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Frederick P. Li, Judy E. Garber, Stephen H. Friend, Louise
C. Strong, Andrea F. Patenaude, Eric T. Juengst, Philip R. Reilly,
Pelayo Correa, Joseph F. Fraumeni, Jr.*
Almost every form of cancer in humans has been reported to aggregate
in families (1,2). These
familial clusters can be due to inheritance of a mutated cancersusceptibility
gene, though other explanations include chance association and shared exposures
to environmental carcinogens (3). In recent
years, the chromosomal locations of some cancerpredisposing
genes have been mapped by the new techniques of molecular genetics.
A few have been identified, including the hereditary retinoblastoma
(Rb) gene, WT1 gene for Wilms' tumor, neurofibromatosis type I
gene, the APC gene of familial polyposis coli, and the p53 gene
in LiFraumeni syndrome (4).
The work of the Human Genome Project (5)
will soon lead to the identification of many more genes for hereditary
diseases, including cancer. The proper use of genetic data on
populations and individuals is a matter of growing concern. Some
issues, such as autonomy, confidentiality, and nondiscrimination,
are generic to testing for any heritable disease. These broader
questions have been the subject of scholarly treatises, position
papers, and legislation (610). Other
issues are disease specific and determined by age at onset, disease
severity, availability of treatment, mendelian inheritance pattern,
and gene penetrance and expressivity (11).
To date, discussions on testing for inherited mutations in cancersusceptibility
genes have been limited, perhaps because the cancers due to these
mutations are rare (retinoblastoma and Wilms' tumor) or are preceded
by distinctive clinical manifestations (neurofibromatosis and
familial adenomatous polyposis).
Recent reports of germ line p53 mutations in families with LiFraumeni
syndrome have raised the possibility of testing at-risk relatives
who have not had cancer (12,13).
This syndrome is an autosomal dominant disorder that predisposes individuals
to multiple forms of cancer and that might serve as a paradigm
for future testing for a variety of sitespecific cancer
susceptibility genes (1215). Two workshops,
sponsored by the National Cancer Institute and the National Center
for Human Genome Research, were held in 1991 to consider recommendations
for p53 testing (16). The discussions focused
on predictive testing, which for present purposes is the use of
molecular genetic assays to detect inherited cancerpredisposing
mutations in clinically healthy individuals. Predictive testing
differs substantially from surveys of cancer patients for germ
line p53 mutations that might explain the cause of cancers that
have already developed. The participants in the workshops were
from diverse fields of study, including clinical medicine, laboratory
science, epidemiology and biostatistics, medical ethics, law,
psychology, and cancer control. The sessions were informal and
interdisciplinary. Participants shared their opinions and experiences
and were not representing the positions of any governmental, voluntary,
or private agency. Presentations and discussions covered several
broad areas: 1) LiFraumeni syndrome and its relationship
to germ line p53 mutations, 2) ethical considerations in predictive
testing for germ line p53 mutations, 3) patient selection and
the status of laboratory techniques for telling, 4) structure
and components of pilot testing programs, and 5) opportunities
for interventions and evaluation of the pilot testing activities.
Recommendations were prepared primarily by participants who volunteered
to serve on subcommittees responsible for distilling the consensus
of the meetings. The recommendations were not voted upon and have
no official status or authority. Rather, they are intended to
call attention to an emerging issue and stimulate further discussion.
Background
This syndrome was initially recognized through clinical observations
at the bedside, followed by epidemiology studies and searches
for the defective gene in the laboratory (12,14).
The syndrome is a clinical diagnosis based on the aggregation
of two or more of the six forms of cancer currently known to occur
in the syndrome. Individually, these cancers are clinically and
histopathologically indistinguishable from their counterparts
that arise in the general population. Approximately 50% of cancers
in reported LiFraumeni families occur before 30 years of
age (14). The most common childhood cancers
have been softtissue sarcomas in the first 5 years of life
and osteosarcomas in adolescence. Acute leukemia and brain tumors
also occur throughout childhood and young adulthood, whereas the
few adrenocortical carcinomas occur primarily in infancy. In young
adults, premenopausal breast cancer is, by far, the most common
neoplasm. Recent data suggest that gonadal germ cell tumors might
be a seventh component of the syndrome and the possibility of
additional component tumors cannot be excluded (15,16).
Cancer patients in these families who survive the first neoplasm
are prone to develop second cancers, particularly within the field
of radiation therapy.
In 1990, five families with LiFraumeni syndrome were reported
to show germ line mutations in the p53 gene (12).
Subsequent studies have found germ line p53 mutations in some
LiFraumeni families, but not in others (13,1720).
The discordant results could be due in part to the failure to
analyze the entire p53 gene. Another explanation is that the syndrome
is genetically heterogeneous, with p53 mutations accounting for
only a fraction of LiFraumeni families. Generally classified
as a tumorsuppressor gene, p53 is the most common site of
somatic mutations in human cancers (21).
The p53 mutations appear to be an important change in the multistep
process of carcinogenesis and, as germ line mutations, represent
a first-hit in Knudson's twomutation model of hereditary
cancer development (3). Germ line mutations
in p53 tend to occur within the conserved regions of the gene
and at codons that undergo somatic mutations in cancer cells.
Problems arise in interpreting the functional importance of germ
line p53 alterations at other codons. Linkage data on p53 mutations
in LiFraumeni families are limited. Among LiFraumeni
families with a germ line p53 mutation, the mutation has not segregated
with cancer in at least one relative (13).
In another family thought to have the clinical syndrome, evidence
for linkage with the retinoblastoma gene was reported in an abstract
(20). Clinically, the range of cancers in
the syndrome remains to be defined.
Recommendations
1) LiFraumeni syndrome is a devastating autosomal dominant
disorder of multiple cancers that are difficult to treat and often
lethal. Cancer control through prevention and early detection
should be pursued in affected families. Availability of a laboratory
test to identify carriers is an important step toward achieving
this goal.
2) Mutations in the tumor suppressor gene p53 are the most common
acquired alterations in human cancers. Germ line p53 mutations
in LiFraumeni syndrome and other rare cancer families can
be considered a biomarker of increased risk for cancer development.
3) Current understanding of LiFraumeni syndrome and its
association with germ line p53 mutations is incomplete. Additional
studies are needed of the cancer spectrum in the syndrome, the
role of environmental carcinogens in cancer development among
family members, possible genetic heterogeneity identifiable by
linkage analysis and other methods, agespecific penetrance
of the mutant gene(s), and rare p53 polymorphisms that might be
mistaken for functional mutations.
4) The deficiencies identified in recommendation 3 do not preclude
predictive testing for germ line p53 mutations in selected cancerfree
subjects. Inherited mutations at sites of somatic p53 mutations
probably convey a substantial increase in cancer risk. Knowledge
of the inherited change can be useful to patients and their physicians.
Background
Predictive testing for p53 mutations should be guided by the four
ethical principles of respect: for autonomy, beneficence, confidentiality,
and justice (69,22).
Autonomy recognizes freedom from coercion, full understanding
of the implications of an action, and respect for an individual's
right to decide about something which may have a profound effect
on his or her life. Beneficence, a fundamental principle of medicine,
is summarized by the phrase ''first do no harm." Beneficence
underlies the responsibility of investigators and counselors to
avoid harming persons who are not equipped to deal with predictive
testing results. Confidentiality requires attention to avoid inadvertent
disclosure of information to third parties. Finally, justice implies
fairness, which includes access to health care and freedom from
discrimination based on predictive testing results. These ethical
principles are applicable to p53 predictive testing in members
of families with LiFraumeni syndrome.
Recommendations
1) All persons chosen for testing on the basis of their family
histories should be given current, relevant information on the
test to make an informed voluntary decision. They should be provided
with the highest quality of information and counseling available.
2) The right to decide to undergo testing rests solely with the
individual concerned. Under no circumstances should any counselor
communicate information concerning the test and its results to
third parties without consent of either the person tested or the
parents/guardian in the case of a minor child or mentally incompetent
adult.
3) Cancers occur with high frequency among children in LiFraumeni
families, and testing these children (rather than delaying it
until young adulthood) is recommended, with the goal of reducing
cancer morbidity and mortality. As children mature, it is appropriate
to consider their assent or dissent to testing as well as their
parents' permission. Parents and investigators should develop
a plan on the timing and person(s) to convey test results to children.
4) Whereas early detection of disorders such as Huntington's disease,
for which there is no treatment, does not improve survival, early
cancer detection can substantially improve the likelihood of cure.
The decision to inform (or not to inform) health care providers
of test results should be discussed fully with the individual
before and after testing.
5) Each participant should be able to take the test regardless
of his or her financial means.
6) A participant can withdraw from the testing program at any
time before the reporting of the test result. Thereafter, the
subject should be encouraged to remain under followup observation
so that support services can be provided and the impact of testing
can be evaluated.
7) Predictive testing for germ line p53 mutations should be initiated
only after counseling and support services are established. It
may also be advisable to postpone testing applicants with evidence
of a serious current psychiatric condition.
8) Explicit compliance with ethical principles of genetic testing
should help minimize psychological, social, economic, and other
harm that might result from predictive p53 testing.
Background
Predictive testing of healthy persons is distinct from surveys
of cancer patients for germ line p53 mutations (16).
Predictive testing, as envisioned, is a sequel to these survey
studies. The purpose of surveys among cancer patients is to identify
the small subset whose disease might be attributable in part to
a germ line p53 mutation. The very low prevalence of germ line
p53 mutations in the general population precludes direct study
of unselected cancerfree subjects. Even among cancer patients,
the prevalence of germ line p53 mutations is a fraction of 1%.
Predictive testing does not pose major technical problems when
the subjects are limited to close relatives of cancer patients
found on surveys to have a germ line p53 mutation. Testing of
these relatives involves only examination for the mutation previously
detected in a family member with cancer. Current methodologies
involve use of polymerase chain reaction (PCR) to amplify the
codon(s) of interest. Although PCR artifacts or contamination
can occur, both should be detectable by repeat analyses of additional
specimens. In marked contrast, surveys for germ line p53 mutations
potentially require analyses of the entire gene, which is approximately
20 kilobases with 11 exons that encode a protein with 393 amino
acids (12). Searches for germ line p53 mutations
have largely been limited to exons 59. These exons contain
highly conserved regions with several codons that are preferred
sites for somatic mutations. Surveys for germ line p53 mutations,
most of which are point mutations, are laborious and costly. Consequently,
several gel electrophoresis methods have been used to screen blood
specimens for p53 mutations (12). The major
advantage of screening methods, such as single strand conformational
polymorphism and constant denaturing gel electrophoresis, is their
relative simplicity. Unfortunately, the sensitivity and specificity
of these gel methods in p53 screening are unknown, but both falsepositive
results and falsenegative results have been encountered.
When a shift in mobility of a DNA specimen is detected in the
gel, the presence of a mutation needs to be established by gene
sequencing.
Biostatistical issues also arise in surveys for germ line p53
mutations (16). The predictive power of
a positive test for p53 is determined by three factors: 1) the
prevalence of p53 mutations in the study population, 2) the sensitivity
(probability of detecting a true positive) of the test, and 3)
the specificity (probability of detecting a true negative) of
the test. Even when sensitivity and specificity are very high
(99%), the predictive power of a positive test is only 50% when
the prevalence of p53 mutations in the survey population is 1%;
i.e., only one half of those with a positive p53 test actually
are cancerprone individuals. The power of the test is increased
substantially by studying populations with high prevalence, preferably
greater than 10%. In predictive testing of siblings and offspring
of cancer patients with a germ line p53 mutation, the prevalence
of mutation is as high as 50%. Available data suggest that the
prevalence of this germinal mutation might be 0.01% in the general
population, 0.1%1% among various cancer patients, and 5%10%
among young patients with multiple primary cancers (16).
Recommendations
1) Predictive testing for germ line p53 mutations is technically
feasible. It should be carried out in pilot research programs
so that benefits and risks to participants can be determined.
2) Clear distinction is needed between predictive testing in healthy
individuals and surveys of cancer patients for germ line p53 mutations.
Surveys for germ line p53 mutations among select subgroups of
cancer patients, particularly those in LiFraumeni families,
should be encouraged as research activities. However, surveys
using current laboratory techniques should be recognized as laborintensive
endeavors that may yield both falsepositive and falsenegative
results.
3) To be highly accurate, predictive testing should presently
be offered only to close relatives of cancer patients whose mutant
codon in the p53 gene has been identified through surveys of affected
members of LiFraumeni families and other cancer patients.
In LiFraumeni families without a surviving cancer patient
to study for a germ line p53 mutation, atrisk relatives
can be tested after appropriate counseling on the limitations
of testing.
4) All laboratories are expected to meet high standards of accuracy.
Exchanges of blinded specimens among testing laboratories should
help maintain quality control. Laboratory researchers must also
work with counselors and other professionals providing the test
service.
5) Predictive testing and counseling should be conducted in a
research setting and should involve experts in oncology, psychiatry,
psychology, genetic counseling, medical ethics, and medical and molecular genetics. However, the DNA test center can
be at a different site from the counseling center.
6) Predictive p53 testing of the general population outside defined
research settings is more likely to be harmful than beneficial.
It is not recommended.
7) Research is needed to develop simpler, cheaper, and more accurate
methods for use in surveys for germ line p53 mutations among cancer
patients. In seeking p53 mutations, one should be cautious in interpreting changes at codons not previously
found in human cancers because some of these changes might be
polymorphisms.
Background
The most extensive experience with predictive testing relates
to Huntington's disease, an autosomal dominant trait with 100%
penetrance, variable age of onset in adulthood, and no available
treatment (7,11,23).
Initial surveys indicated that as many as 80% of individuals at
risk said they wanted the test for purposes of planning for the
future, relieving anxiety, and making childbearing decisions.
A much smaller fraction has actually been tested. To date, the
adverse effects of disclosure on the wellbeing of the patients
have been modest. They include depression, anecdotal reports of
job loss, and psychiatric hospitalization of a few patients. These
experiences with Huntington's disease have relevance to the design
of p53 testing programs. However, the two disorders differ in
clinical spectrum, age at onset, course, and opportunities for
prevention and therapy. Huntington's disease carriers are identified
by linkage analysis because the gene has not been isolated. Although
the experience with Huntington's disease testing indicates little
change in lifestyle of patients after testing, the impact of testing
might have been minimized by the support provided for participants.
We cannot assume that the impact of testing for germ line p53
mutations in less supportive environments would also have minimal
adverse effects. Predictive testing of children, as proposed herein,
has received relatively little attention in the genetics literature
(24). Testing of apparently healthy children
for a trait that might stigmatize them for a lifetime requires
adequate protections and safeguards, particularly informed consent.
Recommendations
1) Protocols and informed consent processes should be developed
and should be approved by an institutional human protection committee
before any predictive testing is initiated.
2) Test centers are encouraged to establish an outside advisory
committee of medical genetics professionals and other experts
to advise and monitor the predictive testing program.
3) According to published federal research guidelines, predictive
testing for germ line p53 mutations should be considered a procedure
involving ''minor increase over minimal risk" (25).
4) Testing should be offered to competent adults at their request,
subject to their willingness to participate in a longterm program
of genetic counseling and psychological evaluation.
5) With regard to children, parents have a legal right to act
as proxies. The decision to test children must be based on concern
for the welfare of the child to be tested, particularly the potential
impact of test results on the child's life.
6) Since our knowledge of the impact of predictive testing on
children is limited, an additional safeguard might be temporary
postponement of the testing of minors until shortterm effects
of predictive testing of adults in their families are known.
7) If they become part of the group to be examined, atrisk
children age 7 and older should be given ageappropriate
explanations of their potential participation in a predictive
testing research program. They should be asked for their decision,
and dissent of adolescents should be strongly considered. In case
of unresolvable disagreement between the minor and parents or
legal guardians, the decision on testing should be handled on
a casebycase basis, preferably with input from the
outside advisory committee and institutional ethics committee
(if available).
8) Before being tested, each candidate should provide a complete
medical and family history, undergo a physical examination and
perhaps laboratory tests, have baseline psychological testing,
and receive genetic and psychological counseling. Counseling should
encompass potential benefits and risks, including socioeconomic
discrimination, psychological distress, family disruption, and
higher insurance and medical expenses.
9) Participants should be given the option of having a partner
to accompany him or her throughout the stages of testing. The
issue of informing health care providers of test results should be determined before testing and should be reviewed at
disclosure of the result.
10) The protocol for testing should specify procedures for delivery
of results and followup, including psychological, social,
and medical evaluation and support.
11) Prenatal testing should be restricted to situations in which
one parent is known to have a germ line p53 mutation. Informed
consent for couples requesting prenatal testing should include information about uncertainties regarding penetrance,
expressivity, and age at onset. At a minimum, the potential of
present and future opportunities for early detection, treatment,
and chemoprevention should be discussed.
12) Cost of participation in testing needs to be addressed, particularly
since equal access to testing should be fundamental to these programs.
13) For the moment, predictive testing should be considered investigational,
and testing for purposes other than health care should be discouraged.
Candidates for testing should be advised to examine their insurance
status before disclosure of the results.
Background
Data suggest that gene carriers in LiFraumeni families have
a 50% likelihood of developing cancer by 30 years of age, as compared
with a 1% likelihood in members of the general population (12).
The frequency of cancer among carriers approaches 90% by 60-70
years of age. None of the component tumors in the syndrome has
a high cure rate, with the exception of early breast cancer, rare germ cell tumors of the testis, and
childhood acute lymphocytic leukemia. The prognosis of patients
with the solid tumors in the syndrome generally improves with
earlier stage at diagnosis. Among these tumors, however, only
screening for breast cancer has been shown to reduce mortality
(26). The reduction occurs primarily among
screening data to breast cancers in young women in LiFraumeni
families is uncertain. There are no proven methods of screening
for cancers in children in the general population, though studies
of neuroblastoma detection in neonates are in progress. There
is precedent for case finding of exceptionally high-risk children,
such as those with aniridia who are prone to Wilms' tumor (27,28).
Routine screening procedures in p53 carriers might include blood
cell counts and perhaps radiographic studies, but the predictive
power of the tests is unknown. Screening is further complicated
by the wide spectrum of tumor types and sites in LiFraumeni
syndrome. One option is not to perform any laboratory tests for
early cancer. At the other extreme, periodic magnetic resonance
imaging of multiple body sites might be advocated as the surveillance
procedure of choice because no radiation is delivered and small
lesions can be detected. The main drawbacks are the cost, an unknown
falsepositive rate, and lack of availability of the study.
The possibility of chemoprevention should be explored, although
the agent of choice is uncertain (29). Given
the marked loss of human potential that results from the death
of a child, pilot research protocols for early intervention in
p53 mutation carriers are justifiable. Because the effects of
testing are unlikely to be known for many years, wellcoordinated,
longterm studies are needed to assess outcomes.
Recommendations
1) An overall benefit of predictive p53 testing cannot be assumed
and should be evaluated along with harmful effects in research
protocols. Potential psychological, economic, and social benefits
to those who test negative should be weighed against the increased
distress to others who test positive.
2) The p53 carriers should be counseled to seek early medical
attention for signs and symptoms of cancer, and their changes
in patterns of utilization of health services should be evaluated.
3) Evaluation should be made of psychosocial effects, both beneficial
and harmful, that result from predictive testing. Effect of support
services to ameliorate harmful consequences should be monitored.
4) The p53 carriers should be counseled and urged to pursue a
healthier lifestyle and diet, with avoidance of cigarette smoking,
excess alcohol use, and exposures to other carcinogens; compliance
should be evaluated.
5) Pilot chemoprevention research studies should be considered
in p53 mutation carriers, such as a tamoxifen trial to prevent
breast cancer.
6) Physicians of test subjects need to be educated about the extraordinary
risk of cancer in p53 carriers, the need for confidentiality,
and the importance of attention to complaints that might be attributed
to cancer.
7) Because reduction in cancer morbidity and mortality will require
many years to evaluate, test subjects should have long-term followup.
8) Evaluation of benefits and harm will be hampered by the limited
numbers of eligible study subjects. Large effects, whether beneficial
or harmful, might be detectable with as few as 1015 subjects.
However, smaller effects are likely to require study of 100 or
more subjects. Therefore, test centers should be encouraged to
use protocols with some similar elements so that these results
can be pooled to increase statistical power.
9) Registries should be established to collect data on LiFraumeni
families and collate findings from p53 testing programs worldwide.
10) A national advisory group should be established to address
issues, such as professional and public education, that are generic
to predictive testing for mutations in cancer susceptibility genes.
Published in the Journal of the National Cancer Institute
84:1156-1160, 1992.
The contents of this report represent contributions of more than
50 investigators who participated in two workshops sponsored by
the National Cancer Institute and the National Center for Human
Genome Research, May 8-9, and November 19, 1991, in Bethesda,
Md. The authors are chairpersons of report-writing subcommittees
and meeting organizers.
F.P. Li, J.E. Garber, A.F. Patenaude, Dana-Farber Cancer Institute,
Boston, Mass.
S.H. Friend, Massachusetts General Hospital, Boston, Mass.
L.C. Strong, M.D. Anderson Cancer Center, Houston, Tex.
E.T. Juengst, National Center for Human Genome Research, Bethesda,
Md.
P.R. Reilly, Shriver Center for Mental Retardation, Waltham, Mass.
P. Correa, Louisiana State University Medical Center, New Orleans
J.F. Fraumeni, Jr., Epidemiology and Biostatistics Program, Division
of Cancer Etiology, National Cancer Institute, Bethesda, Md.
* Correspondence to: Joseph F. Fraumeni, Jr., M.D., Executive
Plaza North, Rm. 543, National Institutes of Health, Bethesda,
MD 20892.
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