Hereditary breast cancer: ever more pieces to the polygenic puzzle

Abstract

Several susceptibility genes differentially impact on the lifetime risk for breast cancer. Technological advances over the past years have enabled the detection of genetic risk factors through high-throughput screening of large breast cancer case-control series. High- to intermediate penetrance alleles have now been identified in more than 20 genes involved in DNA damage signalling and repair, and more than 70 low-penetrance loci have been discovered through recent genome-wide association studies. In addition to classical germ-line mutation and single-nucleotide polymorphism, copy number variation and somatic mosaicism have been proposed as potential predisposing mechanisms. Many of the identified loci also appear to influence breast tumour characteristics such as estrogen receptor status. In this review, we briefly summarize present knowledge about breast cancer susceptibility genes and discuss their implications for risk prediction and clinical practice.

Figure 1

Frequency and risk distribution of breast cancer susceptibility alleles. Minor allele frequency of breast cancer susceptibility alleles plotted against their estimated relative risk. Selected genes are shown for high-risk, intermediate-risk and low-risk categories. Figure modified after Ref. [22].

Figure 2

Network of breast cancer susceptibility proteins in DNA damage signalling and repair. Functional interplay between several known or candidate breast cancer susceptibility gene products in the intracellular response to either DNA double strand breaks (left side) or interstrand crosslinks (right side). Sensed by the Mre11-RAD50-NBN complex or by the Fanconi anemia core proteins, the respective signalling pathways merge into cell cycle arrest/apoptosis as mediated through p53, and into homology-directed recombinational repair mediated by BRCA1, PALB2, BRCA2, and the RAD51 paralogs. As mentioned in the text and in Table 1, some of the underlying genes are evidenced but have not yet been finally confirmed as bona fide breast cancer susceptibility genes, and some may mainly constitute ovarian cancer susceptibility genes. The genes for MERIT40, MDM4, and RAD51B harbour common polymorphisms associated with breast cancer, and RAD51 harbours a common SNP associated with breast cancer risk in BRCA2 mutation carriers.