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Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening
Authors:Smith A  Moran A  Boyd M C  Bulman M  Shenton A  Smith L  Iddenden R  Woodward E R  Lalloo F  Maher E R  Evans D G R
Affiliation:Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK.
Abstract:

Background

The identification of BRCA1 and BRCA2 mutations in familial breast cancer kindreds allows genetic testing of at‐risk relatives. Those who test negative are usually reassured and additional breast cancer surveillance is discontinued. However, we postulated that in high‐risk families, such as those seen in clinical genetics centres, the risk of breast cancer might be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds.

Methods

277 families with pathogenic BRCA1/BRCA2 mutations were reviewed and 28 breast cancer phenocopies identified. The relative risk of breast cancer in those testing negative was assessed using incidence rates from our cancer registry based on local population.

Results

Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardised incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first‐degree relatives (FDRs) and 3.2 (95% confidence interval 2.0 to 4.9) for FDRs in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. 13 of 107 (12.1%) FDRs with breast cancer and no unexplained family history tested negative.

Conclusion

In high‐risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, such women should still be considered for continued surveillance.Epidemiological studies suggest that approximately 5% of breast cancer in Western countries is caused by high‐risk dominantly inherited susceptibility genes.1,2 However, twin studies suggested a genetic component in 27% of breast cancer cases.3 High‐risk dominantly inherited breast cancer susceptibility was first described in 1866 by Broca,4 but proof of dominant inheritance was obtained 120 years later with the localisation and identification of BRCA1 and BRCA2.5,6,7,8 Mutations in these genes account for most high‐risk families with ⩾4 breast cancers in members aged <60 years.9 Studies to find other genes associated with breast cancer continue; the elusive BRCA3 gene has not yet been identified.10 In the mean time, many high‐risk familial breast cancer kindreds are offered BRCA1/BRCA2 mutation analysis. If this is successful, predictive genetic testing is offered to at‐risk relatives. In some centres, relatives who test negative are reassured that their breast cancer risk is at population levels, as recommended by the recently published UK National Institute for Clinical Excellence (NICE) guidelines.11 This policy assumes that, with few exceptions, the risk of a second high‐risk familial mutation is minimal. However, breast cancer risks in high‐risk kindreds with BRCA1/BRCA2 mutations are substantially higher than risks derived from population‐based studies.9,12,13,14 In high‐risk clusters in the Breast Cancer Linkage Consortium, BRCA1 and BRCA2 mutations were estimated to cause cumulative lifetime risks of breast cancer of 85–87% and 77–84% by 70 years, respectively.9,15,16 However, estimates of breast cancer risks by 70 years from population‐based studies are much lower (28–60%)12,13,14 for BRCA1 and still lower for BRCA2. It has been suggested that even these studies may overestimate the effect of BRCA1/BRCA2 alone.17 It is therefore feasible that a substantial proportion of the risk in familial clusters with a BRCA1/BRCA2 mutation (the group of families that are usually seen by a Cancer Genetics Service) might be due to modifier genes.18,19 Such a hypothesis would predict that some members of high‐risk families might be at increased risk of breast cancer even if they tested negative for the pathogenic BRCA1/BRCA2 mutation.20 Phenocopies may be due to chance or environmental effects, another high‐risk mutation in a family, ascertainment bias or the presence of modifier genes. We have identified a large number of phenocopies from 277 families with a pathogenic BRCA1/BRCA2 mutation and have assessed breast cancer risks for people testing negative for a familial pathogenic mutation.
Keywords:
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