Contribution of the Defective BRCA1, BRCA2 and CHEK2 Genes to the Familial Aggregation of Breast Cancer: a Simulation Study Based on the Swedish Family-Cancer Database

Justo Bermejo,Kari Hemminki,Alfonso Pérez

doi:10.1186/1897-4287-2-4-185

Abstract

The known breast cancer susceptibility genes only account for 20% to 25% of the excess familial risk of the disease [1]. The present study assessed the contribution of BRCA1/2 mutations and CHEK2 variants to the relative risk of breast cancer for women with affected mothers or sisters. The familial relative risks were estimated by Poisson regression based on the Swedish Family-Cancer Database. The Database was also used to calculate the distribution of life expectancy, the number of daughters per family and the age specific cumulative risk of female breast cancer. This information, together with the penetrances of BRCA1, BRCA2 and CHEK2 from the literature, was used to simulate the familial clustering of breast cancer under different scenarios. The excess risk explained by BRCA1, BRCA2 and CHEK2 decreased steeply with the age at diagnosis of the cancers. Around 40% of the familial risk for cases diagnosed before the age of 50 years was associated with BRCA1/2 mutations. In contrast, roughly 85% of the familial risk of breast cancer diagnosed before the age of 69 years remained unexplained. The contribution of CHEK2 to familial breast cancer was small.

Highlights

Breast cancer aggregates in families, the disease being about twice as common in mothers and sisters of cases as it is in the general population [2]
Germline mutations in BRCA1 and BRCA2 are frequently found in families containing multiple individuals affected by breast cancer [4]
The variant has shown a frequency of 1.1% in healthy individuals and it has been associated with a breast cancer risk ratio of 1.7 in families without BRCA1/2 mutations

Summary

Introduction

Breast cancer aggregates in families, the disease being about twice as common in mothers and sisters of cases as it is in the general population [2]. Germline mutations in BRCA1 and BRCA2 are frequently found in families containing multiple individuals affected by breast cancer [4]. BRCA1 and BRCA2 mutations are only identified in about 15-20% of multiple-case families affected by breast cancer alone [5]. CHEK2*1100delC, a truncating variant that abrogates the kinase activity of CHEK2 [6], has been found to contribute significantly to the familial clustering of breast cancer [7]. The variant has shown a frequency of 1.1% in healthy individuals and it has been associated with a breast cancer risk ratio of 1.7 in families without BRCA1/2 mutations.

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Conclusion