Cancer Genetics Overview
Significance of the Terms Mutation and Carrier
Assumptions Concerning the Identification of People With an Increased Susceptibility to Cancer
Evaluation of Evidence
Evidence Related to the Clinical Value of Genetic Tests and Family History Information
Analytic validity
Clinical validity
Clinical utility
Genetic Counseling
Quality of Evidence
Study Populations
Evidence Related to Screening
Evidence Related to Cancer Prevention
Knowledge about cancer genetics is rapidly expanding, with implications for all
aspects of cancer management, including prevention, screening, and treatment.
PDQ cancer genetics summaries provide information on the genetics of specific cancers,
inherited cancer syndromes, and the ethical, legal, social, and psychological
implications of cancer genetics knowledge. Sections on the genetics of
specific cancers include information on the prevalence and characteristics of
cancer-predisposing mutations, the risk implications of a family history of
cancer, known modifiers of genetic risk, opportunities for genetic testing,
outcomes of genetic counseling and testing, and interventions available for
people with increased cancer risk resulting from an inherited predisposition.
Significance of the Terms Mutation and Carrier
A mutation is a change in the usual DNA sequence of a particular gene. Mutations can have harmful, beneficial
or neutral effects on health, and may be inherited as autosomal dominant,
autosomal recessive, or X-linked traits. Mutations that cause
serious disability early in life are usually rare in the population, because of
their adverse effect on life expectancy and reproduction. However, if the
mutation is autosomal recessive, that is, if the health effect of the mutation
is caused only when two copies of the mutation are inherited, carriers (healthy
people carrying one copy of the mutation) may be relatively common. “Common”
in this context generally refers to a prevalence of 1% or more. Mutations that
cause health effects in middle and old age, including several mutations known
to cause a predisposition to cancer, may also be relatively common. Many
cancer-predisposing mutations are autosomal dominant, that is, the cancer
susceptibility occurs when only one copy of the mutation is inherited. For
autosomal dominant conditions, the term carrier is often used in a different
way, to denote people who have inherited the genetic predisposition conferred
by the mutation. Detailed information on known cancer-predisposing mutations
is reviewed in relevant PDQ summaries on genetics of specific cancers.
Assumptions Concerning the Identification of People With an Increased Susceptibility to Cancer
Genetic information, including information from family history and from
DNA-based testing, provides a means to identify people who have an increased
risk of cancer. Family history often identifies people with a moderately
increased risk of cancer, and in some cases may be an indicator of the presence
of polymorphisms that influence cancer susceptibility, through
such mechanisms as changes in the rate of metabolism of agents that predispose to cancer or
catabolism of carcinogens, or effects on DNA repair or regulation of cell
division. Less often, family history indicates the presence of an inherited
cancer predisposition conferring a relatively high lifetime risk of cancer. In some
cases, DNA-based testing can be used to confirm a specific mutation as the
cause of the inherited risk, and to determine whether family members have
inherited the mutation.
Identifying a person with an increased risk of cancer can reduce the occurrence of cancer through clinical
management strategies (e.g., tamoxifen for breast cancer,
colonoscopy for colon cancer) or improve that person’s health outcome or quality of life through intrinsic benefits of the information
itself (e.g., no genetic predisposition). Intrinsic benefits may include better ability to plan for the future (having children, career, retirement or other decisions) with improved knowledge about cancer risk. Methods of
genetic risk assessment include assessment of personal and family history of disease and genetic
testing; the latter is generally undertaken only when family history of disease
or other clinical characteristics, such as early onset of cancer, indicate a
substantial likelihood of an inherited predisposition to cancer.
Genetic testing may also be sought by people affected with cancer, both newly
diagnosed individuals and survivors of earlier cancers. Testing may be desired
to define personal cancer etiology, to clarify risk to offspring, to define the
appropriateness of particular surveillance approaches, or to aid in
decision-making about risk-reducing prophylactic surgery.[1] While there are
effective interventions specific for some cancer genetic syndromes (e.g.,
multiple endocrine neoplasia type 2A [MEN 2A], familial adenomatous polyposis
[FAP], retinoblastoma [RB]), genetic testing is still being integrated into the
management of patients with hereditary forms of common cancers (e.g., breast
cancer).[2] Some patients and physicians may wish to include genetic risk
status as a factor in consideration of treatment options (refer to the
Interventions section in the PDQ summary on Genetics of Breast and Ovarian Cancer for more information).
A genetic assessment is likely to aid clinical decision-making only when
management is based on genetic information (e.g., when the clinical
interventions being considered would be offered to genetically susceptible
people but not to those of average risk, or when interventions that are
effective in people of average risk are ineffective in those with genetic
susceptibility). Intrinsic benefits of genetic information, for example,
improvement in quality of life as a result of knowledge about genetic
susceptibility, may be accompanied by potential personal and social risks as
well (e.g., reduced self-worth; guilt; family disruption; stigmatization; or
loss of health, disability, or life insurance). PDQ summaries on cancer
genetics include available evidence addressing these points. Genetic
information may sometimes provide a direct health benefit by demonstrating the
lack of a known inherited cancer susceptibility. For example, if a family is known
to carry a cancer-predisposing mutation, a family member may experience reduced
worry and lower health care costs if his/her genetic test indicates that he/she
does not carry the mutation. The family member may be able to forego certain
medical tests, such as early use of colonoscopy for persons at high risk of a hereditary nonpolyposis colon cancer (HNPCC) mutation.
Evaluation of Evidence
Creating evidence-based summaries in cancer genetics is challenging because the
rapid evolution of new information often results in evidence that is incomplete
or of limited quality. In addition, established methods for evaluating the
quality of the evidence are available for some but not all aspects of cancer
genetics. Varying levels of evidence are available for different topics, and
PDQ summaries are subject to modification as new evidence becomes available.
As in other aspects of medicine, testing and treatment decisions must be based
on information that sometimes falls short of the optimal level of evidence,
i.e., data from randomized trials.
Evidence Related to the Clinical Value of Genetic Tests and Family History Information
In assessing a genetic test (or other method of genetic assessment, including
family history), the analytic validity, clinical validity and clinical utility
of the test need to be considered.[3]
Analytic validity
Analytic validity refers to how well the genetic assessment performs in
measuring the property or characteristic it is intended to measure. In the
case of family history, analytic validity refers to the accuracy of the family
history information. In the case of a test for a specific mutation, analytic
validity refers to the accuracy of a genetic test in identifying the presence
or absence of the mutation. Analytic validity of a genetic test is affected by
the technical accuracy and reliability of the testing procedure, and also by
the quality of the laboratory processes (including specimen handling).
The evaluation of analytic validity is complex for some genetic tests. A panel
test, for example, tests for the presence of a particular set of mutations
(e.g., the known deleterious mutations in the BRCA1 gene), and the analytic
validity of the different components of the test may vary. Some genetic tests
involve the evaluation of the DNA sequence of portions of a gene, to determine
whether any mutations are present. The sensitivity and specificity of these sequencing tests may
vary with the laboratory techniques employed, the proportion of the gene
tested, and the structural nature of the mutations present in the gene.
Clinical validity
Clinical validity refers to the predictive value of a test for a given clinical
outcome (e.g., the likelihood that cancer will develop in someone with a
positive test), and is in large measure determined by the sensitivity and
specificity with which a test identifies people with a defined clinical
condition. Sensitivity of a test refers to the proportion of persons who test
positive from among those with a clinical condition; specificity refers to the
proportion of persons who test negative from among those without the clinical
condition. In the case of genetic susceptibility to cancer, clinical validity
can be thought of at two levels: (1) Does a positive test identify a person as
having an increased risk of cancer? (2) If so, how high is the cancer risk
associated with a positive test? Thus, the clinical validity of a genetic test
is the likelihood that cancer will develop in someone with a positive test
result. This likelihood is affected not only by the presence of the gene
itself, but also by any modifying factors that affect the penetrance of the
mutation, for example, the carrier’s environment or behaviors (or perhaps by
the presence or absence of mutations in other genes). For this reason, the
clinical validity of a genetic test for a specific mutation may vary in different populations. If the
cancer risk associated with a given mutation is unknown or variable, a test for
the mutation will have uncertain clinical validity.
A summary of definitions of concepts relevant to understanding clinical validity and other aspects of cancer genetics testing has been published.[4]
The test should be evaluated in the population in which the test will be used.
Evidence that mutations in a particular gene result in a cancer predisposition
often derives initially from linkage studies that use samples of families
meeting stringent criteria for autosomal dominant inheritance of cancer risk.
The demonstration of strong linkage of cancer to a pattern of autosomal
dominant inheritance supports a causal molecular mechanism for the inherited
cancer predisposition. Once linkage is established, a strong case for
association between the genetic trait and disease can be made, even though the
families used in the study are not representative of the general population.
The genetic trait measured in linkage studies is not always the causal function
itself, but may instead be a genetic trait closely linked to it. Additional
molecular studies are required to identify the specific gene associated with
inherited risk, after linkage studies have determined its chromosomal location.
Linkage studies, however, provide only limited evidence concerning either the
range of cancer types associated with a mutation or the magnitude of risk and
lifetime probability of cancer conferred by a mutation in less selected
populations. In addressing these questions, the best information for clinical
decisions comes from naturally occurring populations in which people with all
degrees of risk are represented, similar to those in which clinical or public
health decisions must be made. Thus, observations about cancer risk in
families having multiple members with early breast cancer are applicable only
to other families meeting those same clinical criteria. Ideally, the families
tested should also have similar exposures to factors that can modify the
expression of the gene(s) being studied. The mutation-associated risk in other
populations, such as families with less dramatic cancer aggregation, or the
general population, can best be assessed by direct study of those populations.
Clinical utility
The clinical utility of the test refers to the likelihood that the test will,
by prompting an intervention, result in an improved health outcome. The
clinical utility of a genetic test is based on the health benefits of the
interventions offered to persons with positive test results. Three strategies
are available to improve the health outcome of people with a genetic
susceptibility to cancer: screening to detect early cancer or precancerous
lesions, interventions to reduce the risk of developing cancer, and
interventions to improve quality of life. Evaluation of interventions should
consider their efficacy (capacity to produce an improved health outcome) and
effectiveness (likelihood that the improved outcome will occur, taking into
account actual use of the intervention and recommended follow-up). Sometimes
genetic information may lead to consideration of changes in the approach to
clinical management, based on expert opinion, in the absence of proof of
clinical utility.
Genetic Counseling
Genetic counseling has been defined by the American Society of Human Genetics
as “a communication process which deals with the human problems associated with
the occurrence or risk of occurrence of a genetic disorder in a family. The
process involves an attempt by one or more appropriately trained persons to
help the individual or family to: - comprehend the medical facts, including
the diagnosis, probable course of the disorder, and the available management;
- appreciate the way that heredity contributes to the disorder and to the risk
of recurrence in specific relatives;
- understand the alternatives for dealing
with the risk of recurrence;
- choose a course of action which seems to them
appropriate in view of their risk, their family goals, and their ethical and
religious standards and act in accordance with that decision; and
- make the
best possible adjustment to the disorder in an affected family member and/or to
the risk of recurrence of that disorder.”[5]
Central to genetic counseling
philosophy and practice are the principles of: voluntary utilization of
services, informed decision-making, nondirective and noncoercive counseling
when the medical benefits of one course of action are not demonstrably superior
to another, attention to psychosocial and affective dimensions of coping with
genetic risk, and protection of client confidentiality and privacy. Genetic
counseling generally involves some combination of rapport building and
information gathering; establishing or verifying diagnoses; risk assessment and
calculation of quantitative occurrence/recurrence risks; education and informed
consent processes; psychosocial assessment, support, and counseling appropriate
to a family’s culture and ethnicity. Readers interested in the nature and
history of genetic counseling are referred to a number of comprehensive
reviews.[6-9]
In the 1990s, genetic counseling expanded to include discussion of
genetic testing for cancer risk as more genes associated with inherited cancer
risk were discovered. Cancer genetic counseling often involves a
multidisciplinary team of health professionals who have expertise in this area.
The team may include a genetic counselor, genetic advanced practice nurse,
medical geneticist, mental health professional, and medical expert such as
oncologist, surgeon, or internist. The process of counseling may require a
number of visits in order to address the medical, genetic testing, and
psychosocial issues. Even when cancer risk counseling is initiated by an
individual, inherited cancer risk has implications for the entire family.
Because genetic risk affects biological relatives, contact with these relatives
is often essential to collect an accurate family and medical history. Cancer
genetic counseling may involve several family members, some of whom may have
had cancer, and others who have not.
Quality of Evidence
The quality of evidence depends on the appropriateness of the type of study to
the question being evaluated and on how well the study is designed and
implemented. In evaluating interventions, the strongest evidence is obtained
from a well-designed and well-conducted randomized clinical trial. Other
questions, particularly those related to the prevalence and clinical validity
of genetic information, and emotional and familial outcomes, require
well-designed descriptive studies. For some studies, particular elements of
study design, such as the nature of the population studied or the duration of
observation, may be crucial in assessing the quality of the study.
During early phases of research in a new area, information relevant to the
needs of patients and clinicians may come from work at all levels of evidence.
These include well-designed quasi-experimental (nonrandomized, controlled
single-group, pre/post, cohort, time, or matched case-control series) or
nonexperimental studies (case reports, clinical examples, qualitative or
narrative studies, or theoretical work). Such research may yield information
important to patients and clinicians who must make decisions before full data
are available on the risks and benefits of cancer genetic testing. In
addition, such work helps to focus future research using rigorous designs with
adequate statistical power.
Evidence cited in PDQ cancer genetics summaries is evaluated in terms of its quality. Where relevant, the level of evidence is cited, as
described below, or particular strengths or limitations of the evidence are
described.
Study Populations
Studies assessing the clinical validity of genetic information from
population-based data are not biased by common selection factors. The level of
evidence required for informed decision-making about genetic testing, however,
depends on the circumstances of testing. Evidence from a sample of high-risk
families may be sufficient to provide useful information for testing decisions
among people with similar family histories, but it may be insufficient to
inform early recommendations for or decisions about testing in the general
public. Even among people with similar family histories, however, other
contributing genes or different exposures could modify the effect of the
mutation for which testing is done. In evaluating evidence, the most important
consideration is the relevance of the available data to the patient for whom a
genetic assessment is being considered. In summaries addressing the cancer
risk associated with mutations and polymorphisms, the study populations used
for each risk assessment will be noted, according to the following categories.
- Population-based.
- Proxy for population-based. (The study population selected is assumed to
be generally representative of the population from which it is drawn. Example:
Persons participating in a community-based Tay-Sachs screening program, as a
proxy for persons of Jewish descent.)
- Public recruitment of volunteers, e.g., using a newspaper ad.
- Sequential case series.
- Convenience sample.
- An affected family or several families.
Evidence Related to Screening
Evidence related to screening is evaluated using the same criteria developed
for other PDQ summaries. Refer to the PDQ screening and prevention summaries
for more information.
The PDQ Cancer Genetics Editorial Board has adopted the following definitions
related to screening:
- Screening is a means of accomplishing early detection of disease in people
without symptoms of the disease being sought.
- Detection examinations, tests, or procedures used in screening are usually
not diagnostic, but sort out persons suspicious for the presence of cancer
from those who are not.
- Diagnosis of disease is made following a work-up, biopsy, or other tests
in pursuing symptoms or positive detection procedures.
Five requirements should be met before it is considered appropriate to screen
for a medical condition:[10,11]
- The medical condition being sought causes a substantial burden of suffering,
measured both as mortality and the frequency and severity of morbidity and loss
of function.
- A screening test or procedure exists that will detect cancers earlier in
their natural history than diagnosis prompted by symptoms, and is acceptable to
patients and society in terms of convenience, comfort, risk, and cost.
- Strong evidence exists that early detection and treatment improve disease
outcomes.
- The harms of screening are known and acceptable.
- Screening is judged to do more good than harm, considering all benefits and
harms it induces as well as the cost, and cost-effectiveness of the screening
program.
In order of strength of evidence, the levels are as follows:
- Evidence obtained from at least one well-designed and conducted randomized
controlled trial.
- Evidence obtained from well-designed and conducted nonrandomized controlled
trials.
- Evidence obtained from well-designed and conducted cohort or case-control
analytic studies, preferably from more than one center or research group.
- Evidence obtained from multiple-time series with or without intervention.
- Opinions of respected authorities based on clinical experience, descriptive
studies, or reports of expert committees.
Evidence Related to Cancer Prevention
Evidence related to cancer prevention is evaluated using the same criteria
developed for other PDQ summaries. Refer to the PDQ screening and prevention
summaries for more information.
Prevention is defined as a reduction in the incidence of cancer and, therefore,
cancer-related morbidity and mortality. Examples of prevention strategies are
a diet high in fiber, fruits and vegetables; regular exercise; smoking
cessation; and drugs such as aspirin and folic acid. The strongest evidence is
obtained from a well-designed and well-conducted randomized clinical trial with
cancer-specific mortality as the end point. It is, however, not always
practical to conduct such a trial to address every question in the field of
cancer prevention. For each summary of evidence statement, the associated
levels of evidence are listed. In order of strength of evidence, the levels
are as follows:
- Evidence obtained from at least one well-designed and conducted randomized
controlled trial that has:
- A cancer mortality endpoint.
- A cancer incidence endpoint.
- A generally accepted intermediate endpoint (e.g., large adenomatous polyps
for studies of colorectal cancer prevention; high-grade squamous
intraepithelial lesions of the cervix for studies of cervical cancer
prevention).
- Evidence obtained from well-designed and conducted nonrandomized controlled
trials that have:
- A cancer mortality endpoint.
- A cancer incidence endpoint.
- A generally accepted intermediate endpoint (e.g., large adenomatous polyps
for studies of colorectal cancer prevention; high-grade squamous
intraepithelial lesions of the cervix for studies of cervical cancer
prevention).
- Evidence obtained from well-designed and conducted cohort or case-control
studies, preferably from more than one center or research group, that have:
- A cancer mortality endpoint.
- A cancer incidence endpoint.
- A generally accepted intermediate endpoint (e.g., large adenomatous polyps
for studies of colorectal cancer prevention; high-grade squamous
intraepithelial lesions of the cervix for studies of cervical cancer
prevention).
- Ecologic (descriptive) studies (e.g., international patterns studies,
migration studies) that have:
- A cancer mortality endpoint.
- A cancer incidence endpoint.
- A generally accepted intermediate endpoint (e.g., large adenomatous polyps
for studies of colorectal cancer prevention; high-grade squamous
intraepithelial lesions of the cervix for studies of cervical cancer
prevention).
- Opinions of respected authorities based on clinical experience or reports of
expert committees (e.g., any of the above study designs using nonvalidated
surrogate endpoints).
References
- MacDonald DJ, Choi J, Ferrell B, et al.: Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment. J Med Genet 39 (7): 526-30, 2002.
[PUBMED Abstract]
- Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 14 (5): 1730-6; discussion 1737-40, 1996.
[PUBMED Abstract]
- Holtzman NA, Watson MS, eds.: Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task Force on Genetic Testing. Baltimore, Md: Johns Hopkins Press, 1998. Also available online. Last accessed September 16, 2004.
- Grann VR, Jacobson JS: Population screening for cancer-related germline gene mutations. Lancet Oncol 3 (6): 341-8, 2002.
[PUBMED Abstract]
- Genetic counseling. Am J Hum Genet 27 (2): 240-2, 1975.
[PUBMED Abstract]
- Baker DL, Schuette JL, Uhlmann WR, eds.: A Guide to Genetic Counseling. New York, NY: Wiley-Liss, 1998.
- Bartels DM, LeRoy BS, Caplan AL, eds.: Prescribing Our Future: Ethical Challenges in Genetic Counseling. New York, NY: Aldine de Gruyter, 1993.
- Kenen RH: Genetic counseling: the development of a new interdisciplinary occupational field. Soc Sci Med 18 (7): 541-9, 1984.
[PUBMED Abstract]
- Kenen RH, Smith AC: Genetic counseling for the next 25 years: models for the future. J Genet Couns 4(2): 115-124, 1995.
- Woolf SH: Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med 333 (21): 1401-5, 1995.
[PUBMED Abstract]
- Winawer SJ, Fletcher RH, Miller L, et al.: Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112 (2): 594-642, 1997.
[PUBMED Abstract]
Back to Top
Next Section > |