Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Age-specific Oncogenesis: The Genetics of Cancer Susceptibility
David Malkin
Division of Oncology, Department of Pediatrics, The Hospital for Sick
Children, University of Toronto, Toronto, Ontario, Canada
Abstract
Cancer is considered to be a multifactorial disease in which a host cell
is transformed from normal to malignant as a result of complex interactions
of external (environmental) stimuli and cancer-predisposing or cancer-suppressing
genes. Although certain chemical carcinogens and ionizing radiation are
known to cause specific alterations at the level of the gene, other correlations
are less clear. Not infrequently, cancer is found to aggregate in families
in an apparently nonrandom fashion. It has been through the study of such
families that our understanding of the genetic events leading to cancer
has developed. Both common and rare tumors may occur together in familial-cancer
families. Frequently, tumors occur at an earlier age than one would expect
in the general population; often, multiple tumors of different organs develop
in a particular affected family member. Recent advances in the genetics
of familial cancer syndromes have led to the possibility to perform genetic
testing on unaffected relatives who might carry a genetic defect that predisposes
them to cancer. Complex ethical, social, and legal implications arise from
these new technical advances. -- Environ Health Perspect 103(Suppl
5):00-00 (1995)
Key words: familial cancer, Li-Fraumeni syndrome, predictive genetic
testing
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
Address correspondence to Dr. David Malkin, Division of
Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto,
Ontario, Canada M5G 1X8. Telephone (416) 813-6200. Fax (416) 813-5327.
Introduction
For many cancers, etiologic environmental associations are well documented.
The link between smoking and lung cancer is well described. It is suspected
that dietary practices have much to do with the global variation in the
incidence of carcinomas of the stomach and colon. The hepatitis B virus
and exposure to aflotoxin may be major etiologic agents for primary
liver carcinoma, and a variety of etiologic associations have been causally
associated with breast cancer. It will be noted, however, that the majority
of those cancers associated with exposures to environmental agents are typically
of adult onset. Weaker epidemiologic associations of ionizing radiation
and cancers of the hematopoietic systems and brain tumors, as well as discrepant
observations linking electromagnetic fields with leukemogenesis in
children have been made. In most instances, however, a direct correlation
between these exposures and cancer development are difficult to make.
Nonrandom aggregations of cancer have been recognized to occur since
the middle of the last century. Although almost every type of cancer has
been reported to occur in a familial form, evidence of hereditary and familial
influences exist in only a few percent of cases (1). The actual
fraction of human cancers that are due to genetic and familial factors is
not known; however, more than 100 single-gene disorders, including autosomal
dominant, recessive, and X-linked conditions have been associated with a
high risk of cancer development. Some of these phenotypes are represented
primarily by the development of cancer clustering in families, whereas in
others such as ataxia-telangectasia, cancer appears to occur as a secondary
event. In fact, as it turns out, the genetic events leading to cancer development
in this disorder may not be dissimilar from those associated with molecular
carcinogenesis in sporadic malignancies. Certain cancers, such as retinoblastoma,
a rare eye tumor of childhood, appear to arise primarily through inherited
(germline) genetic alterations that are passed from parent to child, while
others, including cancers of the lung, bladder, and oral cavity develop
as a result of interactions between intracellular acquired (somatic) genetic
changes induced by external environmental signals.
Epidemiologic studies have demonstrated that some people carry in their
genes a predisposition to develop cancer. Often this genetic predisposition
leads to an increased likelihood of suffering from a specific cancer
or group of cancers compared to the general population. Although individuals
with well-defined cancer family syndromes account for only a small
minority (perhaps 0.1% of all people with cancer), those patients belonging
to families with cancer where heredity plays some role may account for up
to 10% of all cancer. The most characteristic feature of hereditary cancers
is the tendency for their early age of onset. In addition, it is not at
all unusual to find affected children in these kindreds. In addition
to the significant questions surrounding potential detection of genetic
predisposition to cancer in individuals at high risk, the study of hereditary
cancers and cancer families has led to the detection of a class of genes
critical both in carcinogenesis and normal development (2).
Faulty regulation of cellular growth and differentiation leads to neoplastic
transformation and tumor initiation. Many inappropriately activated growth-potentiating
genes, or oncogenes, have been identified through the study of RNA
tumor viruses and the transforming effects of DNA isolated from malignant
cells. Mutations in oncogenes tend to occur in one of the two alleles of
the gene, and act in a dominant manner to the wild-type (normal) allele.
These are, in effect, "gain of function" mutations that constitutively
or permanently signal the cell to divide. Activated dominant oncogenes,
however, do not themselves readily explain a variety of phenomena related
to transformation and tumor formation. Among these are suppression of tumorigenicity
by fusion of malignant cells with their normal counterparts, tumor-associated
specific chromosome deletions, and the existence of hereditary forms
of cancer, as described above. In fact, although mutations in oncogenes
appear to arise spontaneously in somatic tissues over the lifetime of the
organism, naturally occurring inherited forms of these mutations are not
known.
Comparisons between the frequencies of familial tumors and their sporadic
counterparts led Knudson to suggest that familial forms of some tumors could
be explained by constitutional mutations in growth-limiting genes. The resulting
inactivation of these genes would facilitate cellular transformation. Inactivations
of these growth-limiting, or tumor suppressor, genes are the result either
of mutations in both alleles or a mutation in one allele followed by a loss
of, or a "reduction to homozygosity," in the second. Unlike the
dominant oncogenes, mutant tumor suppressor genes may be present in either
germ cells or somatic cells. In the former, they may arise spontaneously
in the gamete or be transmitted from generation to generation within a family.
Although studies have located the chromosomal sites of many putative tumor
suppressor genes, only a few have been isolated to date. These include the
retinoblastoma susceptibility gene (RB1), the Wilms tumor gene (WT1),
p53 in the Li-Fraumeni family cancer syndrome, genes associated with
the development of colon carcinoma [adenomatous polyposis coli (APC), mutated
in colon cancer (MCC)], and the gene associated with neurofibromatosis.
Although the function of the protein encoded by each of these genes differs,
they all share the properties associated with suppression of cell growth
and proliferation.
The paradigm for early age of onset of cancer in extended pedigrees is
the Li-Fraumeni syndrome (3). This disorder, first characterized
in 1969, is now classically represented by the presence of a proband with
sarcoma under the age of 45, a first-degree relative who develops a
sarcoma before the age of 45 years, and a second first-degree relative
with cancer of any type diagnosed under the age of 45 years. Other frequently
occurring tumors include breast cancer, acute leukemias, brain tumors, carcinomas
of the adrenal cortex, and osteosarcomas. Often it is found that affected
family members who survive their first tumor go on to develop a second
malignancy that is different in its histopathology from the first.
It is very common to discover several tumors in different affected family
members that occur at ages earlier than expected for the general population
(4). Heritable germline mutations of the p53 tumor suppressor
gene have been described in probands of Li-Fraumeni syndrome families and
both affected and young unaffected relatives (5,6). In addition,
occasional germline p53 mutations have been described in patients
not belonging to Li-Fraumeni kindreds but who have multifocal osteogenic
sarcoma, multiple primary malignancies, and to a very much lesser degree,
breast cancer. Several studies are ongoing in other populations of cancer
patients to determine the genetic heterogeneity of Li-Fraumeni syndrome,
and the high-risk cancer populations likely to harbor a genetic predisposition
to the cancers they develop.
The very high probability of developing cancer in individuals, and in
particular children, who carry germline alterations of tumor suppressor
genes has led to the possibility of predictive genetic testing in unaffected
relatives. It is now technically feasible to perform such testing in many
molecular biology laboratories worldwide. However, with the imminent identification
of many more genes for hereditary diseases, including cancer, many of which
will directly affect children, the proper use of the genetic information
in both individuals and the population is a matter of growing concern. Many
issues, such as autonomy, confidentiality, and nondiscrimination, are
generic to testing for any heritable disease. For adult-onset genetic disorders
such as Huntington's or Alzheimer's disease, the issue of testing children
is less frequently found to be at issue. However, for diseases such as cancer,
for which primary preventive measures may be available, predictive testing
of children raises important concerns (7,8).
One of the most widely discussed and evaluated testing "programs"
has been that of p53 testing in high-risk patients, including those
who belong to classic Li-Fraumeni families, those who belong to families
with cancer histories resembling this syndrome, and individuals who are
relatives of patients with characteristic features of the syndrome in the
absence of a family history of cancer. These risk groups, as examples of
children and young adults who might benefit or suffer from such testing,
are discussed in more detail elsewhere in the symposium.
I present here recommendations that should be considered in the development
of predictive genetic testing policies for cancer in children and young
adults (9):
* Predictive testing for germline mutations of genes associated with
cancer predisposition should be performed only in pilot research programs
with the availability of knowledgeable psychosocial, genetic, medical,
and oncologic counseling, as well as established molecular screening laboratories
with expertise in the interpretation of the biological significance
of observed genetic alterations.
* Within the above research settings, predictive testing should be offered
only to close relatives of cancer patients in whom a germline gene mutation
has been previously identified. Such testing should be undertaken
only after appropriate counseling on the benefits and limitations
of testing (both technical and interpretive) has been provided.
* Predictive genetic testing on cancer patients or the general population
should not be undertaken outside defined research settings; the harmful
potential of such testing far outweighs the benefits. Furthermore,
the carrier rate for most of the currently isolated cancer-predisposing
genes is demonstrably low.
* It is critical that appropriate counseling be given to carriers of
mutant genes and their relatives regarding the seeking of early medical
attention for signs and symptoms of cancer and pursuit of healthy lifestyle.
* Further study of the impact of predictive testing on children within
the limited research settings outlined above should be carried out.
There are many gaps in our knowledge of the role of genetic predisposition
in cancer development, and many drawbacks of predictive testing as it is
currently available. Nonetheless, the possibility of reducing the marked
loss of human potential resulting from the death of a child or young adult
makes pilot research efforts for early intervention in carriers of germline
mutations of cancer-predisposing genes worthwhile. Further studies into
the development of more accurate testing procedures, understanding of the
effect of germline mutations on cell transformation and tumor formation,
and perhaps the development of animal models will continue to be important.
In addition, studies of evaluation of cancer risk notification addressing
this process, the impact of knowledge, attitudes, emotions, and disease
and health status outcomes are required (10). Ultimately, one would
hope that these studies lead through screening to the early detection and
successful treatment of cancer in children and young adults.
REFERENCES
1. Knudson AG Jr, Strong LC, Anderson DE. Hereditary cancer
in man. Prog Med Genet 9:13-20 (1973).
2. Knudson AG Jr. Hereditary cancers disclose a class of
cancer genes. Cancer 63:1888-1891 (1988).
3. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast
cancer, and other neoplasms: a familial syndrome? Ann Intern Med 71: 747-752
(1969).
4. Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni
JF Jr, Li FP. Follow-up study of twenty-four families with Li-Fraumeni syndrome.
Cancer Res 51:6094-6097 (1991).
5. Harris CC, Hollstein M. Clinical implications of the
p53 tumor-suppressor gene. N Engl J Med 329:1318-1327 (1993).
6. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE,
Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH. Germline
p53 mutations in a familial syndrome of breast cancer, sarcomas and
other neoplasms. Science 250: 1233- 1238 (1990).
7. Birch JM. Germline mutations in the p53 tumor
suppressor gene: scientific, clinical and ethical challenges. Br J
Cancer 66: 424-426 (1992).
8. Lerman C, Rimer BK, Engstrom PF. Cancer risk notification:
psychosocial and ethical implications. J Clin Oncol 9: 1275-1278 (1991).
9. Li FP, Garber JE, Friend SH, Strong LC, Patinaude AF,
Fraumeni JF Jr. Recommendations on predictive testing for germline p53
mutations among cancer-prone individuals.
J Natl Cancer Inst 84:1156-1160 (1992).
10. Li FP. Genetic and familial cancer: opportunities for
prevention and early detection. Cancer Detect Prevent 9:41-50 (1988).
[
Table
of Contents]
Last Update: September 14, 1998
