Wednesday, January 02, 2008

Nature Genetics Article on Breast Cancer Susceptibility

The latest issue of Nature Genetics has an interesting Perspectives piece entitled "The Emerging Landscape of Breast Cancer Susceptibility" by Michael Stratton and Nazneen Rahman. Here is the abstract:

The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alleles and common low-penetrance alleles. The contribution of each component to breast cancer predisposition is still to be fully explored, as are the phenotypic characteristics of the cancers associated with them, the ways in which they interact, much of their biology and their clinical utility. These recent advances herald a new chapter in the exploration of susceptibility to breast cancer and are likely to provide insights relevant to other common, heterogeneous diseases.

And a sample from the article:

In most Western populations, approximately one in ten women develop breast cancer. Epidemiological studies have shown that first-degree female relatives of women with breast cancer are at approximately twofold risk of developing the disease compared to the general population. Although, in principle, this could be attributable to shared environmental or genetic factors, or both, twin studies indicate that most of the excess familial risk is due to inherited predisposition.

....Major advances in understanding breast cancer susceptibility were made in the last decade of the twentieth century through genetic linkage mapping and positional cloning of two major predisposition genes, BRCA1 and BRCA2. Disease-causing variants in BRCA1 and BRCA2 confer a high risk of breast cancer, approximately 10- to 20-fold relative risk. This translates into a 30–60% risk by age 60, compared to 3% in the general population. The relative risks are higher for early-onset breast cancers, and there are also elevated risks of ovarian and other cancers. Disease-causing mutations in BRCA1 and BRCA2 result in inactivation of the encoded proteins, generally by causing premature protein truncation or nonsense-mediated RNA decay. There is population variation in mutation prevalence, but mutations are infrequent in most populations. Approximately 1 in 1,000 individuals in the UK are heterozygous mutation carriers of each gene, and there are numerous different mutations, each of which is very rare. Cancer predisposition is transmitted as an autosomal dominant trait in families harboring mutations. However, at the cellular level, BRCA1 and BRCA2 act as recessive cancer genes, with mutations converted to homozygosity in the cancers which they cause, usually through loss of the wild-type allele. Several years of biological investigation have firmly implicated BRCA1 and BRCA2 in double-strand DNA break repair.

....The recent discoveries described here have together exposed a clearer picture of the genetic architecture of breast cancer susceptibility. BRCA1 and BRCA2 are likely to be the only major high-penetrance breast cancer susceptibility genes, and together with other rare, high-penetrance genes, they account for approximately 20% of the familial risk of disease. The remaining susceptibility is therefore due to genes conferring more modest increases in risk. CHEK2, ATM, BRIP1 and PALB2 are breast cancer susceptibility genes that bear many biological similarities to BRCA1 and BRCA2 but confer a breast cancer relative risk of two- to fourfold. They represent the current paradigms for a second class of rare moderate-penetrance risk alleles, but it would not be surprising if other such genes exist.

As disease-causing mutations in these genes do not generally result in large pedigrees with multiple breast cancer cases, further susceptibility genes of this class will not easily be mapped by genetic linkage analysis. Moreover, because the disease-causing alleles are uncommon, it is unlikely that they will be detected by association studies. Therefore, the most effective strategy to detect this class of gene is likely to remain the systematic screening of entire genes for potential disease-causing variants (usually truncating mutations) in series of breast cancer cases compared to controls. Because the breast cancer risks conferred by these variants are only two- to fourfold and the risk alleles are rare, the numbers of subjects required in these studies are large, rendering the analyses laborious by current technology. The problem can, to some extent, be mitigated by using familial rather than population-based breast cancer cases, as even lower-penetrance breast cancer susceptibility alleles are usually enriched in familial breast cancer cases compared to nonfamilial series.