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Inherited Risk Factors

Inherited factors and other gene-related influences

The primary model for explaining the origins of cancer suggests that a single cell’s DNA goes through multiple mutations over time. These mutations (changes in the nucleotide base sequence or ‘code’ of the DNA) eventually result in uncontrolled cell proliferation, the defining feature of a cancer [Hahn & Weinberg, 2002].

These mutations can be inherited and/or accumulated over the individual’s life.

DNA diagram

Figure 1. The basic structure of the DNA is comprised of a helical structure containing pairs of nucleotide bases: adenine (A) and (T) thymine are paired, as are cytosine (C) and guanine (G). The order of the nucleotide pairs determines the codes of the individual genes along the helix. Changes in the sequence of the nucleotides are called mutations.

Recent advances in the isolation and description of individual genes had led to the hope for fairly simple explanations of complex diseases like breast cancer based on a few mutations of specific gene sequences. However, only a small percentage of breast cancer cases can be attributed to primary inherited mutations. Instead, we are increasingly realizing that the role of gene function in carcinogenesis can only be understood in the context of interactions with other genes, proteins that regulate gene function, and a wide variety of environmental and hormonal factors.

Primary genetic mutations

BRCA1 and BRCA2 (‘breast cancer 1’ or ‘breast cancer 2’) are tumor suppressor genes. This means that they help cells to correct mistakes in DNA replication and therefore decrease the likelihood that a cancer will form. Mutations in these genes are often found in families in which there are multiple diagnoses of breast cancer across generations.

When BRCA1 and BRCA2 were discovered in the early 1990s, researchers believed that they had found the genetic cause of breast cancer. However, despite the importance of these mutations for women and men in which there are clusters of breast cancer cases in their families, we now understand that the vast majority of cases of breast cancer are not caused by primary inherited mutations in the BRCA genes.

Furthermore, for those people who do carry inherited mutations in these genes, only about 60-80% will develop breast cancer [King et al. 2003]. Thus, having either mutation does not mean that a person will necessarily develop the disease. Recent studies suggest that a number of other genetic, reproductive and environmental factors might influence the likelihood and the timing of breast cancer development in people who have mutations in either of the BRCA genes [Rebbeck, 2002; King et al., 2003; Palli et al., 2004].

Polygenic factors

Although most cases of breast cancer cannot be attributed to single mutations, a substantial contribution of genetic makeup may still be important in determining who develops the disease, and under what conditions. Genetic influences do not work in isolation. Polygenic effects result from the interaction of multiple gene mutations. Each of these changes, by itself, may exert only a minor detrimental effect. But together, the multiple errors may be sufficient to alter cellular proliferation and activity, leading to the development of cancer. The likelihood that particular combinations of weak genetic effects will result in breast cancer is often influenced by factors including environmental exposures [Struewing, 2004].

Epigenetic changes

Many cellular processes can lead to altered expression of genes, including those involved in carcinogenesis, without causing traditional mutations or changes in nucleotide sequences in the DNA. These changes in gene function that do not result from direct changes in DNA sequence are called epigenetic changes [Bird, 2001].

For example, chemical tags called methyl groups may bind to one of the nucleotides (cytosine). The result is that the expression of the gene containing the methylated nucleotide is altered. Recent data demonstrate epigenetic changes, including methylated nucleotides, in several genes that are involved in cell regulation from breast tumors [Tlsty et al., 2004; Hu et al, 2005].

DNA figure 2

An example of an epigenetic change: the addition of methyl groups (marker) onto cytosine, one of the basic nucleotides making up the DNA code. The addition of this methyl tag alters the expression of the gene to which it is attached.