Familial Cancer

, Volume 7, Issue 3, pp 233–244

Use of association studies to define genetic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

Authors

    • Department of Clinical Medicine, Trinity College DublinAMNCH Hospital
Article

DOI: 10.1007/s10689-008-9181-0

Cite this article as:
Hughes, D.J. Familial Cancer (2008) 7: 233. doi:10.1007/s10689-008-9181-0

Abstract

Though much progress has been made in understanding the role of two major high-risk breast cancer (BC) susceptibility genes, BRCA1 and BRCA2, it remains unclear what causes the observed variation in risk between mutation carriers. This marked variability in individual cancer risk both between and within BRCA1 and BRCA2 mutation carrier families may be partly explained by modifier genes that influence mutation penetrance. Defining these modifiers should help refine individual cancer risk estimates and is also expected to be an efficient method to identify further BC susceptibility alleles in general. This approach is predicated on the concept that variants in genes that are low to moderate penetrance predisposition genes are likely to have a larger risk modification effect in BRCA1/2 mutation carriers. Association studies are usually used to assess the influence of variants in biologically plausible candidate loci on the penetrance of BRCA1/2 mutations (i.e., differences in age of onset or tissue-specificity of disease). Several such modifier loci, including the genes AIB1 and AR involved in hormone metabolism, and the RAD51 gene acting in DNA repair, have been proposed in the literature. A consortium of laboratories (CIMBA) has recently confirmed the RAD51 135 G/C variant as a BC risk modifier in BRCA2 mutation carriers, though not in BRCA1 carriers. This review describes molecular epidemiological efforts to evaluate the potential influence of polymorphic variants in candidate modifier genes on the risk of BC conferred by the BRCA1 and BRCA2 genes.

Keywords

Association studiesBRCA1BRCA2Breast cancerCancer risk modificationModifiersMutation carrier

Abbreviations

BC

Breast cancer

OC

Ovarian cancer

CIMBA

Consortium of investigators of modifiers of BRCA1 and BRCA2

IBCCS

International breast cancer cohort study

nt

Nucleotides

RR

Relative risk

HR

Hazards ratio

95% CI

95% Confidence intervals

P

Probability value

SNP

Single nucleotide polymorphism

DH

Double heterozygote

IR

Ionizing radiation

MEC

Multi ethnic cohort

2df

Two degrees of freedom

OR

Odds ratio

IHCC

International hereditary cancer center

Poly-Q

multiple glutamine residues

LD

Linkage disequilibrium

Copyright information

© Springer-Verlag 2008