Ethnic differences in cancer incidence: a marker for inherited susceptibility?

Cancer incidence varies markedly by ethnicity and geographic location. Ethnic variation in cancer occurrence has traditionally been ascribed to differences in social, cultural, economic, and physical environments. However, this interpretation of the epidemiologic evidence may need to be revised as a result of new biological evidence and theories of carcinogenesis. Carcinogenesis is now recognized to be a multistep process during which mutations or heritable changes in expression occur in genes involved in cellular growth control and genome stability. Inherited cancer susceptibility may be a stronger determinant of ethnic differences in cancer incidence than is currently appreciated. To examine the potential role of inherited susceptibility, the theoretical contribution of inherited susceptibility to ethnic differences in rates in considered using a simple probability model. Germline mutations in tumor suppressor genes BRCA1 and p53 are used to illustrate the magnitude of the ethnic differences for breast cancer that might arise from differences in inherited susceptibility. Our simple model suggests that ethnic differences in cancer occurrence can result from differences in genetic susceptibility. However, the magnitude of ethnic relative risk is likely to more strongly reflect differences in the distribution of susceptibility genotypes between groups than the magnitude of the disease risk associated with the genotypes. For many scenarios, the ethnic relative risk arising from differences in susceptibility may be bounded by the ratio of the proportion of susceptible individuals in each group.


Introduction
It has long been recognized that cancer rates show enormous variation by ethnicity and geographic location (1)(2)(3)(4). For example, rates for melanoma in whites living in Queensland, Australia, are 155-fold higher than rates for Japanese residents of northern Japan (Table 1). Blacks in the United States have a 70-fold higher incidence rate for prostate cancer compared with rates for several Asian groups. Large variations of cancer rates by ethnic group are still apparent when restricted to one geographic location, the United States (Table 2, 3), where blacks have the highest rate for all sites combined and Native Americans have the lowest rate. The variation in the United States is even greater for specific types of cancer, with some types having a 10-fold difference between ethnic groups. Rates for esophageal cancer, for example, vary from 18.9 for blacks to 1.9 for Native Americans. American females show a similar variation by ethnic group. The data indicate that the large differences in cancer rates by ethnic group are not simply a function of geography.
Explanation for Ethnic Differences in Cancer Occurrence Apparent ethnic variation in cancer incidence may arise from information bias and confounding as well as from true differences in cancer occurrence. The explanations for ethnic differences in cancer rates fall into four categories, which are based in part on lists presented in Polendak (5) and MacMahon and Pugh (6). The categories are as follows: Measurement errors: * Inadequate data-insufficient information, based upon clinical impressions, etc * Differential access to medical care and diagnostic facilities * Differences in reporting due to cultural factors or to difference in the severity of disease; differential use of available facilities * Differing fashions of diagnosis. * Coding death certification Differences between groups with respect to more directly associated demographic variables: * Differences in socioeconomic class and occupation, and secondary factors associated with these differences (see Differences in environment, below) Differences in environment: * Climatic differences and their effects * Geographic variation in disease frequency * Nutrition or diet * Differences in personal customs or habits (e.g., reproductive and nursing habits; use of tobacco and alcohol, and differences in sexual practices) * Differences with respect to social and family structure relationships, role behavior * Cultural factors * Differences related to rates of growth and development Genetic differences: * HIA dass II alleles * HLA-haplotypes * Metabolic enzyme polymorphisms * ABO blood groups Valid comparison of rates depends upon accurate diagnosis and reporting of cancer cases. Bias from measurement errors can result from differences in access to medical care and utilization of care and to differences in diagnosis and death certificate reporting, all of which probably account for a portion of the ethnic variation in cancer rates (2). The bias from measurement error is likely to be substantial and may also explain some of the international variation in cancer mortality rates. However, international standardization of registration procedures has resulted in improved data on cancer incidence worldwide (2), and it is doubtful that information bias explains much of the ethnic variation in rates calculated from data   (2).
that increase the probability of mutations in key genes in conjunction with specific  (16,(18)(19)(20). Mutations in the BRC41 gene are associated with increased risk for breast and ovarian cancer. This gene is composed of 5592 nucleotides spread over 100,000 bases of genomic DNA. It contains 22 coding exons that produce an 1863 amino acid protein, which shows no homology to any known protein except for a RING finger motif near the N-terminus. It is thought to act as a tumor suppressor gene (21).
Carriers of BRCA1 mutations are heterozygotes and have been shown to have a greater than 85% lifetime risk of developing breast cancer and 45% risk of ovarian cancer compared to a 12% risk for women in the general popualtion (22,23). The risk of breast cancer for carriers of BRCAI mutations varies by age; women 50 years of age have a 50% risk for breast cancer. The frequency of BRCA1 mutations within a population varies between ethnic groups, from 1 in > 1000 for Japanese to 1 in 100 for Ashkenazi Jews (16,19,24). Studies have also indicated that some mutations are specific for a given ethnic group, such as the 185 de/AG mutation found in the Ashkenazis (25). Differences in genotype distribution may result from differences in consanguinity, mutation rate, natural selection, and random effects such as founder effects and isolation (4).
To consider the potential contribution of genetic susceptibility to ethnic variation in cancer incidence, we used simple probability models to estimate the magnitude of cancer risk differences that might stem from ethnic differences in genetic susceptibility arising from one of the two pathways to increased risk and inheritance of mutations in a tumor suppressor gene. We assumed the simple case where risk is independent of exposure.

Methods
For populations, genetic susceptibility is defined as the proportion of the population with either germline mutations of key genes, such as oncogenes or tumor suppressor genes, or with susceptibility genotypes. The proportion with susceptibility genotypes depends on the frequency of susceptibility alleles and the functional relationship between alleles. Consider a simple model for genetic susceptibility in an ethnic population: Genetic susceptibility arises from one gene with two alleles, with one allele, N, for nonsusceptibility and the second allele, S, for susceptibility. The alleles follow Mendelian inheritance in either a dominant or recessive pattern.
The proportion of the population with susceptibility genotypes depends upon whether the susceptible allele, S, is dominant or recessive. If it is dominant, as with tumor suppressor genes, both SS and NS genotypes will be susceptible and the proportion of susceptibles in the population will be given by q (2-q), where q is the susceptible allele frequency. For the case where the susceptibility allele is recessive, only the SS genotype will be susceptible and the proportion of susceptibles in the population will be given by q2. For a susceptibility allele frequency of 10%, a dominant susceptibility allele will result in 19% being susceptible. Under a recessive model, only 1% of the population is susceptible. In the following models, the susceptible proportion will be used as the parameter for population genetic susceptibility.
In a comparison of rates in two ethnic groups, where RRe= ethnic relative risk, Ra= the disease risk in ethnic group A, and Rb= the disease risk in ethnic group B RRe = R. Rb is an accepted measure of ethnic variation in cancer risk.
In the simple case in which cancer risk is determined by inheritance of a mutation in a single tumor suppressor gene and ethnic differences in risk arise from differences in the allele distribution of this gene, the ethnic relative risk can be expressed as a ratio of disease risk between the two ethnic groups: RRe -1 P, (Rg -1) + 1 P1(Rg-1)+1 where Pa and Pb are the proportions of susceptibles in groups A and B, respectively, and Rg is the risk ratio for those with the susceptible genotype compared with those with the nonsusceptible genotype. Assumptions for this model are that baseline risks are equal in the two ethnic groups, and Rg is constant and independent of exposure or mutation spectrum. Figures 1 and 2 illustrate the general form of the relationship among RRe, Rg, and the distribution of the proportion of susceptibles. For specific examples, we chose to examine the ethnic relative risk that could arise from differences in the proportion with cancer susceptibility arising from tumor suppressor genes with dif- ferent characteristics, p53 and BRCAI. The germline mutation frequency for p53 is low, approximately i0-5, but the cancer relative risk is high, in the 104 to 105 range (26). For BRCAJ, the frequency is approximately 5 per 1000, but it has been found to show ethnic variation (16,17,25). The relative risk associated with BRCAI varies with age and is approximately 200 in women aged less than 45 years.
Results and Discussion Figure 1 shows the general relationship between the ethnic relative risk (RRe), shown on the y axis, the relative risk for susceptibility genotypes, Rg, shown on the x axis, and two pairs ofvalues for the susceptible proportions in two ethnic groups, denoted by Pa and Pb. The maximum value of the RRe will not exceed the ratio of susceptible proportions in the two groups, Pa/Pb. For example, if the proportion susceptible in ethnic group A is twice that in ethnic group B, the maximum RRe is 2. The maximum ethnic relative risk reflects the ratio of Pa and P1, not the magnitude of Rg, the relative risk for susceptibility genotypes.
Environmental Health Perspectives * Vol 105, Supplement 4 * June 1997 The rate at which the ethnic relative risk approaches its maximum value as Rg increases depends upon the magnitude of the proportion of susceptibles in the groups. To see this more concretely, consider two scenarios, both with a P4/Pb ratio of 5, as shown in Figure 1. First, in the high Pa scenario half of group A is susceptible, so Pa= 0.5 and one-tenth of group B is susceptible, so Pb= 0.1, giving a Pa,Pb ratio of 5. Second, the low Pa scenario, where P4,= 0.05 and Pb= 0.01, again a PalPb ratio of 5. As the relative risk for susceptibility genotypes increases, the ethnic relative risk increases to its maximum faster for the high Pa than for the low Pa scenario. Thus for a given susceptibility genotype, relative risk and Pa,Pb ratio, the higher the proportion of susceptibles, the higher the ethnic relative risk.
In consideration of plausible values of P4 and Pb and relative risks for susceptibility genotypes, Figure 2 shows the ethnic relative risk on the y axis and the relative risk for susceptibility genotype on the x axis. The ranges of the relative risks for the genotype and the groups proportion of susceptibles were chosen for plausible values for tumor suppressor genes p53 and BRCAL. Figure 2 shows a comparison of two ethnic groups with differing BRCA1 mutation frequencies, with RRe for a susceptible proportion of 1 in 100 versus 5 in 1000. The ethnic relative risk increases rapidly to 1.5 for a susceptibility genotype relative risk of 200. These values of the susceptibility proportion and genotype relative risks are in the ballpark for BRCAI in young women from specific ethnic groups (16,17,25). Differences in BRCAI frequency could explain ethnic relative risks for breast cancer in the 1.5 to 2 range for young women.
For a population with lower susceptibility proportions, such as that observed for germline p53 mutations, the ethnic relative risk is small for plausible relative risks for susceptible genotypes. These values are in the range observed for several tumor suppressor genes, indicating that these genes are unlikely to explain even small ethnic differences.
In summary, ethnic differences in cancer occurrence may be a marker of differences in genetic susceptibility. For breast cancer, observed differences in the frequency of BRCA1 mutations could account for ethnic differences in rates for young women. However, the magnitude of ethnic relative risk is likely to more strongly reflect differences in the distribution of susceptibility genotypes between groups than the magnitude of the disease risk associated with the genotypes. For many scenarios, the ethnic relative risk arising from differences in susceptibility may be bounded by the ratio of the proportion of susceptible individuals in each group.