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. 2009 Apr;62(4):350-6.
doi: 10.1136/jcp.2008.062646.

Age-dependent penetrance of different germline mutations in the BRCA1 gene

F Al-Mulla  1 , J M Bland, D Serratt, J Miller, C Chu, G T Taylor
Affiliations

Age-dependent penetrance of different germline mutations in the BRCA1 gene

F Al-Mulla et al. J Clin Pathol. 2009 Apr.

Abstract

Aims: BRCA1 gene mutations have been extensively studied in relation to breast and ovarian cancer susceptibility. Various genotype-phenotype correlation attempts have yielded important data pertaining to the consequences of BRCA1 mutations. However, little is known about the effects of recurrent BRCA mutations on expressivity and the age of onset of cancer in a population. This study addresses whether different exon mutations have variable expressivity especially in relation to the age of onset of breast cancer.

Methods: Using a step-wise systematic approach, culminating in the sequencing of all BRCA1 and BRCA2 exons with the addition of multiplex ligation-dependent probe amplification, the relationship between disease phenotypes and gene mutations in 219 individuals and their family members was examined.

Results: It is shown that different BRCA1 gene mutations have distinct effects that influence the age of onset of breast or ovarian cancer. Mutations in exon 2 of the BRCA1 gene had significantly lower penetrance compared with mutations of exons 11, 13 and 20. The median age of affliction with breast cancer was 55 years for 185delAG in exon 2 (95% confidence interval (CI) 46.7 to 59.5), 47 years for the 4184delTCAA mutation in exon 11 (95% CI 39 to 55.4), and 41 years for exon 13 duplication (95% CI 32.9 to 49.7) of the BRCA1 gene. Moreover, 14 novel mutations in BRCA1 and BRCA2 genes in the Yorkshire/Humberside population were identified.

Conclusions: The 185delAG mutation of the BRCA1 gene is a low penetrance mutation that is age dependent especially when compared with the exon 13 duplication mutation. The data have important ramifications on screening, genetic counselling and prophylactic treatment of BRCA1 gene mutation carriers.

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Conflict of interest statement

Competing interests: None.

Figures

Figure 1
Figure 1
(A) Cumulative incidence for all cancer cases, by various BRCA1 exons. (B) Cumulative incidence of breast cancer cases, by various BRCA1 exons.
Figure 2
Figure 2
Kaplan–Meier plots of cumulative survival and age at diagnosis with breast cancer in relation to specific BRCA1 exon mutations. The p value indicates log-rank test.
Figure 3
Figure 3
Kaplan–Meier plot of overall survival of patients in relation to BRCA1 exon mutations (the table depicts the hazard ratios).
See this image and copyright information in PMC

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References

    1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74–108 - PubMed
    1. Narod SA. Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2002;2:113–23 - PubMed
    1. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66–71 - PubMed
    1. Tavtigian SV, Simard J, Rommens J, et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 1996;12:333–7 - PubMed
    1. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 1994;265:2088–90 - PubMed

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