Cancer Volume 70 Issue Supplement S4 1992-- Genetic Predisposition to Breast Cancer

1747

Genetic Predisposition to Breast Cancer Mark H. Skolnick, Ph.D.,* and Lisa A. Cannon-Albright, Ph.D. t

Breast cancer is the most common cancer among Ameri- can women. Because metastatic breast cancer is an incur- able disease, efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Identification and analysis of a specific genetic susceptibility could permit detection of susceptible women and greatly increase the understanding of the initial step that eventually leads to cancer. Because susceptibility loci have been recognized as sites that often are altered during tumor progression, the identification and cloning of such loci could be important in developing cancer thera- pies. In this article, the progress being made in segregation analysis, linkage analysis, and cloning of breast cancer susceptibility loci is reviewed. The evidence for genetic inheritance is most consistent with dominant inheritance for at least three major susceptibility loci. Pro- liferative breast disease has been hypothesized to be an inherited lesion in breast cancer kindreds with both premenopausal and postmenopausal probands. Currently, there are many genetic markers for mapping the human genome, Technologic advances have progressed from restriction fragment length polymorphisms to highly poly- morphic markers. Using this technology, breast cancer susceptibility in some kindreds with an early onset has been shown to be linked to chromosome 17q. Gene isolation eventually will follow with an increased understanding of the percentage of breast cancer cases that are a result of this genetic locus. Li-Fraumeni syndrome, which often is expressed as breast cancer, is due to mutations in the p53 gene. Characterization of the syndrome and its relationship to the altered gene should proceed rapidly. There is also a group of families exhibiting a genetic susceptibility that is not due to either of these loci. Together, these findings indicate that there are at least

Presented at the National Conference on Integration of Molecu- lar Genetics into Cancer Management, Miami, Florida, April 10-12, 1991.

From the Departments of *Medical Informatics and thternal Medicine, University of Utah Medical Center, Salt Lake City, Utah.

Supported by National Institutes of Health (Bethesda, Mary- land) grants CA-28854, CA-48711, CA-42014, CN-55428, RR-64, CA-41591, AM-35378, CA40641, and CA-36362.

Address for reprints: Mark H. Skolnick, Ph.D., Department of Medical Informatics, University of Utah, 420 Chipeta Way, Room 180, Salt Lake City, UT 84108.

Accepted for publication November 15, 1991.

three separate major loci segregating for breast cancer susceptibility. With the current initiative to map and sequence the entire human genome and the advances that recently have been reported, a detailed molecular understanding of breast cancer predisposition can be envis- aged. Cancer 1992; 70:1747-1754.

Key words: breast cancer, genetic predisposition, familial cancer, inheritance.

One of the most promising approaches for understanding the cause of breast cancer and creating an effective cancer control program is by identifying women who are genetically predisposed to have this disease. How- ever, the contribution of inherited factors is not well understood. Although familial clustering of breast cancer is well known, only a few familial cases provide unambiguous support for an inherited component. However, clustering of breast cancer in families may be explained in more than one way. It has been proposed that all women are equally susceptible and resistant to breast cancer and that families with many affected members represent multiple chance occurrences of this disease. Clustering also may be a result of a risk factor that is elevated in some families. Alternatively, it has been hypothesized that some relatives have inherited a susceptibility that may or may not be expressed as breast cancer. Two factors may explain why solitary breast cancers, which are the most common, in some patients may be caused by a genetic predisposition. In some instances, women may inherit a susceptibility to a premalignant state, which itself cames only an increased probability of conversion to a malignant lesion. In other instances, their relatives with the same predisposition are of the female gender and too young to ex- press the trait as breast cancer or are of the male gender with a low probability of expression. Thus, with the exception of families with unusual clusters, familial breast cancer can be interpreted as caused by a genetic predisposition, common familial risk factors, or chance aggregation of a common disease.

Breast cancer also occurs in families with excesses of other tumors. Cowden syndrome involves multiple

1748 CANCER Supplement September 25, 2992, Volume 70, No. 6

hamartomatous lesions, especially of the skin, mucous membranes, breast, and thyroid. The Li-Fraumeni syndrome consists of a familial aggregation of breast carcinoma, soft tissue sarcomas, brain tumors, osteosarco- mas, leukemia, and adrenocortical carcinoma.' Families also have been reported to have combinations of breast and ovarian and breast and gastrointestinal cancer (especially colonic ~ a n c e r ) . ~ Unfortunately, because ascertainment of these families has not been sys- tematic, it is impossible to determine their overall contribution to breast cancer incidence or the relative frequency at each cancer site. Recently, it was shown that the Li-Fraumeni syndrome is a result of mutations of the p53 gene; this finding should permit additional genetic analy~is .~

Attempts to define the underlying genetic susceptibility precisely are complicated by the late age of the patient when the diagnosis is made, the sex specificity of breast cancer, and other competing causes of death, all of which make the normal segregation pattern of dominant and recessive genes less obvious. Many of these problems would be overcome if our analysis could be expanded to include a recognized premalignant phenotype expressed at an earlier age than overt breast cancer is. The hypothesized premalignant lesion for breast cancer is called proliferative breast disease (PBD). A study of the inheritance of PBD, breast cancer, and other associated cancers can contribute to clarifying the role of inherited factors in patients with cancer who previously were thought to have sporadic disease. Such studies also might explain the observed increased familial incidence of breast cancer in the absence of a clear Mendelian pattern.

Genetic analysis can yield a preliminary model that can be used to find linked neutral markers. This approach recently identified a susceptibility locus for early-onset breast cancer on the long arm of chromosome 17.6 Linked markers, in turn, might provide the means for additional refinement of the initial model. Linkage also permits the construction of a detailed map around the susceptibility locus. The genetic map can be complemented with a physical map. Candidate genes that lie in the mapped regions can be tested until the susceptibility locus is identified. This, in turn, would allow us to improve our estimate of a genetic model for breast cancer susceptibility. After the responsible genes have been isolated, we could study the presence of a specific mutation at a specific locus, and cancer cases that do not aggregate in families but are due to a genetic susceptibility would be recognized as such. Genetic- environmental interaction studies then could be done as case-control studies, and the function of the gene could be analyzed.

Cancer Models and Precursor Lesions

The classic model for hereditary cancer hypothesizes that the initial alteration, or the susceptibility to alteration, is inherited. This change may be responsible for the appearance of a precursor to a malignant lesion or to its promotion or progression to a malignant state. In hereditary cases, the primary event may be a mutation in a gene occurring in the ancestral germline, which is inherited by the carriers. Mutation of this gene on the homologous chromosome or in other genes important to the progression to cancer in a somatic cell then would cause malignant transformation. Not all cells transform to a malignant lesion, suggesting that, in genetically predisposed persons, although all cells may have an increased susceptibility to initiation, only some cells undergo the necessary change(s) that result in lesions. Genetic predisposition to the formation of precursor lesions could determine which ceIls become initiated and how many cells are initiated.

This model involves many genetic changes that cause alterations of one or more cellular genes affecting the cell properties associated with malignant growth. These genetic changes result in cellular changes that lead to a loss of control of cell growth and/or development; the precursor lesion then grows. Many mechanisms can be responsible for this loss of control, including activation of an oncogene, deletion or alteration of a tumor-suppressor gene, amplification or enhancement of a growth factor gene, and loss of one or more normal differentiation genes.

The theoretic basis for the hypothesized role of the premalignant lesion in carcinogenesis is the suggestion that cells and tissues exposed to carcinogens may undergo a series of changes in proliferation and differentiation, becoming more atypical at each step, with a malignant end point reached in some cells. In the multistep model, benign tumors and hyperplasias, which are steps on the pathway to cancer, are considered to be clones of intermediate cells. Agents that affect differentiation could cause increased proliferation of the intermediate cells and increase the probability of conversion to malignancy.' According to such a model, the increase seen in breast cancer rates could be explained by in- creases in "second-hit'' exposures.

The study of precursor lesions, an early event in the multistep model of carcinogenesis, has a major advan- tage over studying the fully developed cancer. Defining precursor or premalignant lesions as the abnormal trait creates an abnormal phenotype that is more frequent and more penetrant at an early age, even though other factors (both genetic and environmental) that affect the expression of a genotype can interact at any stage of carcinogenesis (Fig. 1).

Genetic Predisposition to Breast CA/Skolnick and Cannon-Albright 1749

Figure 1. Hypothesized model of the role of inherited predispositions as a cause of cancer.

GENE - ENVIRONMENT INTERACTIONS

GENES

I STAGE PREDISPOSITIO- INITIATION- PROMOTION- PROGRESSION I ENVIRONMENT

WHYDOSOME WHY ARE WWDO WHYDO INDIVIDUALS SOME CELLS SOME CELLS SOME CELLS DEVELOP DYSPLASTIC ? CONVERT ? PROGRESS ? PRECURSORS ?

Population Studies The increased risk of cancer in relatives of individuals with breast cancer has been recognized for a long time and studied e x t e n s i ~ e l y . ~ ~ ~ A standard method for detecting increased familial clustering of cancer is to identify increased rates of cancer among relatives of affected individuals. The frequency of a particular cancer among relatives of different degrees is compared with the frequency among control subjects of various types or with expected frequencies calculated from population rates. These analyses have been consistent over time; subgroups of women have been recognized who have a higher risk than the group of women with a positive family history considered as a whole.

Another method used to quantify the aggregation of breast cancer cases is the genealogic index.lO," This method examines the relationship between all possible pairs of individuals in a group and quantifies the relationships by the degree of relatedness in each pair. The degree of relatedness is measured by the Malecot coefficient of kinship." This coefficient expresses the probability that randomly selected homologous genes from two individuals are identical by descent from a common ancestor. Use of the technique requires ascertainment of all cases in a well-defined population and that the genetic relationships between all the cases are known. These requirements were met in the Utah Popu- lation Data Base (UPDB) that incorporates genealogic records with a statewide cancer registry. The use of these combined data sources allows an unbiased assessment of the degree of cancer clustering in families.

The genealogic index analysis technique involves calculating the mean kinship or relatedness of a group with a particular cancer site and then comparing that kinship with the mean kinship of a group of age- and sex-matched control subjects. Increased relatedness in

the group of patients with cancer is expressed as a higher mean kinship coefficient. Breast cancer rates in Utah are 20% lower than national rates, primarily because of an earlier average age for first full-term pregnancy. Analysis of kinship for breast cancer in the Utah population showed excess familiality. Breast cancer alone ranked high among all cancer sites for such a link, but it was lower than cancer of the prostate and lip and melanoma when each was considered separately. In addition, a high mean kinship was found for early-onset cases analyzed alone, an expected result.

Surprisingly, we also found an equally high level of kinship (significantly higher than that for control subjects) for patients whose age was older than 50 years when the diagnosis was made when they were analyzed alone. These results support the existence of more than one breast cancer gene and different causes of this disease, at least with respect to age at onset.

The genealogic index method also has been used to analyze coaggregation of cancer sites. Many cancer sites coaggregate significantly with breast cancer, many at a higher degree than those commonly reported to coaggregate in specific "syndromes." Those cancer sites that coaggregate significantly with breast cancer include (in order of mean coefficient of kinship): melanoma, prostate, ovary, skin, bladder, and lung, lymph nodes, and sites of the gastrointestinal tract and brain or central nervous system.13 These results may support the existence of syndromes similar to Li-Fraumeni syndrome, in which many sites are related to mutations at a single genetic locus. Genes related to basic cellular functions are the hypothesized causes of disease.

Segregation Analysis The traditional approach of clinical geneticists has been to collect information on families with breast cancer that have come to their attention as unusual clusters of


individual patients. These kinds of efforts traditionally have produced valuable descriptions of simple dominant or recessive traits, but they have not given us in- sight into the predisposition for this disease, which involves age and gender specificity, genetic heterogeneity, multiple loci, and probably genetic and environmental interactions. The approach is poorly suited to provide data sets that can be analyzed formally to determine the mode of inheritance, but it has been use- ful in collecting families for linkage studies. The first confirmation of the 17q breast cancer susceptibility locus came from a set of families cosegregating breast and ovarian cancers.

An important aspect of the study of breast cancer for determination of the mode of inheritance is the ascertainment of families for study and the sampling scheme used in the families studied. In a segregation study of nonrandomly chosen families, it is necessary to retain knowledge of the reason each family was chosen for study and to correct for this ascertainment event in the analysis to keep the results free from bias.I4 Ascer- tainment correction is accomplished by dividing the likelihood of the data by the likelihood of the ascertainment event for each pedigree. This correction is appro- priate for the situation in which the probability of the ascertainment event is low,l5 and it has been shown that parameter estimates in pedigree analysis are robust to a large variation in the probability of the ascertainment. Two rules for sequential sampling of pedigrees have been presented, which, if followed, will guarantee the absence of sampling-induced bias.I4 The rules require that (1) subjects to be studied may be chosen only on the basis of data already collected and (2) each sub- ject chosen must be included in the analysis. Segrega- tion analysis of families selected and sampled using these simple rules will provide bias-free estimates of model parameters. When families specifically selected for linkage studies are sampled and extended using these rules, they also may be studied for segregation and will provide accurate estimates.

Segregation analysis is a statistical method that evaluates whether the pattern of disease in a pedigree is consistent with Mendelian inheritance of a putative susceptibility gene by fitting probability models to family data. The likelihood of the observed proportion and pattern of affected members is compared with the expected according to one of several genetic hypotheses. A comparison of likelihoods associated with different parameterization of the general model leads to tests of hypotheses and identification of the most likely mode of inheritance. When an adequate correction has been applied to adjust for the manner in which the pedigrees were ascertained and extended, the results of segregation analysis in pedigreesI6 can be related back to the

reference population from which the pedigrees origi- nally were sampled.

In segregation analysis, the researcher describes the genetic model of interest. This genetic model specifies: (1) the number of loci and alleles at each of these loci, (2) the genotypic frequencies of founder members in the pedigree, (3) the segregation probabilities at the loci in question, and (4) the probability of each possible genotype given the phenotype of the individual (penetrance). Penetrances for breast cancer are age and sex specific. They also can be related to other risk factors observed, such as the age at first pregnancy.

Several investigators have examined clusters of familial breast cancer in large pedigrees. Lynch and co- w o r k e r ~ ~ , ~ characterized a subset of this disease that appears to be transmitted as an autosomal dominant trait; pedigrees were found where breast cancer coag- gregates with several other cancer sites. These authors suggest that 5% of breast cancer is autosomal dominant, 82% “sporadic,” and 13% p01ygenic.l~ A segregation analysis on a large kindred (K107).” Analysis indi- cated the most likely model was an autosomal dominant genetic susceptibility with no evidence for residual heritability. Similar results were reported in another study” that analyzed 200 Danish pedigrees selected from a population-based cancer resource. These authors concluded that the observed distribution of breast cancer was compatible with transmission of an autoso- ma1 dominant gene with no evidence for residual family resemblance. The estimated gene frequency of the abnormal allele was 0.008. The gene accounted for a significant proportion of breast cancer in young women, whereas, by an advanced age, 87% of affected women were estimated to be phenocopies. When 1579 nuclear families ascertained through a population- based series of breast cancer probands were analyzed, it was concluded that an autosomal dominant model with a highly penetrant susceptibility allele fully explained the disease clustering.20 The frequency of the susceptibility allele was estimated to be 0.0006 in the general population. The lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. When only families with probands whose ages were younger than 40 years when the disease was diagnosed were analyzed, similar results were obtained, although the oldest probands in the full data set were younger than 55 years of age. Analysis of a population-based case-control study of 4730 confirmed breast cancer cases and matched con- trols” included the cases previously examined” as a subset. Segregation analysis and goodness-of-fit tests of genetic models provided evidence for the existence of a rare autosomal dominant allele with frequency of 0.003 linked to an increased susceptibility to breast


cancer. Carriers of the allele appeared to be at greater risk than noncarriers at all ages, with the ratio of age- specific risks greatest at younger ages and declining steadily thereafter. The cumulative lifetime risk of breast cancer for women carrying the susceptibility allele was predicted to be approximately 92%; the risk for noncarriers was estimated to be approximately 10%.

Most studies of familial breast cancer emphasize its importance in the subset of women with premenopausal breast cancer. In our studies of the UPDB, however, we found that aggregation occurs in both premenopausal and postmenopausal forms.” Additional segregation analyses of breast cancer show clear evidence of single-gene inheritance patterns in families including premenopausal patients with cancer but not in those with affected postmenopausal members.’9~21~23*24

From a large series,” it was estimated that inherited susceptibility affected only 4% of families with breast cancer probands (diagnosis made before the patient was 55 years of age), including 20% of affected mother-daughter pairs and that many cases of breast cancer occurred in other families by chance. Others estimated that the proportion of cases predicted to carry the susceptibility allele was 36% among cases aged 20- 29 years; the proportion gradually decreased to 1 % among cases aged 80 years or older.’l

Although segregation analysis supports the hypothesis that the genetic predisposition to breast cancer may be a single major gene, it has been recognized that breast cancer may be more than a single disease. The different clinical and pathologic types and their different natural histories support the hypothesis of heteroge- n e i t ~ . ’ ~ Suggested differences in risk by age and lateral- ity of the proband also support this claim, which has been confirmed by the identification of two susceptibility loci that appear to be responsible for a portion of early-onset breast cancer.

PBD

Several lines of evidence suggest that precursor lesions are present in breast tissue for many years before malignant lesions appear and that women with these changes are at increased risk for cancer. ”Benign breast conditions” can be divided into nonproliferative lesions and proliferative lesions. A subset of proliferative lesions also may display cellular atypia (atypical hyperplasia), and this may convey a particularly high risk. Several cohort studies show that women with discrete suspicious lesions of the breast found to be proliferative at biopsy are at increased risk of having breast cancer compared with women with nonproliferative lesions and other benign breast diseases.z6-2s In these studies, PBD was diagnosed from cytologic material from suspi-

cious breast masses using fine-needle aspiration biopsy techniques.

This technique recently has been extended, using multiple aspirations of all four breast quadrants in an attempt to detect the precancerous lesions of PBD (ductal hyperplasia and atypical ductal hyperplasia) in breasts without masses.29 During this procedure, a 22- gauge needle is inserted into each quadrant of the breast, and the needle is redirected repeatedly to sam- ple a given quadrant broadly. All biopsy specimens are reviewed and segregated histologically into proliferative and nonproliferative lesions using an earlier classifi- cation scheme and riter ria.'^,^'

We did random fine-needle aspiration biopsies of the breasts of relatives of patients with breast cancer cases and control subjects. We evaluated first-degree relatives of affected sister-sister probands and control subjects (women who married into these families but were not related genetically). PBD was diagnosed origi- nally from breast mass lesions and defined as the presence of one or more moderately atypical or atypical hy- perplastic epithelial fragments.26 Using a cytologic defi- n i t i ~ n , ~ l we found 4 of 30 control subjects and 27 of 77 (35%) first-degree relatives had PBD (P = 0.02). Prelimi- nary pedigree analysis using the classic definition of PBD in 20 pedigrees of sister-sister or mother-daughter pairs with breast cancer provided evidence for an age- specific highly penetrant major gene for the combined PBD-breast cancer trait.32

Linkage Mapping of Genetic Predispositions to Cancer

Based on numerous advances in restriction fragment length polymorphism technique^,^^ human gene mapping has moved from a relatively unrewarding en- deavor to one where major discoveries of disease local- izations are being published every month.34 In 1980, dozens of genetic markers were available. By 1985, there were hundreds and, by 1987, more than 1000. Because of the intense effort to map and sequence the human genome, there soon will be a high density of markers that are mapped along each chromosome.

The development of the linkage map of the human genome has resulted in many successful mapping studies of rare monogenic syndromes. Although optimal strategies for mapping ”simple” phenotypes have evolved during the last 5 years, little is known about strategies for mapping more complex phenotypes.

The goal of linkage studies is to find the location of genes that determine susceptibility to the disease of interest. This is accomplished by collecting (1) pedigree information from segregating families, including genetic relationships of relatives and disease status, and


(2) marker data, which determine inheritance from par- ents to offspring at each chromosomal location. When nonrandom cosegregation of the phenotype and a marker is observed, it suggests linkage, When sufficient evidence for linkage is obtained, it may be concluded that the marker location of interest is close to the disease gene being studied.

One method used to identify linkage includes the classic approach of adding a marker to a segregation model detailing the genetics of the disease locus.35 Test- ing for linkage involves estimating the recombination fraction between the disease locus and a marker locus. The null hypothesis is free recombination between the loci (recombination = 0.5). Another approach is the affected-pair m e t h ~ d . ~ ~ - ~ ~ The basis for this method is the study of sibling concordance (sharing of alleles identical by descent). Deviations from the expected concordance imply a nonrandom association and suggest linkage, among other possibilities. The methods usually are termed ”model-free,” referring to the fact that they do not require understanding the mode of inheritance. However, these assumptions can limit the power of the method.

One of the major reasons susceptibilities to breast cancer have not been mapped is the sex and age specificity of this disease. Female members who are much younger than the median age of onset of breast cancer cannot provide linkage information because their phenotype must be considered to be ”unknown” rather than “unaffected’ if they have not had breast cancer. Likewise, male members can be considered to be gene carriers only if they both carry the gene and segregate it to at least one daughter who expresses it. The presence of PBD offers an opportunity to validate the phenotype of younger family members before the onset of breast cancer. This provides more informative members per family and the opportunity for more informative gener- ations per family. To avoid being mislead by linkage analysis that incorporates a precursor lesion, a linkage analysis that includes PBD to identify a possible location of a susceptibility locus must be confirmed by an analysis of breast cancer alone.

In parallel with the progress in molecular technolo- gies and the development of the human gene map, genetic epidemiologists have been examining the role that segregation analysis plays in mapping. Various studies have shown that resolution of the underlying genetic model is not a prerequisite to detecting linkage. When the effect of misspecifying penetrance parameters on linkage analysis was examined, it was shown that con- fusion of recessive and dominant modes of inheritance impeded identification of linkage.40 However, among dominant or recessive modes, the biases were not suffi- ciently large to preclude mapping. This principle was expanded at the Sixth Genetic Analysis Workshop. For

example, linkage was found using penetrance parameters chosen to reflect partially penetrant dominant and recessive traits.41 These authors did not do segregation analysis, and even though their models were far from the true model, they effectively extracted all the rele- vant linkage information. There was as much evidence for linkage under numerous single-locus models as with the true two-loci Contrary to previous dogma, the results of this workshop suggested that, in a complex underlying model, only by establishing linkage can the underlying model be deduced.42

Linkage Analysis of Breast Cancer

Linkage of breast cancer to AB0,43 Rh,44 and Gpt45 has been suggested. The combined Gpt LOD score indicates a lack of linkage in all families combined.46 However, under the hypothesis of heterogeneity, any of the three loci remain possibilities. Others47 did not find linkage between a breast cancer susceptibility locus and candidate oncogenes.

Recently, breast cancer susceptibility was linked in some kindreds with early-onset disease to chromosome 17q.6 This finding was confirmed in three of five kindreds with both breast cancer and ovarian cancer.48 In addition, two Utah kindreds selected for a pair of breast cancer first-degree relatives appeared to segregate a 17q linked s~sceptibility.~~

The possibility of underlying genetic heterogeneity for common diseases often dampens enthusiasm for linkage studies. Such heterogeneity does exist for breast cancer because only a subset of families with breast cancer, which have been studied for linkage to date, map to the 17q I o c u s . ~ ~ ~ ~ The p 5 3 locus includes only another small subset of patients with early-onset disease. In the face of such heterogeneity, the importance of extended pedigrees with large numbers of affected patients becomes apparent; small families are uninfor- mative in regard to linkage. Because most families selected and studied for linkage do not show either a 17q or 17p linked susceptibility, there must be at least one more breast cancer susceptibility locus.

The identification of susceptibility loci for breast cancer probably will lead to isolation of the genes. After the locus is identified, characterization of the penetrance of the locus will be straightforward as will calcu- lation of the frequency of the gene in common breast cancer. Similarly, characterization of mutations at the p53 breast cancer susceptibility locus can proceed. In identified Li-Fraumeni kindreds, all tumors and first- degree relatives of affected patients can be examined for the presence of the p 5 3 mutation. The patients with cancer and confirmed mutations can be studied to determine sex and age-specific incidence rates of all cancer sites. In addition, the penetrance of the cancer


trait can be estimated from all sampled members who carry the mutation. Heterogeneity analysis between mutations can be done. Current estimates of the probability of a family member carrying a p53 mutation and having invasive cancer are probably high because the families were selected and studied without correcting for a~certainment.~

Conclusion

We reviewed approaches to the genetic analysis of predisposition to breast cancer. Epidemiologic analysis of relative risk for those whose family members are affected has quantified this predisposition for close relatives but cannot analyze the nature of the hypothesized genetic basis. The genealogic index analysis examines this disease in a manner similar to the relative risk but is extended to genetic relationships that have a low probability of shared nongenetic risk factors. The most complex svddies, both in terms of data collection and analysis, are family studies that have led to the inference of genetic susceptibility through segregation analysis. Seg- regation analysis, in turn, has led to linkage analysis, and a gene that maps to the long arm of chromosome 17 has been identified. The p53 gene also has been identified as a second susceptibility locus. These loci define the genetic susceptibility of a subset of common breast cancer cases. These advances represent the first steps toward understanding the biologic mechanisms underlying the genetic susceptibility to breast cancer and elu- cidating how genetic susceptibility interacts with other risk factors.

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Cancer Volume 70 Issue Supplement S4 1992-- Genetic Predisposition to Breast Cancer