Biomedical Engineering Reference
In-Depth Information
Figure 1
. Cancer is a result of gene-environment interactions that lead to genetic mutations in pieces of
DNA that in turn lead to survival advantage. Every person inherits a different set of genes from their
parents. Some genes carry with them an inherent risk or susceptibility to cancer. Within this genetic
background, we are exposed to multiple different carcinogens in the form of diet, infections, chemicals,
radiation, etc. These exposures are processed by the body to varying extents. The carcinogen can directly
cause DNA damage, or its risk may be modulated by intrinsic modulators. For example, each person
processes the chemicals in tobacco smoke differently based on the genetic doses of modifying enzymes.
In addition, the relative risk of exposures can be altered by extrinsic modulators, such as the antioxidants
found in chemoprevention agents. Finally, the damaging factor must mutate a relevant part of the DNA.
Many mutations occur in sequences of DNA that do not provide a survival advantage but occur rather in
survival-neutral or deleterious genome sequences.
2.
CANCER RISK IN THE CONTEXT OF AN
EVOLUTIONARY PARADIGM
How then does a cancer cell evolve from a normal cell (see Figure 1). At
the most basic level, it is the potential result of an accumulation of DNA damage
that may count toward a survival advantage (2). Mutations to the genome must
occur in places where they (a) do not lead to the death of the cell, (b) do not oc-
cur in a sequence of DNA that does not change behavior, and (c) occur in a
place that conveys a growth or survival advantage. Meaningful DNA damage is
the result of gene-environment interactions on multiple levels. First, cells may
inherit "susceptibility" for damage from parental alleles. This can be at a very
recognizable and measurable level—for example, a damaged DNA repair en-
zyme in Li-Fraumeni syndrome (4). Within this genetic background, the cells
are assaulted by a variety of genome damaging exposures. These include radia-
tion, viruses, microbes, carcinogens, chemicals, hormones, and other agents too
numerous to list. But these risk factors to the genome are modulated in two im-
portant ways prior to their ability to damage the DNA.
First, the factors must pass through a phalanx of both organ- and non-organ-
specific intrinsic risk modulators. Intrinsic risk modulators are inherited traits
that do not contribute directly to DNA damage but modulate the environment to
