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. The cancer incidences in the classified families were compared with the incidences in the general population. The percentages of individuals with cancer in families eligible for BRCA1/2 mutation testing were compared with data in the literature to estimate the proportion of malignancies related to BRCA1/2 mutations.
Results: Families with two breast cancers before the age of 50 years showed increased risk of early onset pancreatic, prostate and ovarian cancers; families with ovarian and breast cancers presented increased incidences for ovarian and ocular cancers; families with two breast cancers, at least one of them under the age of 50 years, showed increased risks of prostate and primary liver cancers. Stomach cancer before age 70 years was twice as frequent in families with breast and ovarian cancers as in the general population. BRCA1/2 mutations probably explain most of the aggregation of ovarian cancer in families with male breast cancer, and in families with at least two breast cancers diagnosed before age 50 years.
Conclusions: The association of BRCA1/2 mutations with ovarian, pancreatic, prostate and stomach cancers was confirmed at a population level. However, the clustering of early pancreatic cancer in families with two breast cancers under age 50 years, the aggregation of ovarian cancer in families with breast and ovarian cancers, and the increased incidence of early onset prostate cancer in families with male breast cancer seem to be due to other effects unrelated to BRCA1/2 mutations.
Key words: BRCA1, BRCA2, mutation testing, clinical criteria
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Introduction |
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Recommendations about genetic testing of BRCA1/2 germline mutations are based on clinical criteria which summarise the personal and/or family histories of breast and ovarian cancers. The German Consortium for Hereditary Breast and Ovarian Cancer (GCHBO) recently classified 989 families according to specific criteria and found the highest frequency of BRCA1 mutations (43%) in families with breast and ovarian cancer and the highest frequency of BRCA2 mutations (23%) in families with male breast cancer [14]; similar clinical criteria have been proposed, e.g. by the National Comprehensive Cancer Network [15
].
The objective of this study was to assess the risk of cancer in high-risk breast/ovarian cancer families at a population level. The families of the Swedish Family-Cancer Database were classified according to the criteria proposed by the GCHBO and the cancer incidences in those families, in which BRCA1/2 mutations were suspected, were compared with the incidences in the general population. Increased cancer risks for sites other than the breast or the ovary may be indicative of additional cancer types, which might warrant clinical follow-up in families that fulfil the clinical criteria. Population-based data on the risk of cancer in families eligible for BRCA1/2 mutation testing may help to reach a consensus about the association of BRCA1/2 mutations with cancer at sites other than the breast and the ovary. Furthermore, increased incidences of cancer at sites that have not been associated with BRCA1/2 mutations may reflect new, non-BRCA1/2 related components of the familial aggregation of cancer in those families. The close-to-100% histological verification of cancers in the Swedish Family-Cancer Database [16], the size of the Database and its coverage, offered unique possibilities for this population-based analysis.
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Patients and methods |
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Only families with at least three generations in the Database were considered in this study. If a founder parent of the family was missing or if he/she was married several times, the family was excluded. 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, but the present study also analysed 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 separately.
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The risk of developing cancer before the age of 50 years in the absence of other causes of death was estimated by dividing the number of site-specific cancers diagnosed under the age of 50 years by the number of individuals who reached this age. Emigrants before the age of 50 years, persons younger than 50 years by 2000, patients diagnosed with cancer at sites different from the site under consideration before age 50 years and individuals deceased through other causes before this age were excluded from the denominator. Similar ratios were calculated for cancers diagnosed under the age of 70 years and were referred to as the percentage of affected individuals. Confidence intervals (95% CI) were calculated assuming a Poisson distribution [17]; 99% CIs of the SIRs were also presented. Significant associations were explored in further detail by analysing second cancers and other malignancies that occurred in the affected families.
In order to estimate the cumulative risk of ovarian cancer attributable to BRCA1/2 mutations in families eligible for mutation testing, the BRCA1/2 prevalences from the GCHBO study [16] were multiplied by the average risks of ovarian cancer associated with BRCA1/2 mutations reported by Antoniou et al. [18
]. For example, 24% of the families with two cases of breast cancer under the age of 50 years presented with BRCA1 mutations and 13% of those families showed BRCA2 mutations in the GCHBO study. The average cumulative risks of ovarian cancer by the age of 70 years estimated by Antoniou et al., 39% in BRCA1 and 11% in BRCA2 mutation carriers, would result in (24 x 0.39) + (13 x 0.11) = 10.79% of the women affected with ovarian cancer by the age of 70 years in families with two cases of breast cancer before the age of 50 years. The proportions of pancreatic and prostate cancers related to BRCA1/2 mutations were calculated in the same way by using the cumulative cancer risks reported by the Breast Cancer Linkage Consortium [1
, 10
].
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Results |
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SIRs of site-specific cancers for members of the classified families are presented in Table 2Table 2. Families with two cases of breast cancer before age 50 years showed significant SIRs (different from 1.00) for ovarian and prostate cancers, the SIR of pancreatic cancer before age 50 years was also increased in those families. Members of families with male breast cancer did not show significant SIRs for cancer at sites different from the breast. Families with at least one member affected by breast cancer and at least one member affected by ovarian cancer presented significant SIRs for ovarian and ocular cancers. The SIR for breast and ovarian cancer in a single woman was also increased in those families. In one of the four families with breast, ovarian and ocular cancers, one woman had leukaemia and another woman was diagnosed with leukaemia after ovarian cancer. The 23 families with breast, ovarian and stomach cancers included 23 men and one woman with stomach cancer (one family had two men with stomach cancer); three of those families included women affected by both breast and ovarian cancers. Families with two breast cancers, at least one of them diagnosed before age 50 years, showed significant SIRs for liver and prostate cancers. Among the 16 families with liver and two breast cancers, two families had two members with hepatic malignancies (gall bladder and ampulla of Vater tumours in one, and gall bladder and liver primary cancers in the other). Families with two cases of breast cancer after age 50 years did not show significant SIRs. Families with breast cancer diagnosed before age 35 years presented significant SIRs for ovarian and pancreatic cancers. Families with two women diagnosed with breast cancer under age 50 years showed significant SIRs for ovarian cancers, whereas families with bilateral breast cancer diagnosed before age 50 years presented increased SIRs for ovarian, pancreatic and prostate cancers.
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Discussion |
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The GCHBO counted bilateral breast cancer as two independent cases, but some differences were found in the present study among families with two women affected by breast cancer before age 50 years and those families that included bilateral breast cancer under age 50 years. The risk of ovarian cancer was higher in families that included two women affected by breast cancer before age 50 years. In contrast, families with bilateral breast cancer diagnosed under age 50 years showed higher risks for pancreatic and prostate cancers. Therefore, the two criteria should be analysed separately in future studies.
The mutation prevalences from the GCHBO study and the cumulative risks estimated by Antoniou et al. [18] would result in 10.8% of the women with ovarian cancer by age 70 years in families with both breast and ovarian cancers. In the present study, 68.9% of the women had ovarian cancer by age 70 years in those families. These data suggest that, in addition to BRCA1/2 mutations, other effects are probably involved in the aggregation of ovarian cancer in families with both breast and ovarian cancers. Similar reasoning was applied to estimate the proportion of ovarian malignancies that can be attributed to BRCA1/2 mutations in other families eligible for mutation testing. As shown in Table 3, 6.16% of the women had ovarian cancer by age 70 years in families with two cases of breast cancer before age 50 years, and 2.59% of the women had ovarian cancer by age 70 years in families with male breast cancer. The cumulative risks of ovarian cancer attributable to BRCA1/2 mutations suggest that most of the aggregation of ovarian cancer in families with two breast cancers before age 50 years, and in families with male breast cancer, is probably due to BRCA1/2 mutations.
Stomach cancer before age 70 years was twice as frequent in families with breast and ovarian cancer than in the general population. Both BRCA1 [10] and BRCA2 mutations [5
, 8
] have been reported to increase the risk of stomach cancer, but the number of tumours observed in previous studies has been small and the excess risk was attributed to some extent to misclassification of ovarian cancer. In the present study, almost all individuals diagnosed with stomach cancer in families with breast and ovarian cancers were males. Moreover, concomitant breast/ovarian cancer in the same woman was frequent in those families and one family included two males with stomach cancer. Since the risk of stomach cancer was not increased in families with male breast cancer, and it was only slightly increased in families with two cases of breast cancer before age 50 years, some association of BRCA1 mutations with stomach cancer is probable.
Earlier studies have found some association of BRCA1 mutations with colon cancer, but the excess risk of colon cancer has been attributed to misdiagnosed ovarian or rectal cancers [1]. Although cervical cancer has been previously associated with both BRCA1 and BRCA2 mutations [10
, 13
], the strength of this association remains unclear. In the present study, the families that fulfilled the clinical criteria for BRCA1/2 mutation testing did not show increased risks for colon or cervical cancers. The risk of cancer of the peritoneum was high in families with breast cancer before age 35 years, but only two cases were observed and the corresponding SIR was not statistically significant.
The risk of liver cancer has been found to be increased among BRCA1 mutations carriers in earlier studies, but the excess risk has been attributed to misreported metastases from other sites [1]. In the present study, the SIR for primary liver cancer was increased in families with two breast cancers, at least one of them under age 50 years, but the percentage of individuals affected by liver cancer in families with breast and ovarian cancers was only slightly increased, thus limiting the strength of the association of BRCA1 mutations and hepatic malignancies. BRCA2 mutations have been associated with hepatocelullar carcinomas, gall bladder and bile duct cancers [8
]. In the present study, the risk of liver cancer was not increased in families with male breast cancer but gall bladder cancer was the only hepatic malignancy by age 70 years in those families, thus suggesting some histological specificity of the hepatic carcinomas found in families with male breast cancer.
The percentage of patients with pancreatic cancer by age 50 years was higher in families with two cases of breast cancer under age 50 years than in the general population. The cumulative risks of pancreatic cancer by age 50 years have been estimated to be 0.12% for BRCA1 mutation carriers [1] and 0.2% for BRCA2 mutation carriers [8
]. These average estimates, together with the mutation frequencies found by the GCHBO in families with two breast cancers under age 50 years [14
], would result in a cumulative risk of pancreatic cancer by age 50 years of 0.05% (Table 3). The percentage of individuals with pancreatic cancer by age 50 years found in the present study among those families was 0.16%. We did not find any pancreatic cancers before age 50 years in families with breast and ovarian cancers but the risk of pancreatic cancer was significantly increased in families with breast cancer before age 35 years. These data suggest some association of early onset breast and pancreatic cancers through causes unrelated to BRCA1 mutations.
The percentage of men affected with prostate cancer by age 50 years was significantly increased in families with male breast cancer, probably due to the association of BRCA2 mutations and prostate cancer. However, the average cumulative risk of prostate cancer by age 50 years estimated in an earlier study [8] and the BRCA2 mutation prevalences found by the GCHBO, would result in a cumulative risk of 0.02% by age 50 years (Table 3). In the present study, 0.27% of the men had prostate cancer by age 50 years in families with male breast cancer. In contrast, the percentage of men affected by prostate cancer in families with suspected BRCA1 mutations was only slightly increased in the present study, which probably reflects the moderate risk of prostate cancer conferred by BRCA1 mutations [1
]. The percentage of individuals affected by ocular melanomas was slightly increased in families with breast and ovarian cancers and in families with male breast cancer, which is in agreement with the association of BRCA2 mutations and ocular malignancies found in a previous study [19
].
In conclusion, breast and ovarian cancers are the major worry in the clinical counselling of families that fulfill the clinical criteria for BRCA1/2 mutation testing. In families with bilateral breast cancer or two breast cancers before age 50 years, there is concern about early onset pancreatic cancers. Prostate cancers are also in excess in these families but the risk is only moderate. Most cases of ovarian cancer in families with male breast cancer, and in families with at least two breast cancers diagnosed before age 50 years, are probably attributable to BRCA1/2 mutations. Other, non-BRCA1/2 related effects are probably involved in the clustering of early onset pancreatic cancer in families with two breast cancers under age 50 years, in the aggregation of ovarian cancer in families with breast and ovarian cancers, and in the increased incidence of early prostate cancer in families with male breast cancer. Remarkably, in this large study no entirely novel associations were found at previously unreported sites.
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Acknowledgements |
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Received for publication April 19, 2004. Revision received July 14, 2004. Accepted for publication July 15, 2004.
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References |
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