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Are We Ready to Screen for Inherited Susceptibility to Cancer?

Are We Ready to Screen for Inherited Susceptibility to Cancer?

ABSTRACT: The discovery of inherited gene mutations that increase the risk of certain cancers could greatly expand the use of predictive genetic testing in healthy individuals. In families with hereditary forms of cancer, the use of genetic tests to determine whether family members have inherited suseptibility mutations (ISMs} may improve out come. Even within high risk families, questions remain about the role of other genetic, nutritional, and environmental factors in the development of cancer, the value of monitoring people with ISMs, and the safety and efficacy of preemptive interventions. Before screening is under taken in the general population, these questions must be addressed. Also, the frequency and penetrance of ISMs in the population at large must be determined, as well as the safety and effectiveness of screening. Lastly, mechanisms need to be established to ensure that those offered screening give full, informed, autonomous consent and that laboratories involved in testing meet quality standards. [ONCOLOGY 10(1):57-67, 1995]

Introduction

Recent discoveries of inherited mutations that increase the risk
of breast, ovarian, and colon cancers have raised expectations
that screening for those cancers will soon be possible [1,2].
Biotechnology companies and clinical laboratories are already
offering tests to predict those at risk [3-5]. The expectations
are premature. Scientists have studied these mutations in only
a small number of families; their role in the general population
is unknown. Nor is it clear whether interventions will improve
quality of life or survival in all individuals found to harbor
inherited mutations.

In this paper, I will first describe our current understanding
of positive and negative test results for inherited mutations.
I will then distinguish between testing in high-risk families
and screening the general population. Finally, I will consider
questions that should be addressed before screening is offered
routinely. The National Advisory Council for Human Genome Research
and the American Society of Human Genetics both urge that testing
for genetic predispositions to cancer, even in high-risk families,
remain investigational until many of these questions are answered
[6,7].

Interpretation of Test Results

Tests for cancer-related genes have intrinsic limitations. These
limitations result, first, from the imperfect association between
a mutation discovered by a test and the subsequent occurrence
of cancer and, second, from the inability of current tests to
detect all mutations that could lead to cancer. The former leads
to false-positive test results, the latter, to false-negatives.

Meaning of a Positive Result

Within families in which individuals are at high risk of breast
cancer [8,9], hereditary nonpolyposis colon cancer (HNPCC) [10],
or malignant melanoma [11], most, but not all, who test positive
for inherited susceptibility mutations (ISMs) will develop cancer.
In geneticists' parlance, this failure of all people to manifest
disease despite having mutant alleles in a gene dosage strongly
associated with disease is called "incomplete penetrance."
Moreover, a positive test result does not predict the "natural
history" of the disease in individuals. The age at onset
and even the tissues and organs that become cancerous in people
who have an inherited defect in the same "cancer gene"
vary. Geneticists call this "variable expressivity. "

Basis for Incomplete Penetrance--Before either familial
or sporadic cancers develop, more than one mutational event is
necessary [12-14]. Originally postulated by Knudson, it has now
been confirmed that before retinoblastoma occurs, mutations in
both alleles of the same tumor-suppressor gene are needed [15].
This finding has been extended to other familial cancers [16].
Loss of function of both alleles of a gene also has been observed
in sporadically occurring cancers of many different organs [17].

For many cancers, mutations at more than one gene locus are needed
for malignant transformation [14,18]. Inherited (germ-line) and
somatic cell mutations in three classes of genes have been found:
tumor-suppressor genes, DNA mutation repair genes, and oncogenes.
In general, harmful mutations in both alleles of the first two
classes are needed for malignant transformation [16,19], but only
one allele of oncogenes need be mutated [16]. For some cancers,
such as retinoblastoma, mutations in one class will suffice for
malignant transformation, but in others, mutations in all three
classes may be necessary.

The multihit theory at once explains why people with an ISM are
at higher risk of cancer than those who have inherited no gene
mutations and why penetrance is incomplete. In a person who has
not inherited a mutant tumor-suppressor or DNA repair allele not
only the additional mutation(s) but also the first one have to
be acquired within the same somatic cell in order to begin
the malignant process. If the chance of an acquired tumor-suppressor
mutation occurring in a cell is .00001, the chance of two susceptibility
mutations developing at the same locus in the same cell, assuming
that they are independent, is .0000000001 in people without an
ISM but .00001 in people with one. Incomplete penetrance is observed
when a person who has inherited a mutant tumor-suppressor allele
fails to acquire all of the somatic mutations needed to result
in malignant transformation.

The penetrance of an ISM depends on the number of loci at which
acquired susceptibility mutations (ASMs) are needed for malignant
transformation. When the same ISM is implicated in cancer of two
different organs, the cancer that appears first, and with greater
frequency, may be the one that requires fewer ASMs. For example,
over 10% of people with inherited retinoblastoma develop second
nonocular tumors, most commonly osteosarcoma [20]. More than the
two mutations needed for retinoblastoma may be needed for osteosarcoma.

Basis for Variable Expressivity--For virtually all of the
inherited cancers, more than one ISM has been found at each gene
locus examined so far. One mutation may totally destroy the function
of a gene, while another may only cripple it. In tumor-suppressor
and DNA repair genes, the ISM and the ASM in the homologous genes
at a single locus may occur at different positions, resulting
in a variety of effects. Different ISMs at a gene locus can influence
the occurrence of secondary tumors. Some mutations at the BRCA1
locus may be more likely than others to increase the risk of ovarian
as well as breast cancer [9,21].

Differences in the ISMs at a gene locus may also account for differences
in age of onset, response to therapy, and metastasis. It is also
possible that the same cancer could result from more than one
combination of mutated gene loci [14,16,18]. If the chance of
mutation at each of these loci is equal, the age at which cancer
appears would be younger when ASMs damage the smallest
number of genes needed for malignant transformation in people
possessing an ISM.

Although expressivity would be expected to vary among people who
inherit different mutations at the same locus, differences also
occur among people who inherit the same mutations. This is the
case for single gene disorders, such as cystic fibrosis [22],
and is even more likely when several loci must be mutated before
disease appears. Differences in genetic background, nutritional
and environmental factors, and health care all contribute to variable
expressivity.

Genetic-Environmental Interactions--Alleles at other gene
loci can modulate the effects of an ISM, as well as the carcinogenic
effects of physical and chemical agents. ISMs can do the same
thing by altering the expression of the genes in which they reside.
Carcinogenicity of external agents (some of which are mutagens)
can be influenced by a number of biochemical reactions, which
are determined by the alleles present at different gene loci.
These reactions include:

  1. DNA repair, such as in HNPCC [23], xeroderma pigmentosum [24],
    and ataxia-telangiectasia [25].
  2. Activation of mutagen precursors, as in extensive debrisoquine
    metabolizers [26], and, possibly, high inducers of aryl hydrocarbon
    hydroxylase [27].
  3. Detoxification of carcinogens, as in slow acetylators of N-substituted
    aryl compounds [26].

The traits given as examples under (2) and (3) are common polymorphisms,
each present in at least 10% of the population. There is evidence
that the 1% of the population who are ataxia-telangiectasia heterozygotes
carriers may be at increased risk of cancer from exposure to ionizing
radiation [28]. The presence of predisposing alleles at these
loci could affect both the penetrance and expressivity of ISMs.

Diet, food processing, or other environmental factors may also
alter organ involvement in people with ISMs. In the early part
of this century, gastric carcinoma, which has declined steadily
over the past 60 years [29], was the primary cancer in some families
in which HNPCC predominates today [30]. In Japan and Italy, gastric
cancer may still be the presenting cancer in some people with
HNPCC, perhaps due to dietary and food processing differences
(Henry Lynch, MD, personal communication).

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