The availability and general awareness of hereditary cancer predisposition tests has grown substantially in the past several years, owing in part to the continued discovery of cancer susceptibility genes, the reversal of gene patent laws, and high-profile celebrity cases. The result is that numerous laboratories now offer genetic tests for inherited breast, colorectal, and other cancers. The types of tests offered is changing as well, due to the introduction of next-generation sequencing technologies, which allow for faster and cheaper analysis of genetic variation. The field is moving away from testing single genes and toward testing panels of genes. Recently, we have seen a nearly 10-fold drop in the cost of genetic testing. Patients with a personal or family history of cancer may be candidates for inherited cancer predisposition testing, and in time with fewer barriers to access, screening for cancer risk may spread to the general population.
Cancer is typically a late onset disease, which appears in some cases to cluster in families. For frequently occurring cancers like prostate, lung, colon, breast, and bladder, the risk to siblings of an affected patient is about two- to fourfold increased. Familial risk may reflect an inherited predisposition to cancer, but may also simply be a sign of shared environment or chance (larger families will have higher chance of a family history of cancer). The majority of cancer cases (90%) occur sporadically, the result of environment or intrinsic biological factors. Up to 10% of cancer is thought to be heritable, but the genetic basis of that heritability is complex. Much of the heritability probably reflects the combined effects of numerous low-risk variants and complex gene by environment interactions, but high-risk Mendelian (single gene) forms of cancer exist as well.
GENETIC BASIS OF FAMILIAL CANCERS
The genetic architecture of cancers is complex and only partially understood. About half of the genetic basis of familial cancers remains unexplained, leaving family history remaining as an important risk factor for some cancers. The genetic basis of breast cancer is illustrated in Figure 8-1. There are dozens of common low-penetrance genetic variants that have been robustly associated with breast cancer, but each contributing only a very small increase in risk. These common variants do not make good predictive genetic tests.
The genetic basis of breast cancer. Five to ten percent of breast cancer is thought to be hereditary, but the genetic basis of only about half of that is understood and consists of moderate to high penetrance gene variants (BRCA1/2 and other genes) and common variants of small effect.
The genetic basis of breast cancer also includes two main, highly penetrant (high risk) ...