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:
- DNA repair, such as in HNPCC [23], xeroderma pigmentosum [24], and ataxia-telangiectasia [25].
- Activation of mutagen precursors, as in extensive debrisoquine(Drug information on debrisoquine) metabolizers [26], and, possibly, high inducers of aryl hydrocarbon hydroxylase [27].
- 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).
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
