Genetic epidemiology of prostate cancer

Biochimica et Biophysica Acta 1423 (1998) F1^F13

Full-review

Genetic epidemiology of prostate cancer Steven Narod * Department of Medicine, Women's College Hospital, 790 Bay Street, Toronto, Ont. M5G 1N8, Canada Received 18 June 1998; received in revised form 15 October 1998; accepted 16 October 1998

Abstract A family history of prostate cancer is a consistent risk factor for prostate cancer, and can also be used to predict the presence of prostate cancer among asymptomatic men who undergo PSA screening. Approximately 5% of cases of prostate cancer have a familial component. The genetic epidemiology of prostate cancer is complex, and genes on chromosome 1 and X chromosome contribute to familial aggregation. Neither of these prostate cancer susceptibility genes have been identified, but are the subject of an active search. Hereditary prostate cancer resembles non-hereditary prostate cancer in terms of age of onset, pathologic appearance and grade. ß 1998 Elsevier Science B.V. All rights reserved. Keywords: Prostate cancer; Genetics ; Hereditary ; HPC1; Familial; Linkage analysis

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Ethnic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3. Familial aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4. Twin studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5. Case-control studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6. Cohort studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7. Segregation analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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8. Linkage studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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9. Age of onset of familial and hereditary prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . .

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10. Pathology of hereditary prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Fax: +1 (416) 351-3767; E-mail: [email protected] 0304-419X / 98 / $ ^ see front matter ß 1998 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 4 - 4 1 9 X ( 9 8 ) 0 0 0 3 0 - 4

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11. Other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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12. Association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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13. Prostate cancer progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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14. Screening for familial prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Approximately 10^15% of all cases of prostate cancer are classi¢ed as familial, meaning that the cancer patient reports at least one a¡ected relative with the same disease. Prostate cancer is common and it is possible that two or three cancers will occur in one family by chance. These cases of familial prostate cancer should be distinguished from hereditary cases; the latter category is reserved for men with a clear-cut inherited predisposition. Cases may be putatively classi¢ed as hereditary because they are from families which appear to segregate a dominant trait, because there are two or more cases of very young prostate cancer (less than 60 years at diagnosis) or because the family shows linkage to markers near the HPC1 locus on chromosome 1. There are no prostate cancer genes yet identi¢ed, so the diagnosis of hereditary cancer cannot be con¢rmed by a laboratory test. A potential susceptibility gene, HPC1, has been mapped to chromosome 1q2425. Because the risk of cancer associated with a mutation in this gene is estimated to exceed 50%, HPC1 is considered to be a major susceptibility gene. In contrast, the relative risk associated with other (minor) susceptibility genes is in the range of 2- to 5-fold. Examples of the latter class include the androgen receptor and the vitamin D receptor. Many hereditary cancer syndromes have been delineated in the recent past, and are characterized by an early age of onset, the presence of preclinical lesions, and by familial association with other cancer types. Examples include familial adenomatous polyposis (due to mutations in the APC gene) and the familial breast ovarian cancer syndrome (due to mutations in BRCA1 or BRCA2). This is not yet the

case for familial prostate cancer; no predisposing gene has yet been discovered, and there are no features which allow us to distinguish between hereditary and non-hereditary cases. Nevertheless, there has been much recent progress in our appreciation of the genetic features of prostate cancer. These advances are discussed below. It is hoped that our ability to recognize individuals at high risk for prostate cancer will facilitate targeted prevention practices, for the present including screening and, eventually, chemoprevention. 2. Ethnic studies Prostate cancer incidence rates vary markedly between ethnic groups [43]. This variation is probably due to a combination of genetic and environmental factors, although the relative contribution of each of these is so far unknown. Di¡erences in diet and other risk factors appear to explain only a small proportion of the observed ethnic variation. African-American men have the highest incidence and mortality rate of any population studied. The rates in Asian men may be 50-fold less [43]. Although prostate cancer is more frequent among African-American men, it is not known if the fraction attributable to genetic factors is higher in this group. In a study by Whittemore et al. [53] a family history of two or more a¡ected ¢rst-degree relatives with prostate cancer was associated with a higher relative risk in blacks (RR = 9.7) than in whites (RR = 3.9) or in Asians (RR = 1.6). In a second study, no di¡erences were seen in the magnitudes of the familial relative risks between blacks and whites [25]. The utilization of prostate cancer screen-

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ing in di¡erent ethnic groups may di¡er, and may in£uence the incidence rates. 3. Familial aggregation It is clear that there are rare families in which prostate cancer is a hereditary trait. Families with multiple cases of prostate cancer have been reported, including several large kindreds from Utah [5]. Gronberg et al. [20] describe a family from Sweden in which the father developed prostate cancer at age 62 and four sons later developed prostate cancer below the age of 58. No known environmental factors could account for this degree of clustering. Families with clearly dominant prostate cancer di¡er from smaller families in the characteristic age of onset of the cancers (see below). However, these large families are rare ^ much more prevalent are families with two or three cases of prostate cancer. In general, these families are not striking and may be overlooked if a family history is not taken. 4. Twin studies Other than anecdotal reports of large prostate cancer families, there are several lines of evidence which support the hypothesis that inherited factors are critical in determining prostate cancer risk. Twin studies provide some of the best evidence for a genetic component to prostate cancer. Among a registry of 4840 male twin pairs in Sweden, there were 458 cases of prostate cancers identi¢ed [19]. There were 16 concordant pairs among 1649 monozygotic twins (1.0%), but only six concordant pairs among 2983 dizygotic twin pairs (0.2%) [19]. Because it is assumed that environmental factors are similar for the twins in both groups, the di¡erence in observed concordance rates is attributed to a greater degree of shared genes in the monozygous twins. The average age in the concordant monozygous pairs was slightly younger (72.6 years) than that of the dizygous pairs (75.1 years) ^ but neither subset could be considered to be early-onset cancer. A second study conducted in the United States found similar results [42]. These authors identi¢ed 1009 twin pairs from a national twin registry, where

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at least one member had been a¡ected with prostate cancer. Among monozygous twins, 15.7% were concordant (both twins a¡ected with cancer), compared to only 3.7% for dizygous twins. 5. Case-control studies In a case-control study, the risk of cancer is compared for the relatives of men with cancer and the relatives of healthy controls. In its simplest form, prostate cancer cases and control men are asked if they have one or more relatives with prostate cancer, and the two proportions are compared. In a more elaborate design, the number of a¡ected relatives and the relationship of each to the case is also considered. Case-control studies generate an estimate of the relative risk for prostate cancer (the risk of cancer developing in a man with one or more a¡ected relatives compared to the risk in a man with no a¡ected relative). With our increasing interest in genetic factors in cancer, newer and more complex study designs have been developed. These take into account the number of a¡ected and una¡ected male relatives, the ages of onset of the cancers in these men, and the current age or age of death of the relatives. This extra detail permits the investigator to calculate the expected number of cancers in the relatives of the cases and the controls (and to compare this with the observed number). For an example of a study of this type see Foulkes et al. [15]. There have many case-control studies of prostate cancer. Almost all show that a family history of prostate cancer is an important risk factor, but the magnitude of the estimated risks varies. The risks for particular relatives may also vary between studies. If a susceptibility gene is dominant, then the relative risks for fathers and brothers should be the same. If the susceptibility gene is recessive, then the relative risk for brothers should exceed that of the father (or son). If the susceptibility gene is X-linked (i.e. on the X chromosome), then the risk for the mother's brothers should exceed that for the father's brothers. Many studies to date have distinguished between risks in fathers and brothers, and between fathers and uncles, but none have discriminated between maternal and paternal relatives.

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This may be important if X-linked inheritance is to be evaluated. In a case-control study, the information about family history is usually made after the case is informed of his diagnosis. This introduces two potential weaknesses. The history of prostate cancer in family members is based on the recollection of the index patient, and the cancer in the relative is rarely con¢rmed by a pathology report. Reported histories of prostate cancer in second-degree relatives tend to be inaccurate. Prostate cancer patients may be more likely to be aware of the diagnosis of prostate cancer in relatives, may be more diligent in their search for additional cases, or may be more likely to misinterpret benign disease as cancer, than are healthy controls. The e¡ect of this recall bias will be to increase the magnitude of the relative risks associated with a family history, especially for second-degree relatives, where the information is weaker. The second concern is that the history of cancer in a man may prompt a screening test in a relative and thereby lead to his diagnosis. This detection bias is less a concern for cases ascertained prior to the 1990s. In a large case-control study (691 cases) a relative risk of 3.0 was found for brothers of men with prostate cancer, 2.0 for fathers, 1.9 for grandfathers and 1.7 for uncles [51]. The odds ratio for a ¢rst-degree relative, 2.1, was not much di¡erent from the odds ratio for a second-degree relative (1.8). For both dominant and recessive genetic diseases, the attenuation of relative risk between ¢rst- and second-degree relatives should be greater than this. Furthermore, the frequency of prostate cancer was reported to be 7.5% in the fathers of una¡ected controls but only 2.7% in uncles of controls. The di¡erence in these two estimates is likely due to recall bias. Keetch et al. [31] compared family histories of prostate cancer in 1084 consecutive incident cases of prostate cancer and 935 spouse controls. They found the risk was highest if the brother had prostate cancer (relative risk 4.7) followed by fathers (3.5), uncles (2.7) and grandfathers (2.5). Again, because the risk ratios are similar for a¡ected fathers and uncles, the possibility of recall bias must be considered. Fincham et al. [14] studied 382 incident cases of prostate cancer in the Alberta Cancer Registry. They found a relative risk of 3.1 for prostate cancer in the

father, compared to 3.3 for cancer in a brother. Both risks were signi¢cant at the level of P = 0.01. In a second Canadian population-based case-control study (640 cases, 639 controls) the relative risk for any a¡ected ¢rst-degree relative was 3.3 [16] and was not di¡erent for fathers or brothers. Not all studies of prostate cancer have concluded that the data best ¢t a dominant model. In several studies, the risk for brothers was found to be greater than the risk for sons or fathers of cases. This is consistent with a recessive, or X-linked component to prostate cancer inheritance. In 1960, Woolf [61] studied familial risks of prostate cancer in Utah. Deaths from prostate cancer among 228 cases and their relatives were identi¢ed by review of Utah State vital statistics records, thereby eliminating the possibility of recall bias. The observed numbers of deaths were compared to the expected number based on rates from the Utah State Bureau of Vital Statistics and to deaths in a control group. There were 12 deaths from prostate cancer among brothers of prostate cancer cases, compared to 4.3 expected (RR = 2.81; P = 0.002), and 3 deaths in fathers compared to 2.4 expected (RR = 1.25; not signi¢cant). In this study, bias was avoided by using the Utah Registry to identify cancer in relatives, rather than relying on patient recall. It is also possible to avoid recall bias if the family history of prostate cancer is taken before the diagnosis is made, e.g., in the interval between the report of an elevated PSA and the diagnostic biopsy. Narod and colleagues [40] recorded prostate cancer family histories from 6390 men attending a screening clinic in Quebec City. Family histories were taken prior to screening, and recall bias was not possible. Prostate cancer was found in 10.2% of subjects who reported a brother a¡ected; this number was 2.6 times higher than that for men with no reported a¡ected relative. The corresponding relative risk for men with an a¡ected father was only 1.2. Monroe and colleagues [39] studied a population-based cohort of blacks, whites, Japanese and Hispanics and found that the relative risk for prostate cancer was approximately two-fold larger if the brother was a¡ected than if the father was a¡ected. This was true for all four ethnic populations. Greater relative risks for brothers were also found in case-control studies by Whittemore et al. [53] and by Hayes et al. [25] and Lesko et al. [34].

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In the study of Lesko et al. [34] the relative risk of cancer increased with the number of relatives affected, and with an early age of onset of the proband. The association was particularly strong for case diagnosed before age 60 (relative risk 5.9). Linkage studies have con¢rmed that prostate cancer is a genetically heterogeneous disease. It is possible that some of the susceptibility genes act in a dominant fashion and that others are X-linked or recessive. It will be very di¤cult to con¢rm such complex inheritance on the basis of pedigree study alone and it is hoped that molecular studies will resolve this issue. A few case-control studies have extended the clinical phenotype to include the presence of benign prostatic disease or measurement of serum hormones. Narod et al. [40] observed an increase in the frequency of abnormal rectal examinations in the relatives of prostate cancer patients. The exact nature of these lesions was unclear, but a proportion of these were likely to be cases of benign prostatic hyperplasia. A second study reported that a family history of prostate disease (cancer or hyperplasia) was more frequent in relatives of men with benign hyperplasia (20%) than in relatives of men with prostate cancer (12.8%) or in healthy controls (5.1%) [46]. These results suggest that common genetic mechanisms may predispose to benign and malignant prostate disease. Meikle et al. [38] investigated serum levels of androgens, estrogens and sex hormone binding globulin in prostate cancer cases, brother-in-law controls, and their sons. The cumulative incidence of prostate cancer was four times greater in the brothers of cases than expected. Interestingly, sons of cases had signi¢cantly reduced levels of testosterone and dihydrotestosterone compared to sons of controls. These observations need to be extended to other populations. 6. Cohort studies Goldgar et al. [18] performed a historical cohort study among the Mormon population of Utah. They calculated the observed and expected numbers of cancer in the relatives of probands with cancer at 28 speci¢c cancer sites. The relative risk for prostate cancer for ¢rst-degree relatives of 6350 prostate can-

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cer patients was 2.2, and was 4.1 for relatives of probands diagnosed before age 60. One of the best studies to date detailing prostate cancer familial risks is a recent historical cohort study from Sweden. Gronberg et al. [20] identi¢ed 8515 men with prostate cancer reported to the Swedish Cancer Register from 1959 to 1963. Information about the nuclear families was available from parish records. 5496 sons of these cases were identi¢ed, of whom 304 also had prostate cancer. Based on the ages of the sons, only 178 cases were expected. Overall, the relative risk was 1.70 (95% CI 1.51^1.90). The relative risk declined with increasing age of cancer in the father. This elegant study has many strengths ^ it is population-based and nationwide, the expected number of cases could be accurately estimated and the diagnosis of prostate cancer was con¢rmed with registry records. 7. Segregation analysis Twin studies and case-control studies support the importance of genetic factors in prostate cancer development, but cannot be used to infer the genetic mode of transmission. Results from family studies of prostate cancer have not led to a consistently favored genetic model. Several studies have suggested that prostate cancer susceptibility is best modelled as a dominant trait, and in other studies a recessive (or X-linked) mode is favored. A segregation analysis was performed on the set of families studied by Steinberg and colleagues [51]. This analysis led these investigators to conclude that prostate cancer inheritance best ¢t an autosomal dominant model, where a rare susceptibility gene (gene frequency 0.0033) with a high lifetime penetrance was transmitted [6]. The gene was thought to be the cause of 9% of prostate cases occurring before the age of 80 years. The average age of diagnosis of prostate cancer in this data set was atypically young (59 years). A second segregation analysis was performed on families of unselected Swedish prostate cancer patients [23]. These were all nuclear families, including an a¡ected father and his (a¡ected or una¡ected) sons. The data also ¢t a dominant model. However, in this study, information was not collected on the

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brothers of the probands and so it was not possible to compare the risks for brothers and sons directly. Recently, Schaid et al. [45] performed a segregation analysis on a sample of 5486 men who underwent a radical prostatectomy at the Mayo Clinic from 1966 to 1995. The data best ¢t a model of a rare autosomal dominant gene. The model predicted a gene frequency of 0.006 and a penetrance to age 85 of 89%. However, the patterns of inheritance were not completely explained by this model; the cancer risk was 1.5 times greater for brothers of probands, compared to fathers of probands (P = 0.0001). 8. Linkage studies It is challenging to study the genetic basis of prostate cancer by linkage analysis. Prostate cancer typically occurs at a late age, and it is rare to have DNA available from living a¡ected men for more than one generation. Prostate cancer is common and sporadic cases (phenocopies) may exist in families alongside hereditary ones. The ¢rst chromosomal localisation of a gene for prostate cancer was reported in 1996 [49]. Isaacs and his colleagues [29] identi¢ed a cluster of linked markers on chromosome 1q which de¢ned the locus of a prostate cancer susceptibility gene. This unidenti¢ed gene, named HPC1, accounted for 34% of a panel of 66 North American pedigrees with three or more men a¡ected with prostate cancer. These authors estimate that one in 170 men might carry a predisposing mutation. About one-half of the evidence in favor of linkage was derived from a few African-American families. A re-analysis of this data set showed that the positive evidence for linkage came from families with an average age of onset of less than 65 years of age [21]. Shortly after, Cooney et al. [9] con¢rmed the presence of the chromosome 1q prostate cancer susceptibility gene in a linkage study of 59 prostate cancer families. The overall evidence for linkage in this study was weak by conventional standards, but helped con¢rm the presence of the hypothetical gene. In this study, the African-American families also contributed disproportionately to the linkage. Hsieh et al. [26] also found modest evidence for linkage in a panel of 92 prostate cancer families from the western United States and Canada.

There have been four negative linkage studies as well. McIndoe et al. [36] excluded the region of HPC1 in a panel of 49 North American prostate cancer families. Eeles et al. [12] studied 76 families with three or more cases of prostate cancer from Canada, the United Kingdom and Texas, and found no signi¢cant evidence of linkage to the HPC1 locus. An additional 60 families with two a¡ected men were studied and no evidence of linkage was seen. Thibodeau et al. [59] studied 166 families from the Mayo Clinic Database, each with three or more cases of prostate cancer. No evidence of linkage was found to the HPC1 locus. Recently, a European prostate consortium found evidence of linkage for a set of prostate cancer families to a second locus on chromosome 1q42 [3]. This region is 60 centiMorgans from the estimated position of the HPC1 gene. These families were of French or German origin. The evidence in favor of linkage was marginal, the maximal two-point lod score was 2.7. It was estimated that 50% of the families were linked to this locus. However, nine families with early onset prostate cancer (average age less than 60) gave a multipoint lod score of 3.3. This group found no evidence of linkage to the region of HPC1. Because the genetic distance between HPC1 and the second chromosome 1q prostate cancer locus is large, it appears to be unlikely that both groups have identi¢ed linkage to an intermediate locus. The case-control studies and segregation analyses reported to date have generated mixed results in terms of absolute risks and the favored genetic models. It appears that aggregated data cannot be explained entirely by a single gene model, i.e. it is more likely that there is a mixture of family types, due to a small number of genes with di¡erent e¡ects. In particular, several studies indicate that the risk for brothers is higher than that for fathers of prostate cancer cases. This raises the possibility of an Xlinked component to prostate cancer susceptibility ^ this possibility has now been tested formally by linkage analysis [62]. This international group studied 360 families with multiple cases of prostate cancer, collected from the USA, Finland and Sweden. Evidence for a susceptibility locus on the X-chromosome was demonstrated. Assuming homogeneity (all families linked to the same gene) a maximum

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lod score of 4.6 was obtained for the marker DXS1113. The proportion of linked families was estimated to be 16%. Interestingly, there was positive evidence for linkage in families both with and without male-to-male transmission. In summary, although there is inconsistency across studies, the overall evidence is su¤cient to establish the presence of two, and possibly three prostate cancer susceptibility genes. The exact proportion of prostate cancer families attributable to each of these genes is unknown. Further molecular studies will delineate if, in fact, two prostate cancer genes exist on chromosome 1q. It will also be important to type a large number of families with markers at all loci. If multiple susceptibility genes are present, then families which generate negative lod scores at two loci should be enriched for linkage to the third. It is also possible that the X-linked locus is a genetic modi¢er of cancer risk among carriers of mutations in HPC1. 9. Age of onset of familial and hereditary prostate cancer In many hereditary cancer syndromes, the age of cancer onset is much younger than that of the sporadic, or non-familial cancers. This is clearly the case for hereditary breast and colon cancer, but is not apparent for familial prostate cancer. Screening practices in£uence the age at which prostate cancer is diagnosed, and it is di¤cult to de¢ne the age-of-onset of cancer in an individual, or to compare ages between two studies. The diagnosis of prostate cancer is rarely made because of symptoms due to cancer; more commonly the diagnosis is made when a man undergoes a prostatectomy for symptoms of benign hyperplasia (and malignant cells are found) or due to an elevated PSA or abnormal rectal exam. Men with a family history of cancer may be more likely to request screening than men with no a¡ected relative. Age-of-onset estimates are also subject to ascertainment bias. Families may be selected for study on the basis of early-onset cancer. A second problem may arise because all relatives included in the estimate are not followed until death. For example, a man may have a brother, aged 60. If the brother has prostate cancer he will be considered to be a familial

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case and his age of diagnosis will be used to generate the mean for the a¡ected men. However, the brother may develop prostate cancer at age 70, but this late onset-cancer will not be included in the age-of-onset calculation. For this reason, it is important that results of age-of-onset be adjusted for the current ages of the relatives. In general, cumulative incidences are adjusted for follow-up, but mean ages are not. The ages of onset in families with two or three cases of cancer do not appear to be much younger than expected. There is, however, evidence that cases of hereditary cancer occur earlier than expected. Cannon et al. [5] found the relative risk increased with decreasing age of the proband. Carter et al. [7] calculated the cumulative incidence of prostate cancer in the ¢rst-degree relatives of 691 men with prostate cancer. The cumulative risk was signi¢cantly greater for men who were a¡ected below 53 years, compared to 53 years or above. In the segregation analysis based on this data set the probability of an a¡ected man carrying the putative susceptibility allele was greater for men diagnosed with prostate cancer at a young age. In a study from Sweden it was found that hereditary prostate cancer appears at about six years younger than non-familial cancer [20]. In a later study, with chromosome 1q markers, Gronberg and colleagues [22] compared 133 cases of prostate cancer from 22 families which were potentially linked to HPC1 with 172 men from 41 apparently unlinked families. A modest di¡erence in age-of-onset was noted; the age of diagnosis was two years lower for the men from the HPCA1-linked families. 10. Pathology of hereditary prostate cancer In many hereditary cancer syndromes there are characteristic pre-neoplastic lesions. For example, multiple adenomatous polyps precede the diagnosis of frank colon cancer in patients with familial adenomatous polyposis. In some cases hereditary cancers have a di¡erent spectrum of histology than nonhereditary ones. For example, breast tumors associated with BRCA1 mutations are almost always of high grade [4]. However, there is no clear benign precursor for hereditary prostate cancer, and familial cancers do not appear to be systematically di¡erent

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from sporadic ones [2]. Hereditary and familial prostate cancers do not show an increased frequency of associated prostatic intra-epithelial neoplasia [2]. The small amount of data about cancers from men from HPC1-linked families suggests that these are more likely to be of high grade and to present with disease which has spread beyond the prostatic capsule [22].

Cancer Registry containing four sons with early onset prostate cancer. It is of interest that three of the four daughters were a¡ected with early-onset breast cancer. To date, no BRCA1 or BRCA2 mutation has been identi¢ed in this family.

11. Other cancers

Because of the inherent di¤culties in using linkage analysis to study prostate cancer susceptibility, many investigators have taken the candidate gene approach. The association study is one strategy for assessing the importance of candidate genes. These studies are similar to case-control studies, but exposure is de¢ned as the presence of a particular allele of a candidate gene. As a ¢rst step, polymorphic genetic variation is sought within the candidate gene, or in a nearby region. In some cases, the polymorphic allele may alter the amino acid sequence of the protein. These coding polymorphisms are often given priority for study because the di¡erent forms of the protein may have di¡erent functional activities. A second class of polymorphisms of interest are those which are present in the untranslated region of the RNA. These polymorphic variants are believed to in£uence transcript stability. A third, more common class of polymorphisms includes those which are situated in the non-coding region of the DNA; however, the impact of these on protein activity is believed to be minimal. Even if a statistically signi¢cant association is found between a speci¢c allele of the candidate gene and prostate cancer, this does not prove that the polymorphism itself is involved in carcinogenesis. It may be that a nearby (linked) gene, or a second polymorphism within the same gene, is more relevant. If particular alleles of two polymorphisms are associated in a population (i.e. their joint distribution is non-random) then association will be observed. This is referred to as linkage disequilibrium. Linkage disequilibrium between two adjacent loci may exist in some ethnic groups, but not in others, depending on founder e¡ects and population admixture. This means that association between a polymorphism and a disease state may be seen in some populations but not in others. Candidate genes are often chosen because they

It is not yet clear if a family history of prostate cancer is associated with an increased risk of cancer at other sites. Results to date have been contradictory. Several studies have reported that a family history of prostate cancer increases the risk of breast cancer [1,5,18,47,58,60] but there have been negative studies as well [29]. In an extensive study of the Mormon Genealogical Database, modest excesses of cancer of the breast, colon and brain were seen in the ¢rst-degree relatives of prostate cancer patients [18]. Isaacs et al. [29] did not ¢nd an excess of breast cancer in prostate cancer families but found an excess risk of tumors of the central nervous system. Slattery and Kerber [48] reported a familial association between colon cancer and prostate cancer in the Utah Population Database. A signi¢cant de¢cit of prostate cancer was reported in the fathers of Norwegian patients with testicular cancer [24]. It is not yet clear to what extent the clustering in families of breast and prostate cancer is due to the BRCA1 or BRCA2 genes. Prostate cancer has been reported in excess in families with mutations of both types [13,56,57]. Langston et al. [33] screened for BRCA1 mutations in a set of 49 men with either very early onset prostate cancer ( 6 53 years of age at diagnosis) or with prostate cancer and a family history of premenopausal breast cancer or of prostate cancer. Only one clear example of a BRCA1 mutation (185delAG) was found; however, the 185delAG mutation is present in up to 1% of Jewish individuals [52] and this may have been a chance ¢nding. Jishi et al. [30] found an excess of prostate cancer in families with three or more cases of ovarian cancer in the Gilda Radner Familial Ovarian Cancer Registry. It is assumed that the majority of these families are due to mutations in BRCA1 or BRCA2. Gronberg et al. [21] reported an extreme family from the Swedish

12. Association studies

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code for enzymes, or for hormone receptors, which are known to be involved in prostate growth and di¡erentiation, or because they have been implicated in carcinogenesis at other sites. Cancer genes of interest may be involved in cell cycle control, in DNA stability or repair, or may in£uence sensitivity to mutagens. Testosterone is the principal steroid hormone involved in prostate growth, and dihydrotestosterone is the most active metabolite. Testosterone exerts its e¡ect on cell growth through binding to the androgen receptor. The gene for the androgen receptor contains a polymorphic CAG repeat sequence which ranges in length from 8 to 31 repeat units. Short repeat lengths are associated with high transcriptional activity. Because of the central role of androgen in prostate cancer growth and progression, the androgen receptor has been a favorite candidate gene. There is a higher frequency of short alleles of the androgen receptor (those with less than 20 repeat units) in blacks than in whites [8]. It has been proposed that this distributional di¡erence may account to some degree for the higher cancer incidence in blacks. Several case-control studies address this hypothesis by asking if short alleles of the androgen receptor polymorphism are associated with an increased risk of prostate cancer. Stanford et al. [50] analyzed the androgen receptor polymorphism in 301 prostate cancer cases and 277 controls. They found a (non-signi¢cant) 3% decrease in risk with each increase of one repeat unit. The results were statistically signi¢cant for the subgroup of thin men. Ingles et al. [28] found that men with short CAG repeat lengths (less than 20 repeat units) had a doubling of their risk of prostate cancer. This di¡erence was borderline signi¢cant. A third group found that the association with the androgen receptor was restricted to tumors of high grade, or advanced stage. In the Physician's Health Study, Giovannucci et al. [17] found that repeat lengths of less than 19 units were associated with a doubling of the risk of cancer which had spread beyond the prostate (P = 0.002). In contrast, the risk of cancers con¢ned to the gland was not measurably increased. Although the results of the studies to date are not completely consistent, and the association is not yet proven, these studies together suggest that the androgen receptor may be associated with the risk of pros-

F9

tate cancer in some populations, and in particular, with advanced cancers. It appears that the androgen receptor in£uences prostate cancer susceptibility, but there is no evidence to date that families with multiple cases of prostate cancer are attributable to variation in this gene. The androgen receptor is on the X-chromosome, and father-to-son transmission e¡ectively rules X-linked inheritance for many large families. Xu et al. [62] identi¢ed linkage to a locus on the X-chromosome distinct from that of the androgen receptor. In addition, Sun et al. [54] found no linkage between the androgen receptor and prostate cancer susceptibility in 47 sets of brothers with multiple cases of prostate cancer. A second candidate gene is the vitamin D receptor. Vitamin D has antitumor properties, and one report suggests that increased serum levels of vitamin D protect against prostate cancer [10]. There are several polymorphisms of the vitamin D receptor. Polymorphisms in the 3P-region of the VDR correlate with transcriptional activity; three have been studied in detail in association with prostate cancer risk. Two of these are restriction fragment type polymorphisms (RFLP) and one is a poly(A) tract at the 3P-end of the gene. Taylor et al. [55] studied a TaqI RFLP at codon 352 in a white population. The allele which contains the TaqI restriction site o¡ered some protection. Only 8% of 108 cases were homozygous for this allele, compared to 22% of controls (odds ratio = 0.32; P 6 0.01). A second polymorphism is in the non-coding 3P-untranslated region of the vitamin D receptor. This polymorphism is based on variation in the length of a poly(A) tract. Ingles et al. [28] found that the presence of a long allele of this vitamin D receptor polymorphism (i.e. greater than 17 repeat units) was associated with a four-fold increase in risk of prostate cancer in non-Hispanic whites. However, 95% of the control population carried at least one copy of the susceptibility allele. Only 5% of the population had two short alleles and could be considered at low risk. Because the high risk allele is common, this polymorphism is not expected to account for clustering of prostate cancer in families. Ingles et al. [27] then extended their study to include African-Americans. The poly(A) polymorphism was

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found not to be associated with prostate cancer in this population. However, a third polymorphism, characterized by a BsmI restriction site, was associated with advanced disease (odds ratio 0.39; P 6 0.05). Surprisingly, the presence of the allele was protective in African-Americans, in contrast to a previous study of Caucasians, which found that the allele was associated with increased risk. It is possible that these inconsistent results are due to small sample sizes. However, it is also possible that the BsmI polymorphism is in linkage disequilibrium with the true susceptibility allele, and that di¡erent alleles of the BsmI polymorphisms are associated with susceptibility in the two di¡erent populations. Kibel et al. [32] found no di¡erence in the frequency of alleles of either of the two vitamin D receptor polymorphisms (TaqI and poly(A)) between a group of 41 men who died of prostate cancer and 41 healthy controls. In the largest study to date, Ma et al. [35] found no overall association between prostate cancer risk and either of the two RFLPs in the vitamin D receptor among men enrolled in the Physician's Health Study. However, among the subgroup of men with low levels of plasma 25-hydroxyvitamin D, there was a 57% reduction of risk observed for one genotype. Men with this genotype also had signi¢cantly higher circulating levels of 1,25-vitamin D. The reduction was greatest among oldest men. A third candidate gene is poly(ADP ribose) polymerase (PADPRP). Doll et al. [11] reported an association between a speci¢c allele of the (PADPRP) and prostate cancer in black Americans, but their sample size was small and their observations have not yet been replicated. 13. Prostate cancer progression Theoretically, genetic factors might in£uence any of the stages of prostate carcinogenesis, and a¡ect the cancer incidence rate, or the rate of cancer progression [41]. For example, the observation that an increased incidence of prostate cancer is associated with a particular allele might be because the allele increases susceptibility to prostate cancer, or that, once established, the allele is associated with an increased rate of tumor growth, or a tendency to metastasize. For this reason, it is possible that di¡erent

genetic patterns may be observed, or di¡erent susceptibility genes described, depending on how the cancer phenotype is de¢ned. For example, studies based on the occurrence of prostate cancer at autopsy may give di¡erent results from studies of men who are known to have died from prostate cancer. Similarly, a study of men with metastatic disease may give results which di¡er from a study based on a series of men who were detected with prostate cancer through an elevated PSA. Data from the Physician's Health Study suggest that the androgen receptor polymorphisms a¡ect the rate of metastatic progression from localized disease. Ingles et al. [28] suggest that the presence of the vitamin D receptor polymorphism was a particular risk factor for advanced disease. Rebbeck et al. [44] studied the e¡ect of a CYP3A4 polymorphism on stage of prostate cancer at diagnosis. This gene is a member of the cytochrome P450 supergene family and is involved in androgen metabolism. Individuals can be classi¢ed into di¡erent CYP3A4 genotypes based on the presence or absence of a polymorphism in the nifedipine-speci¢c element in the 5P-regulatory region of the gene. The authors divided prostate cancer patients by clinical subgroup, family history and age. The variant CYP3A4 allele was present in 43% of stage T3/T4 tumors, but only 15% of T1/T2 tumors (P 6 0.001). Studies to date have compared stage and grade at presentation with the distribution of alleles of the candidate gene. Direct evidence that a candidate gene is involved in cancer progression will come when it is shown that among men diagnosed with localized disease, the presence of a particular allele is associated with more rapid progression to metastatic disease. 14. Screening for familial prostate cancer One of the main goals of identifying genetic markers for prostate cancer is that these markers will allow clinicians to identify men at high risk of cancer for preventive strategies. Because little is known about environmental causes of prostate cancer, current preventive strategies focus on early detection through screening. Family history is probably the most important known factor which can be used

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to identify men at high risk. The serum test for prostate speci¢c antigen (PSA) is proposed to be a sensitive and speci¢c means of detecting asymptomatic prostate cancer prior to metastatic spread. It is hoped that population-based screening programs using PSA will be successful in reducing mortality from the disease. The positive predictive value of a screening test will increase with the prevalence of the condition in the screened population. Narod and colleagues [40] found that the positive predictive value of a PSA test above 3.0 was higher for men with a positive family history of prostate cancer. For example, among men with a normal rectal examination and a PSA greater than 3.0 mg per liter, 12% were found to have cancer if the family history was negative, but 27% were found to have cancer if there was an a¡ected ¢rst-degree relative. Genetic factors other than a positive family history have not been evaluated in the context of prostate cancer screening. It will be of interest to determine if speci¢c alleles of the androgen receptor, or of other candidate genes, are useful in improving the positive predictive value of the PSA test. It is currently recommended in many centers that PSA screening be o¡ered to men with a family history of prostate cancer, but there is no consensus yet as to the appropriate age at which screening should begin. It appears that hereditary prostate cancer occurs at a young age, but it is not clear if prostate cancer screening for men with only one a¡ected relative should begin prior to age 50. McWhorter et al. [37] screened 34 healthy men from high risk prostate cancer families. Each family contained two brothers a¡ected with prostate cancer. Screening was performed using both PSA and random four quadrant needle biopsies. Prostate cancer was found in eight (24%) of the men. The PSA level was elevated in only three of the men with cancer. This study suggests that enhanced surveillance is warranted in high risk men based on family history and raised the possibility that such surveillance should also include a random biopsy. Acknowledgements I thank William Foulkes and Robert Nam for helpful discussion.

F11

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[54] S. Sun, S.A. Narod, A. Aprikian, P. Ghadirian, F. Labrie, Androgen receptor and familial prostate cancer, Nat. Med. 1 (1995) 848^849. [55] J. Taylor, A. Hirvonen, M. Watson, G. Pittman, J.L. Mohler, D.A. Bell, Association of prostate cancer with vitamin D receptor gene polymorphism, Cancer Res. 56 (1996) 4108^ 4110. [56] P. Tonin, P. Ghadirian, C. Phelan, G.M. Lenoir, H. Lynch, S.A. Narod, A large multisite cancer family is linked to BRCA2, J. Med. Genet. 32 (1995) 982^984. [57] S. Thoralacius, G. Olafsdottir, L. Tryggvadottir, S. Neuhausen, J.G. Jonasson, S.V. Tavtigian, H. Tulinius, H.M. Ogmundsdottir, J.E. Eyfjord, A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes, Nat. Genet. 12 (1996) 298^302. [58] E.U. Theissen, Concerning a familial association between breast cancer and both prostatic and uterine malignancies, Cancer 34 (1974) 1102^1107. [59] S.N. Thibodeau, Z. Wang, D.J. Tester, A.S. French, J.J. Schrodeer, A.S. Bissonet, S.G. Roberts, M.L. Blut, D.S. Schaid, J.R. Smith, J.M. Trent, Linkage analysis at the HPC1 locus in hereditary prostate cancer families, Am. J. Hum. Genet. 61 (1997) A297. [60] H. Tulinius, V. Egilsson, G.H. Olafsdottir, H. Sigvaldason, Risk of prostate ovarian and endometrial cancer among relatives of breast cancer patients, Br. Med. J. 305 (1992) 855^ 857. [61] C.M. Woolf, An investigation of the familial aspects of carcinoma of the prostate, Cancer 13 (1960) 739^744. [62] J. Xu, D. Meyers, D. Freije, S. Isaacs, K. Wiley, D. Nusskern, C. Ewing, E. Wilkens, P. Bujnovszky, G.S. Bova, W. Isaacs, J. Schleutker, M. Matikainen, T. Tammela, T. Visakorpi, O.-P. Kallioniemi, R. Berry, D. Schaid, A. French, S. McDonnell, J. Schroeder, M. Blute, S. Thibodeau, J. Gronberg, M. Emanuelsson, J.-E. Dambert, A. Bergh, B.-A. Jonsson, J. Smith, J. Bailey-Wilson, J. Carpten, D. Stephan, E. Gillanders, I. Amundson, T. Kainu, D. Freas-Lutz, A. Ba¡oe-Bonnie, A.V. Aucken, R. Sood, F. Collins, M. Brownstein, J. Trent, Evidence for a prostate cancer susceptibility locus on the X chromosome, Nat. Genet. 20 (1998) 175^179.

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