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Inherited genetic factors can influence cancer risk in many ways. Tumor suppressor genes (e.g., the retinoblastoma gene) can have a strong effect on cancer risk. Such cancer susceptibility is inherited as an autosomal dominant trait, in which one altered tumor suppressor gene is inherited from a parent and one normal-functioning tumor suppressor gene is inherited from the other parent. In individuals who develop cancer, the normal-functioning gene acquires a mutation or is lost; therefore, neither gene functions normally. In the known examples of such alterations, cancer risk is greatly increased over the risk of the general population. For example, studies of very high-risk families suggest that lifetime breast cancer risk may be as high as 85% for women who carry a deleterious BRCA1 mutation.[1]
Defective DNA repair mechanisms may also increase cancer risk. When DNA repair systems are not functioning optimally, genes that control cell growth may have a greater chance of acquiring mutations that compromise their function. Cancer susceptibility inherited through this mechanism can be transmitted as an autosomal dominant trait (e.g., DNA mismatch repair (MSH2 gene) and nonpolyposis colon cancer risk).[2] Rare, autosomal recessive cancer predisposition syndromes, in which an altered gene is inherited from each parent, provide evidence that inadequate repair of exposure-induced DNA damage can substantially increase cancer risk (e.g., xeroderma pigmentosum, UV radiation exposure, and skin cancer).[3] Individuals who carry 1 copy of an altered gene, along with a normal gene, are more common in the population and may be at increased cancer risk. For example, 1% to 2% of the population may be at increased breast cancer risk because they carry a single copy of an ataxia telangiectasia gene mutation.[4] Since cancer susceptibility is increased by having only 1 copy of the gene, susceptibility is inherited as an autosomal dominant trait. Cancer risk in these individuals, however, may not be as high as in individuals who carry an altered tumor suppressor gene.
Common inherited variation in enzymes that metabolize carcinogens may also affect cancer risk. For example, glutathione S-transferase M1 deficiency, an autosomal recessive trait that nearly 50% of U.S. Caucasians have, is associated with increased lung cancer risk.[5] DNA repair proficiency and carcinogen metabolism are factors that may interact with environmental exposures to alter cancer risk. That is, certain exposures may have a lesser effect or greater effect on cancer risk in individuals, depending on each individual's ability to metabolize carcinogens or repair exposure-induced DNA damage.
1. Good estimates are needed of the risks associated with specific mutations
or types of mutations in cancer susceptibility genes. Estimates of how these
risks may differ in various populations are also needed. Almost all of the
available information is based on specific populations or families who were
selected because they have a very high incidence of cancer. For example,
breast and ovarian cancer risks associated with BRCA1 mutations have been
estimated from families selected for having a very high incidence of breast
and/or ovarian cancer.[1] The risks associated with specific mutations in
these families may differ from those found outside of such families.[2] Cancer
risks may differ because, in addition to sharing genes at a specific cancer
susceptibility locus, individuals in very high-risk families may also share
other genes and lifestyles that affect cancer risk.
In addition to estimating risks for the primary cancer(s) of interest (e.g., breast and ovarian cancer risk for BRCA1 mutation carriers), accurate risk estimates for other medical conditions (such as other cancers) are needed. For example, in addition to increased colon cancer risk, women who carry an altered MSH2 gene are at increased risk of endometrial and ovarian cancer.[3]
2. When testing the gene, it is necessary to identify which mutations are
likely or unlikely to alter an individual's cancer risk. Some mutations will
result in structurally altered proteins (e.g., mutations that produce truncated
proteins) and will almost certainly increase cancer risk. Some mutations do
not alter protein structure at all and will almost certainly not increase
cancer risk. There are other mutations, however, whose functional significance
is unknown. Definitions of "normal" and "abnormal" test results are also
necessary.
3. The cancer risk associated with a "normal" test result (no mutation
detected) should be understood. The interpretation will differ according to
the individual's family history of cancer and the recognized presence or
absence of specific mutations in her or his family. For example, if a
high-risk mutation has already been detected in a family and an individual in
that family does not have that mutation, it is very unlikely that the
individual has inherited genetic susceptibility to cancer -- he or she is
highly likely to be at average cancer risk. In contrast, if a person comes
from a family that appears to represent inherited cancer susceptibility but a
high-risk mutation has not been identified in that family, having a "normal"
test result provides that person little new information about his or her cancer
risk.
4. It is important to acknowledge that there are some mutations for which risk
information is uncertain. It is assumed that mutations occurring with cancer
in the very high-risk cancer families confer increased cancer risk. Additional
mutations that may change protein structure have been observed, however,
outside these families. It is uncertain if such mutations confer an increased
cancer risk or, if there is increased risk, what the magnitude of increase in
cancer risk will be.
5. Intervention to reduce cancer mortality should be offered to individuals
who carry a cancer susceptibility gene. Depending on the cancer site, the
following interventions are offered: early cancer detection, prevention through
prophylactic surgeries, and chemoprevention. The efficacy of these measures,
however, especially among individuals in the general population, is unproved in
many instances. Efficacy among individuals who carry cancer susceptibility
genes is largely unknown. Also, there is a practical limit to surgical
strategies for individuals at high risk for cancer in multiple organs. For
carriers of breast/ovarian cancer susceptibility genes, for example, the main
options are early detection and prevention through prophylactic surgical
procedures. It is uncertain, however, if enhanced early detection efforts will
reduce mortality. It is not clear if mammography in these high-risk women
younger than 50 years is beneficial; there is no proven early detection
strategy for ovarian cancer. A retrospective cohort study of women with a
family history of breast cancer suggests a substantially reduced risk of breast
cancer associated with having had prophylactic mastectomy.[4] (Refer to the
PDQ summary on Prevention of Breast Cancer for more information.) Tamoxifen
reduces breast cancer risk in women at increased risk, but information for
high-risk gene carriers is not yet available.[5] Another example is
chemoprevention for individuals with familial adenomatous polyposis; sulindac
reduces both the size and numbers of colorectal adenomas.[6] The long-term
risks and benefits of such therapy, however, are unknown.
6. Genetic testing for cancer risk has several unusual characteristics. This
is "predictive testing" in which the lifetime risk of developing cancer is less
than 100%. The test result may have important health and social implications
for biologic relatives, including future generations. The test result is not
modifiable (although the cancer risk associated with the test result may be)
and, therefore, cannot be used to measure the impact of preventive strategies
on risk. These characteristics raise a host of social, legal, and ethical
issues for the individuals being tested and for their relatives. These issues,
which have not yet been resolved, include difficulty obtaining insurance and
restricted educational and employment opportunities.
7. Genetic testing for cancer susceptibility must be acceptable to the public.
Members of very high-risk cancer families, as well as the general public, are
interested in genetic testing for cancer risk. It is clear, however, that
clinicians, scientists, and the general public are only beginning to understand
the limitations and social, legal, and ethical issues surrounding such testing.
It is necessary to determine what conditions/situations the public considers to
be acceptable for genetic testing. Current genetic testing strategies are
focused on genes that confer greatly increased cancer risk, sometimes referred
to as "inherited cancer" or "inherited cancer susceptibility" genes; these
genes account for about 5% to 10% of all breast and colon cancers.
8. Genetic testing protocols that are acceptable to scientists, clinicians,
and the public must be available. Like genetic testing in general, genetic
counseling is an integral part of the process of genetic testing for cancer
susceptibility. Specialists in oncology and mental health will also need to be
a part of the process.[7,8] Genetic testing protocols are being developed and
tested. Testing minors for cancer risk should be given special consideration
because minors are particularly vulnerable. Testing minors should be
considered only when it is clear that intervention will provide medical
benefits for young people.
Genetic testing is available in academic settings and through commercial laboratories for individuals at increased risk of carrying a high-risk mutation (e.g., BRCA1 and BRCA2 mutation testing in families with a high incidence of young-onset breast and/or ovarian cancer). Regardless of the setting, informed consent is an essential part of the genetic counseling and testing process. Individuals who are considering genetic testing for cancer susceptibility should be given the opportunity to consider the physical, social, and legal risks balanced against the potential benefits of genetic testing for cancer risk, including the uncertainties of the state of our knowledge of cancer risk and effective interventions.
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