrome [10
]. The GCHBO study found BRCA1/2 mutations in 21% of the families that fulfilled this criterion, but a lower prevalence of mutations (7.5%) among those families was reported by Frank et al. [21
].
Among Swedish families, few of them fulfilled more than one set of criteria. The GCHBO counted bilateral breast cancer as two independent cases, but some differences were found among families with two women affected by breast cancer before the age of 50 years and those families that included bilateral breast cancer under the age 50 years. In 84.6% of the families with early bilateral breast cancer, only one woman had breast cancer. The percentages of women diagnosed with breast cancer by the ages of 50 and 70 years in families with two affected women under the age of 50 were significantly higher than the corresponding percentages for families with early bilateral breast cancer. The SIRs of ductal, lobular and tubular breast carcinoma were significantly higher in families with two women affected by breast cancer under the age of 50 years than in families with bilateral breast cancer before the age of 50. Therefore, the two classification criteria, which may result in different BRCA1/2-mutation prevalences, should be used separately in future studies.
The GCHBO found 42% BRCA1 and 10% BRCA2 mutation carriers in German families with both breast and ovarian cancers [8]. Families with those malignancies have shown 46% BRCA1 and 5.6% BRCA2 mutation rates in the Netherlands [9
], 30% BRCA1 and 22% BRCA2 mutation rates in Finland [22
] and 23% BRCA1 and 18% BRCA2 mutation rates in Spain [23
]. The average risks associated with BRCA1/2 mutations [1
] would result in 23%32% of the women with breast cancer, but we found that 69% of the women had breast cancer by the age of 70 in families with breast and ovarian cancers. These data suggest that, in addition to BRCA1/2 mutations, other effects are involved in the aggregation of breast cancer in those families. Table 5 presents the cumulative risks of breast cancer attributable to BRCA1/2 mutations based on the BRCA1/2 prevalences from the GCHBO study [8
] and the average risks associated with BRCA1/2 mutations estimated by Antoniou et al. [1
]. According to these data, about 30% of the clustering of breast cancer in families with two breast cancers before age 50 years would be attributable to BRCA1/2 mutations. Most studies have identified BRCA2 mutations exclusively in families with male breast cancer, with prevalences ranging from 4% to 100% [21
, 23
26
]. In the GCHBO study, 23% of the families with male breast cancer showed BRCA2 and 2% of those families presented with BRCA1 mutations. Based on our data, BRCA2 mutations would explain most of the familial aggregation of breast cancer in families with male breast cancer, in contrast to the other families eligible for mutation testing.
Data on the association of BRCA1/2 mutations with specific histological types of breast cancers can be used to improve the criteria for mutation testing and may help to identify new heritable causes for breast cancer. The high SIRmedullary in this study was in agreement with the prevalences of BRCA1 mutations detected by the GCHBO; the SIRmedullary was 57.1 in families with breast and ovarian cancers (BRCA1 mutation rate 42%), 37.1 in families with two breast cancers before the age of 50 (BRCA1 mutation rate 24%) and 36.2 in families with two breast cancers, at least one of them before the age of 50 (BRCA1 mutation rate 18%). These data agree with earlier studies, which have found medullary carcinomas more often in BRCA1 than in BRCA2 mutation carriers or in other familial cancers [5, 6
]. The association of mucinous carcinoma with familial breast cancer suggested by the Breast Cancer Linkage Consortium [5
] was also corroborated in this study at a population level. We have shown that patients with a first-degree familial history of breast cancer showed the highest SIR for the mucinous histology. The number of histology-specific breast cancers in families with male breast cancer was small, but the distribution of ductal and lobular types in those families agreed with the findings of Lakhani et al. in BRCA2 mutation carriers [6
]. However, Lakhani et al. did not find any tubular carcinomas, whereas we found two tubular breast cancers in families with male breast cancer. The SIRcomedo was significantly higher than the SIRductal in families with two cases of breast cancer under the age of 50 years, which may be associated with an increased prevalence of BRCA1 mutations among patients affected by comedo breast cancer. Contrary to the medullary histology, lobular breast cancer has been found more often in non-BRCA1/2 families than in BRCA1 mutation carriers [6
]. Furthermore, lobular carcinomas are more likely to be oestrogen receptor positive, whereas BRCA1 tumours are mostly oestrogen receptor negative [27
]. Families with both breast and ovarian cancer showed a SIRlobular lower than the SIRductal in this study, but the inverse relationship was observed in families with two cases of breast cancer before the age of 50. The lower prevalence of BRCA1 mutations found by the GCHBO in families with two breast cancers before the age of 50 years than in families with breast and ovarian cancers indicates that, in addition to BRCA1 mutations, other effects are probably involved in the aggregation of lobular breast cancer in families with two early breast cancers.
In conclusion, families that fulfilled the clinical criteria for BRCA1/2 mutation testing included a limited proportion of women with breast cancer: less than 1% of the women with breast cancer belonged to families with breast and ovarian cancers. Most of the breast malignancies in families with male breast cancer are likely to be related to BRCA2 mutations. In contrast, non-BRCA1/2 related effects are probably involved in the strong aggregation of breast cancer among families with early breast and ovarian cancers. This study confirmed the association between BRCA1 mutations and the medullary histology of breast cancer at a population level.
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Acknowledgements |
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Received for publication June 23, 2004. Revision received August 31, 2004. Accepted for publication September 9, 2004.
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