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Familial
Factors
Frederick P. Li,
M.D., a Mary C. Fraser, R.N., M.A. b
Most cancers are caused by a variable mix
of heredity and environment (Knudson, 1985). While an inherited defect can lead
to cancer clusters in multiple members of certain families, the age at which
cancers first appear will differ among these relatives, due in part to
environmental triggers (Li et al, 1989). Other cancers, such as lung cancers in
cigarette smokers, while caused primarily by external factors, are still
influenced by genes which modify an individual's risk of disease. To further our
understanding of cancer etiology and risk factors, scientists are currently
studying the complex ways in which genes and environment interact.
Some ethnic groups apparently possess
traits that protect them against specific cancers. For example, chronic
lymphocytic leukemia is extremely rare among Asians; Ewing's sarcoma, skin
cancers, and testicular cancer are very rare among blacks.
Family clusters have been reported for
virtually every form of cancer (Li, 1988). In general, close relatives of a
cancer patient have twice the usual risk for developing the same type of cancer,
but among different cancer families the level of excess risk can vary widely.
Familial cancer clusters are often due to inherited factors, but environmental
influences, chance association, or a combination of these factors also must be
considered. The effect of chance is considerable; within the U.S. population
there is approximately a 45 percent lifetime risk of developing cancer,
including the common nonmelanoma skin cancers (Li, 1990). Thus, it is not
unusual for most families to have at least some individuals with a history of
cancer (Mulvihill, 1985).
An inherited susceptibility often becomes
apparent when cancers of the same body site or organ occur in multiple blood
relatives (Lynch and Lynch, 1993). These cancers tend to occur at earlier ages
than usual, and often develop in more than one site in a particular organ, e.g.,
two primary breast cancers in the same breast or one in each breast. Hereditary
cancers can also arise in multiple organs, as seen in the Li-Fraumeni syndrome,
a disorder characterized by the early onset of breast cancer in mothers of
children with leukemia and/or bone and soft tissue sarcomas (Srivastava et al,
1990). In addition, cancer can occur as part of a non-cancerous hereditary
disease with diverse features, such as neurofibromatosis.
In familial cancers that are triggered by
environmental carcinogens, patient education regarding the avoidance of harmful
exposures can help prevent or delay the onset of cancer. For example, members of
melanoma-prone families who avoid significant ultraviolet radiation exposure can
reduce substantially their risk of melanoma.
Recent laboratory findings have emphasized
the importance of studying cancer-prone families (Benz, 1990). New methods in
molecular biology have been used to identify several human cancer genes and to
reveal a new class of cancer genes, called tumor suppressor genes or
antioncogenes (Friend et al, 1988). These genes normally function by inhibiting
the development of cancer. However, when they are damaged they lose their
protective effect and cancer arises with greater frequency. The first such
inherited cancer susceptibility gene to be discovered was that for
retinoblastoma (RB1), a malignant eye tumor which occurs in children (Friend,
1988).
Several additional tumor suppressor genes
have been identified, predominantly through studies of cancer-prone families
with hereditary cancers (Li, 1993). For example, inherited alterations in the
p53 gene have been found in the Li-Fraumeni Syndrome (Srivastava et al, 1990).
The WT1 gene for Wilms' tumor, the APC gene for colon cancers associated with
familial adenomatous polyposis coli, the NF1 and NF2 genes for neurofibromatosis,
types 1 and 2, the p16 gene found in some melanoma families and the VHL gene for
renal cancer and other tumors associated with von Hippel-Lindau disease have all
been recently identified and characterized (Li, in press).
Major discoveries within the last year
include the identification of BRCA1, a gene for hereditary breast and ovarian
cancer, the localization of BRCA2, another breast cancer gene, and mismatch
repair genes--such as MLH1 and MSH2 for heriditary nonpolyposis colorectal
cancer (Bronner, et al., 1994, Futreal, et al., 1994, Miki et al., 1994). (The
function of mismatch repair genes is to prevent DNA from making errors during
replication.) Approximately 5 percent of breast or colon cancer patients might
carry one or more inherited susceptibility genes. The discovery of these genes
has increased greatly the numbers of cancer susceptibility gene carriers who can
possibly be identified (Peters, 1994, Offit and Brown, 1994).
The primary purpose of identifying gene
carriers would be to promote earlier detection of cancer and, since prognosis is
correlated closely with stage of disease at diagnosis, increased survivability
(Parry et al. 1987, Wattenberg, 1993). However, identifying gene carriers in
cancer-free populations is a new concept with many clinical, ethical, legal and
psychosocial implications yet to be explored (Lerman et al. 1991, American
Society of Human Genetics, 1994, Li et al. 1992). Predisposition testing
presents certain advantages when prevention and early detection measures are
available. On the other hand, there is a great potential for harm--from loss of
insurability and employability, psychological stress, social stigmatization and
other adverse consequences. As more and more inherited susceptibility genes are
identified, their clinical relevance will require careful evaluation. The
challenge to research is to identify testing procedures and guidelines that
maximize benefits while minimizing harm (Loescher, 1995).
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a
From the Dana Farber Institute, Boston, Massachusetts
b
From the Department of Nursing, Warren G. Magnuson Clinical Center, and the
Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Maryland
National Cancer Institute
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