Genetic epidemiology of prostate cancer

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 thepresence of prostate cancer among asymptomatic men who undergo PSA screening. Approximately 5% of cases of prostatecancer have a familial component. The genetic epidemiology of prostate cancer is complex, and genes on chromosome 1 andX 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 ofonset, 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F2

2. Ethnic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F2

3. Familial aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F3

4. Twin studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F3

5. Case-control studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F3

6. Cohort studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F5

7. Segregation analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F5

8. Linkage studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F6

9. Age of onset of familial and hereditary prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . F7

10. Pathology of hereditary prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F7

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

* Fax: +1 (416) 351-3767; E-mail : [email protected]

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11. Other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F8

12. Association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F8

13. Prostate cancer progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F10

14. Screening for familial prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F10

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F11

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F11

1. Introduction

Approximately 10^15% of all cases of prostatecancer are classi¢ed as familial, meaning that thecancer patient reports at least one a¡ected relativewith the same disease. Prostate cancer is commonand it is possible that two or three cancers will occurin one family by chance. These cases of familial pros-tate cancer should be distinguished from hereditarycases; the latter category is reserved for men with aclear-cut inherited predisposition. Cases may be pu-tatively classi¢ed as hereditary because they are fromfamilies which appear to segregate a dominant trait,because there are two or more cases of very youngprostate cancer (less than 60 years at diagnosis) orbecause the family shows linkage to markers near theHPC1 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 susceptibilitygene, HPC1, has been mapped to chromosome 1q24-25. Because the risk of cancer associated with a mu-tation in this gene is estimated to exceed 50%, HPC1is considered to be a major susceptibility gene. Incontrast, the relative risk associated with other(minor) susceptibility genes is in the range of 2- to5-fold. Examples of the latter class include theandrogen receptor and the vitamin D receptor.

Many hereditary cancer syndromes have been de-lineated in the recent past, and are characterized byan early age of onset, the presence of preclinical le-sions, and by familial association with other cancertypes. Examples include familial adenomatous poly-posis (due to mutations in the APC gene) and thefamilial breast ovarian cancer syndrome (due to mu-tations in BRCA1 or BRCA2). This is not yet the

case for familial prostate cancer; no predisposinggene has yet been discovered, and there are no fea-tures which allow us to distinguish between heredi-tary and non-hereditary cases.

Nevertheless, there has been much recent progressin our appreciation of the genetic features of prostatecancer. These advances are discussed below. It ishoped that our ability to recognize individuals athigh risk for prostate cancer will facilitate targetedprevention practices, for the present including screen-ing and, eventually, chemoprevention.

2. Ethnic studies

Prostate cancer incidence rates vary markedly be-tween ethnic groups [43]. This variation is probablydue to a combination of genetic and environmentalfactors, although the relative contribution of each ofthese is so far unknown. Di¡erences in diet and otherrisk factors appear to explain only a small propor-tion of the observed ethnic variation. African-Amer-ican men have the highest incidence and mortalityrate of any population studied. The rates in Asianmen may be 50-fold less [43].

Although prostate cancer is more frequent amongAfrican-American men, it is not known if the frac-tion attributable to genetic factors is higher in thisgroup. In a study by Whittemore et al. [53] a familyhistory of two or more a¡ected ¢rst-degree relativeswith prostate cancer was associated with a higherrelative risk in blacks (RR = 9.7) than in whites(RR = 3.9) or in Asians (RR = 1.6). In a secondstudy, no di¡erences were seen in the magnitudesof the familial relative risks between blacks andwhites [25]. The utilization of prostate cancer screen-

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ing in di¡erent ethnic groups may di¡er, and mayin£uence the incidence rates.

3. Familial aggregation

It is clear that there are rare families in whichprostate cancer is a hereditary trait. Families withmultiple cases of prostate cancer have been reported,including several large kindreds from Utah [5]. Gron-berg et al. [20] describe a family from Sweden inwhich the father developed prostate cancer at age62 and four sons later developed prostate cancer be-low the age of 58. No known environmental factorscould account for this degree of clustering. Familieswith clearly dominant prostate cancer di¡er fromsmaller families in the characteristic age of onset ofthe cancers (see below). However, these large familiesare rare ^ much more prevalent are families with twoor three cases of prostate cancer. In general, thesefamilies are not striking and may be overlooked ifa family history is not taken.

4. Twin studies

Other than anecdotal reports of large prostate can-cer families, there are several lines of evidence whichsupport the hypothesis that inherited factors are crit-ical in determining prostate cancer risk. Twin studiesprovide some of the best evidence for a genetic com-ponent to prostate cancer. Among a registry of 4840male twin pairs in Sweden, there were 458 cases ofprostate cancers identi¢ed [19]. There were 16 con-cordant pairs among 1649 monozygotic twins (1.0%),but only six concordant pairs among 2983 dizygotictwin pairs (0.2%) [19]. Because it is assumed thatenvironmental factors are similar for the twins inboth groups, the di¡erence in observed concordancerates is attributed to a greater degree of shared genesin the monozygous twins. The average age in theconcordant monozygous pairs was slightly younger(72.6 years) than that of the dizygous pairs (75.1years) ^ but neither subset could be considered tobe early-onset cancer.

A second study conducted in the United Statesfound similar results [42]. These authors identi¢ed1009 twin pairs from a national twin registry, where

at least one member had been a¡ected with prostatecancer. Among monozygous twins, 15.7% were con-cordant (both twins a¡ected with cancer), comparedto only 3.7% for dizygous twins.

5. Case-control studies

In a case-control study, the risk of cancer is com-pared for the relatives of men with cancer and therelatives of healthy controls. In its simplest form,prostate cancer cases and control men are asked ifthey have one or more relatives with prostate cancer,and the two proportions are compared. In a moreelaborate design, the number of a¡ected relatives andthe relationship of each to the case is also considered.Case-control studies generate an estimate of the rel-ative risk for prostate cancer (the risk of cancer de-veloping in a man with one or more a¡ected relativescompared to the risk in a man with no a¡ected rel-ative).

With our increasing interest in genetic factors incancer, newer and more complex study designs havebeen developed. These take into account the numberof a¡ected and una¡ected male relatives, the ages ofonset of the cancers in these men, and the currentage or age of death of the relatives. This extra detailpermits the investigator to calculate the expectednumber of cancers in the relatives of the cases andthe controls (and to compare this with the observednumber). For an example of a study of this type seeFoulkes et al. [15].

There have many case-control studies of prostatecancer. Almost all show that a family history ofprostate cancer is an important risk factor, but themagnitude of the estimated risks varies. The risksfor particular relatives may also vary between stud-ies. If a susceptibility gene is dominant, then therelative risks for fathers and brothers should bethe same. If the susceptibility gene is recessive,then the relative risk for brothers should exceedthat of the father (or son). If the susceptibilitygene is X-linked (i.e. on the X chromosome), thenthe risk for the mother's brothers should exceed thatfor the father's brothers. Many studies to date havedistinguished between risks in fathers and brothers,and between fathers and uncles, but none have dis-criminated between maternal and paternal relatives.

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This may be important if X-linked inheritance is tobe evaluated.

In a case-control study, the information aboutfamily history is usually made after the case is in-formed of his diagnosis. This introduces two poten-tial weaknesses. The history of prostate cancer infamily members is based on the recollection of theindex patient, and the cancer in the relative is rarelycon¢rmed by a pathology report. Reported historiesof prostate cancer in second-degree relatives tend tobe inaccurate. Prostate cancer patients may be morelikely to be aware of the diagnosis of prostate cancerin relatives, may be more diligent in their search foradditional cases, or may be more likely to misinter-pret benign disease as cancer, than are healthy con-trols. The e¡ect of this recall bias will be to increasethe magnitude of the relative risks associated with afamily history, especially for second-degree relatives,where the information is weaker. The second concernis that the history of cancer in a man may prompt ascreening test in a relative and thereby lead to hisdiagnosis. This detection bias is less a concern forcases ascertained prior to the 1990s.

In a large case-control study (691 cases) a relativerisk of 3.0 was found for brothers of men with pros-tate cancer, 2.0 for fathers, 1.9 for grandfathers and1.7 for uncles [51]. The odds ratio for a ¢rst-degreerelative, 2.1, was not much di¡erent from the oddsratio for a second-degree relative (1.8). For bothdominant and recessive genetic diseases, the attenu-ation of relative risk between ¢rst- and second-degreerelatives should be greater than this. Furthermore,the frequency of prostate cancer was reported to be7.5% in the fathers of una¡ected controls but only2.7% in uncles of controls. The di¡erence in thesetwo estimates is likely due to recall bias.

Keetch et al. [31] compared family histories ofprostate cancer in 1084 consecutive incident casesof prostate cancer and 935 spouse controls. Theyfound the risk was highest if the brother had prostatecancer (relative risk 4.7) followed by fathers (3.5),uncles (2.7) and grandfathers (2.5). Again, becausethe risk ratios are similar for a¡ected fathers anduncles, the possibility of recall bias must be consid-ered.

Fincham et al. [14] studied 382 incident cases ofprostate cancer in the Alberta Cancer Registry. Theyfound a relative risk of 3.1 for prostate cancer in the

father, compared to 3.3 for cancer in a brother. Bothrisks were signi¢cant at the level of P = 0.01. In asecond Canadian population-based case-controlstudy (640 cases, 639 controls) the relative risk forany a¡ected ¢rst-degree relative was 3.3 [16] and wasnot di¡erent for fathers or brothers.

Not all studies of prostate cancer have concludedthat the data best ¢t a dominant model. In severalstudies, the risk for brothers was found to be greaterthan the risk for sons or fathers of cases. This isconsistent with a recessive, or X-linked componentto prostate cancer inheritance. In 1960, Woolf [61]studied familial risks of prostate cancer in Utah.Deaths from prostate cancer among 228 cases andtheir relatives were identi¢ed by review of Utah Statevital statistics records, thereby eliminating the possi-bility of recall bias. The observed numbers of deathswere compared to the expected number based onrates from the Utah State Bureau of Vital Statisticsand to deaths in a control group. There were 12deaths from prostate cancer among brothers of pros-tate cancer cases, compared to 4.3 expected(RR = 2.81; P = 0.002), and 3 deaths in fathers com-pared to 2.4 expected (RR = 1.25; not signi¢cant).

In this study, bias was avoided by using the UtahRegistry to identify cancer in relatives, rather thanrelying on patient recall. It is also possible to avoidrecall bias if the family history of prostate cancer istaken before the diagnosis is made, e.g., in the inter-val between the report of an elevated PSA and thediagnostic biopsy. Narod and colleagues [40] re-corded prostate cancer family histories from 6390men attending a screening clinic in Quebec City.Family histories were taken prior to screening, andrecall bias was not possible. Prostate cancer wasfound in 10.2% of subjects who reported a brothera¡ected; this number was 2.6 times higher than thatfor men with no reported a¡ected relative. The cor-responding relative risk for men with an a¡ected fa-ther was only 1.2. Monroe and colleagues [39]studied a population-based cohort of blacks, whites,Japanese and Hispanics and found that the relativerisk for prostate cancer was approximately two-foldlarger if the brother was a¡ected than if the fatherwas a¡ected. This was true for all four ethnic pop-ulations. Greater relative risks for brothers were alsofound 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 ofcancer increased with the number of relatives af-fected, and with an early age of onset of the pro-band. The association was particularly strong forcase diagnosed before age 60 (relative risk 5.9).

Linkage studies have con¢rmed that prostate can-cer is a genetically heterogeneous disease. It is possi-ble that some of the susceptibility genes act in adominant fashion and that others are X-linked orrecessive. It will be very di¤cult to con¢rm suchcomplex inheritance on the basis of pedigree studyalone and it is hoped that molecular studies will re-solve this issue.

A few case-control studies have extended the clin-ical phenotype to include the presence of benignprostatic disease or measurement of serum hor-mones. Narod et al. [40] observed an increase inthe frequency of abnormal rectal examinations inthe relatives of prostate cancer patients. The exactnature of these lesions was unclear, but a proportionof these were likely to be cases of benign prostatichyperplasia. A second study reported that a familyhistory of prostate disease (cancer or hyperplasia)was more frequent in relatives of men with benignhyperplasia (20%) than in relatives of men with pros-tate cancer (12.8%) or in healthy controls (5.1%)[46]. These results suggest that common geneticmechanisms may predispose to benign and malig-nant prostate disease. Meikle et al. [38] investigatedserum levels of androgens, estrogens and sex hor-mone binding globulin in prostate cancer cases,brother-in-law controls, and their sons. The cumula-tive incidence of prostate cancer was four timesgreater in the brothers of cases than expected. Inter-estingly, sons of cases had signi¢cantly reduced lev-els of testosterone and dihydrotestosterone com-pared to sons of controls. These observations needto be extended to other populations.

6. Cohort studies

Goldgar et al. [18] performed a historical cohortstudy among the Mormon population of Utah. Theycalculated the observed and expected numbers ofcancer in the relatives of probands with cancer at28 speci¢c cancer sites. The relative risk for prostatecancer for ¢rst-degree relatives of 6350 prostate can-

cer patients was 2.2, and was 4.1 for relatives ofprobands diagnosed before age 60.

One of the best studies to date detailing prostatecancer familial risks is a recent historical cohortstudy from Sweden. Gronberg et al. [20] identi¢ed8515 men with prostate cancer reported to the Swed-ish Cancer Register from 1959 to 1963. Informationabout the nuclear families was available from parishrecords. 5496 sons of these cases were identi¢ed, ofwhom 304 also had prostate cancer. Based on theages of the sons, only 178 cases were expected. Over-all, the relative risk was 1.70 (95% CI 1.51^1.90). Therelative risk declined with increasing age of cancer inthe father. This elegant study has many strengths ^ itis population-based and nationwide, the expectednumber of cases could be accurately estimated andthe diagnosis of prostate cancer was con¢rmed withregistry records.

7. Segregation analysis

Twin studies and case-control studies support theimportance of genetic factors in prostate cancer de-velopment, but cannot be used to infer the geneticmode of transmission. Results from family studies ofprostate cancer have not led to a consistently favoredgenetic model. Several studies have suggested thatprostate cancer susceptibility is best modelled as adominant trait, and in other studies a recessive (orX-linked) mode is favored.

A segregation analysis was performed on the set offamilies studied by Steinberg and colleagues [51].This analysis led these investigators to concludethat prostate cancer inheritance best ¢t an autosomaldominant model, where a rare susceptibility gene(gene frequency 0.0033) with a high lifetime pene-trance was transmitted [6]. The gene was thoughtto be the cause of 9% of prostate cases occurringbefore the age of 80 years. The average age of diag-nosis of prostate cancer in this data set was atypi-cally young (59 years).

A second segregation analysis was performed onfamilies of unselected Swedish prostate cancer pa-tients [23]. These were all nuclear families, includingan 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 possibleto compare the risks for brothers and sons directly.

Recently, Schaid et al. [45] performed a segrega-tion analysis on a sample of 5486 men who under-went a radical prostatectomy at the Mayo Clinicfrom 1966 to 1995. The data best ¢t a model of arare autosomal dominant gene. The model predicteda gene frequency of 0.006 and a penetrance to age 85of 89%. However, the patterns of inheritance werenot completely explained by this model; the cancerrisk 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 pros-tate cancer by linkage analysis. Prostate cancer typ-ically occurs at a late age, and it is rare to have DNAavailable from living a¡ected men for more than onegeneration. Prostate cancer is common and sporadiccases (phenocopies) may exist in families alongsidehereditary ones. The ¢rst chromosomal localisationof a gene for prostate cancer was reported in 1996[49]. Isaacs and his colleagues [29] identi¢ed a clusterof linked markers on chromosome 1q which de¢nedthe locus of a prostate cancer susceptibility gene.This unidenti¢ed gene, named HPC1, accounted for34% of a panel of 66 North American pedigrees withthree or more men a¡ected with prostate cancer.These authors estimate that one in 170 men mightcarry a predisposing mutation. About one-half of theevidence in favor of linkage was derived from a fewAfrican-American families. A re-analysis of this dataset showed that the positive evidence for linkagecame from families with an average age of onset ofless than 65 years of age [21].

Shortly after, Cooney et al. [9] con¢rmed the pres-ence of the chromosome 1q prostate cancer suscept-ibility gene in a linkage study of 59 prostate cancerfamilies. The overall evidence for linkage in thisstudy was weak by conventional standards, buthelped con¢rm the presence of the hypotheticalgene. In this study, the African-American familiesalso contributed disproportionately to the linkage.Hsieh et al. [26] also found modest evidence for link-age in a panel of 92 prostate cancer families from thewestern United States and Canada.

There have been four negative linkage studies aswell. McIndoe et al. [36] excluded the region ofHPC1 in a panel of 49 North American prostatecancer families. Eeles et al. [12] studied 76 familieswith three or more cases of prostate cancer fromCanada, the United Kingdom and Texas, and foundno signi¢cant evidence of linkage to the HPC1 locus.An additional 60 families with two a¡ected men werestudied and no evidence of linkage was seen. Thibo-deau et al. [59] studied 166 families from the MayoClinic Database, each with three or more cases ofprostate cancer. No evidence of linkage was foundto the HPC1 locus.

Recently, a European prostate consortium foundevidence of linkage for a set of prostate cancer fam-ilies to a second locus on chromosome 1q42 [3]. Thisregion is 60 centiMorgans from the estimated posi-tion of the HPC1 gene. These families were ofFrench or German origin. The evidence in favor oflinkage was marginal, the maximal two-point lodscore was 2.7. It was estimated that 50% of the fam-ilies were linked to this locus. However, nine familieswith early onset prostate cancer (average age lessthan 60) gave a multipoint lod score of 3.3. Thisgroup found no evidence of linkage to the regionof HPC1. Because the genetic distance betweenHPC1 and the second chromosome 1q prostate can-cer locus is large, it appears to be unlikely that bothgroups have identi¢ed linkage to an intermediate lo-cus.

The case-control studies and segregation analysesreported to date have generated mixed results interms of absolute risks and the favored genetic mod-els. It appears that aggregated data cannot be ex-plained entirely by a single gene model, i.e. it ismore 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 forbrothers is higher than that for fathers of prostatecancer cases. This raises the possibility of an X-linked component to prostate cancer susceptibility ^this possibility has now been tested formally by link-age analysis [62]. This international group studied360 families with multiple cases of prostate cancer,collected from the USA, Finland and Sweden. Evi-dence for a susceptibility locus on the X-chromo-some 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 markerDXS1113. The proportion of linked families was es-timated to be 16%. Interestingly, there was positiveevidence for linkage in families both with and with-out male-to-male transmission.

In summary, although there is inconsistency acrossstudies, the overall evidence is su¤cient to establishthe presence of two, and possibly three prostate can-cer susceptibility genes. The exact proportion ofprostate cancer families attributable to each of thesegenes is unknown. Further molecular studies will de-lineate if, in fact, two prostate cancer genes exist onchromosome 1q. It will also be important to type alarge number of families with markers at all loci. Ifmultiple susceptibility genes are present, then familieswhich generate negative lod scores at two loci shouldbe enriched for linkage to the third. It is also possiblethat the X-linked locus is a genetic modi¢er of cancerrisk among carriers of mutations in HPC1.

9. Age of onset of familial and hereditary prostatecancer

In many hereditary cancer syndromes, the age ofcancer onset is much younger than that of the spora-dic, or non-familial cancers. This is clearly the casefor hereditary breast and colon cancer, but is notapparent for familial prostate cancer. Screening prac-tices in£uence the age at which prostate cancer isdiagnosed, and it is di¤cult to de¢ne the age-of-on-set of cancer in an individual, or to compare agesbetween two studies. The diagnosis of prostate can-cer is rarely made because of symptoms due to can-cer; more commonly the diagnosis is made when aman undergoes a prostatectomy for symptoms ofbenign hyperplasia (and malignant cells are found)or due to an elevated PSA or abnormal rectalexam. Men with a family history of cancer may bemore likely to request screening than men with noa¡ected relative.

Age-of-onset estimates are also subject to ascer-tainment bias. Families may be selected for studyon the basis of early-onset cancer. A second problemmay arise because all relatives included in the esti-mate are not followed until death. For example, aman may have a brother, aged 60. If the brother hasprostate cancer he will be considered to be a familial

case and his age of diagnosis will be used to generatethe mean for the a¡ected men. However, the brothermay develop prostate cancer at age 70, but this lateonset-cancer will not be included in the age-of-onsetcalculation. For this reason, it is important that re-sults of age-of-onset be adjusted for the current agesof the relatives. In general, cumulative incidences areadjusted for follow-up, but mean ages are not.

The ages of onset in families with two or threecases of cancer do not appear to be much youngerthan expected. There is, however, evidence that casesof hereditary cancer occur earlier than expected.Cannon et al. [5] found the relative risk increasedwith decreasing age of the proband. Carter et al.[7] calculated the cumulative incidence of prostatecancer in the ¢rst-degree relatives of 691 men withprostate cancer. The cumulative risk was signi¢cantlygreater for men who were a¡ected below 53 years,compared to 53 years or above. In the segregationanalysis based on this data set the probability of ana¡ected man carrying the putative susceptibility al-lele was greater for men diagnosed with prostatecancer at a young age.

In a study from Sweden it was found that heredi-tary prostate cancer appears at about six yearsyounger than non-familial cancer [20]. In a laterstudy, with chromosome 1q markers, Gronberg andcolleagues [22] compared 133 cases of prostate cancerfrom 22 families which were potentially linked toHPC1 with 172 men from 41 apparently unlinkedfamilies. A modest di¡erence in age-of-onset wasnoted; the age of diagnosis was two years lowerfor the men from the HPCA1-linked families.

10. Pathology of hereditary prostate cancer

In many hereditary cancer syndromes there arecharacteristic pre-neoplastic lesions. For example,multiple adenomatous polyps precede the diagnosisof frank colon cancer in patients with familial ad-enomatous polyposis. In some cases hereditary can-cers have a di¡erent spectrum of histology than non-hereditary ones. For example, breast tumors associ-ated with BRCA1 mutations are almost always ofhigh grade [4]. However, there is no clear benignprecursor for hereditary prostate cancer, and familialcancers do not appear to be systematically di¡erent

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from sporadic ones [2]. Hereditary and familial pros-tate cancers do not show an increased frequency ofassociated prostatic intra-epithelial neoplasia [2]. Thesmall amount of data about cancers from men fromHPC1-linked families suggests that these are morelikely to be of high grade and to present with diseasewhich has spread beyond the prostatic capsule [22].

11. Other cancers

It is not yet clear if a family history of prostatecancer is associated with an increased risk of cancerat other sites. Results to date have been contradic-tory. Several studies have reported that a family his-tory of prostate cancer increases the risk of breastcancer [1,5,18,47,58,60] but there have been negativestudies as well [29]. In an extensive study of theMormon Genealogical Database, modest excessesof cancer of the breast, colon and brain were seenin the ¢rst-degree relatives of prostate cancer patients[18]. Isaacs et al. [29] did not ¢nd an excess of breastcancer in prostate cancer families but found an ex-cess risk of tumors of the central nervous system.Slattery and Kerber [48] reported a familial associa-tion between colon cancer and prostate cancer in theUtah Population Database. A signi¢cant de¢cit ofprostate cancer was reported in the fathers of Nor-wegian patients with testicular cancer [24].

It is not yet clear to what extent the clustering infamilies of breast and prostate cancer is due to theBRCA1 or BRCA2 genes. Prostate cancer has beenreported in excess in families with mutations of bothtypes [13,56,57]. Langston et al. [33] screened forBRCA1 mutations in a set of 49 men with eithervery early onset prostate cancer (6 53 years of ageat diagnosis) or with prostate cancer and a familyhistory of premenopausal breast cancer or of prostatecancer. Only one clear example of a BRCA1 muta-tion (185delAG) was found; however, the 185delAGmutation is present in up to 1% of Jewish individuals[52] and this may have been a chance ¢nding. Jishi etal. [30] found an excess of prostate cancer in familieswith three or more cases of ovarian cancer in theGilda Radner Familial Ovarian Cancer Registry. Itis assumed that the majority of these families are dueto mutations in BRCA1 or BRCA2. Gronberg et al.[21] reported an extreme family from the Swedish

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

12. Association studies

Because of the inherent di¤culties in using linkageanalysis to study prostate cancer susceptibility, manyinvestigators have taken the candidate gene ap-proach. The association study is one strategy forassessing the importance of candidate genes. Thesestudies are similar to case-control studies, but expo-sure is de¢ned as the presence of a particular allele ofa candidate gene. As a ¢rst step, polymorphic geneticvariation is sought within the candidate gene, or in anearby region. In some cases, the polymorphic allelemay alter the amino acid sequence of the protein.These coding polymorphisms are often given priorityfor study because the di¡erent forms of the proteinmay have di¡erent functional activities. A secondclass of polymorphisms of interest are those whichare present in the untranslated region of the RNA.These polymorphic variants are believed to in£uencetranscript stability. A third, more common class ofpolymorphisms includes those which are situated inthe non-coding region of the DNA; however, theimpact of these on protein activity is believed to beminimal.

Even if a statistically signi¢cant association isfound between a speci¢c allele of the candidategene and prostate cancer, this does not prove thatthe polymorphism itself is involved in carcinogenesis.It may be that a nearby (linked) gene, or a secondpolymorphism within the same gene, is more rele-vant. If particular alleles of two polymorphisms areassociated in a population (i.e. their joint distributionis non-random) then association will be observed.This is referred to as linkage disequilibrium. Linkagedisequilibrium between two adjacent loci may exist insome ethnic groups, but not in others, depending onfounder e¡ects and population admixture. Thismeans that association between a polymorphismand a disease state may be seen in some populationsbut not in others.

Candidate genes are often chosen because they

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code for enzymes, or for hormone receptors, whichare known to be involved in prostate growth anddi¡erentiation, or because they have been implicatedin carcinogenesis at other sites. Cancer genes of in-terest may be involved in cell cycle control, in DNAstability or repair, or may in£uence sensitivity tomutagens.

Testosterone is the principal steroid hormone in-volved in prostate growth, and dihydrotestosterone isthe most active metabolite. Testosterone exerts itse¡ect on cell growth through binding to the andro-gen receptor. The gene for the androgen receptorcontains a polymorphic CAG repeat sequence whichranges in length from 8 to 31 repeat units. Shortrepeat lengths are associated with high transcription-al activity. Because of the central role of androgen inprostate cancer growth and progression, the andro-gen receptor has been a favorite candidate gene.

There is a higher frequency of short alleles of theandrogen receptor (those with less than 20 repeatunits) in blacks than in whites [8]. It has been pro-posed that this distributional di¡erence may accountto some degree for the higher cancer incidence inblacks. Several case-control studies address this hy-pothesis by asking if short alleles of the androgenreceptor polymorphism are associated with an in-creased risk of prostate cancer.

Stanford et al. [50] analyzed the androgen receptorpolymorphism in 301 prostate cancer cases and 277controls. They found a (non-signi¢cant) 3% decreasein risk with each increase of one repeat unit. Theresults were statistically signi¢cant for the subgroupof thin men. Ingles et al. [28] found that men withshort CAG repeat lengths (less than 20 repeat units)had a doubling of their risk of prostate cancer. Thisdi¡erence was borderline signi¢cant. A third groupfound that the association with the androgen recep-tor was restricted to tumors of high grade, or ad-vanced stage. In the Physician's Health Study, Gio-vannucci et al. [17] found that repeat lengths of lessthan 19 units were associated with a doubling of therisk of cancer which had spread beyond the prostate(P = 0.002). In contrast, the risk of cancers con¢nedto the gland was not measurably increased.

Although the results of the studies to date are notcompletely consistent, and the association is not yetproven, these studies together suggest that the andro-gen receptor may be associated with the risk of pros-

tate cancer in some populations, and in particular,with advanced cancers.

It appears that the androgen receptor in£uencesprostate cancer susceptibility, but there is no evi-dence to date that families with multiple cases ofprostate cancer are attributable to variation in thisgene. The androgen receptor is on the X-chromo-some, and father-to-son transmission e¡ectively rulesX-linked inheritance for many large families. Xu etal. [62] identi¢ed linkage to a locus on the X-chro-mosome distinct from that of the androgen receptor.In addition, Sun et al. [54] found no linkage betweenthe androgen receptor and prostate cancer suscepti-bility in 47 sets of brothers with multiple cases ofprostate cancer.

A second candidate gene is the vitamin D receptor.Vitamin D has antitumor properties, and one reportsuggests that increased serum levels of vitamin Dprotect against prostate cancer [10]. There are severalpolymorphisms of the vitamin D receptor. Polymor-phisms in the 3P-region of the VDR correlate withtranscriptional activity; three have been studied indetail in association with prostate cancer risk. Twoof these are restriction fragment type polymorphisms(RFLP) and one is a poly(A) tract at the 3P-end ofthe gene.

Taylor et al. [55] studied a TaqI RFLP at codon352 in a white population. The allele which containsthe TaqI restriction site o¡ered some protection.Only 8% of 108 cases were homozygous for this al-lele, compared to 22% of controls (odds ratio = 0.32;P6 0.01).

A second polymorphism is in the non-coding3P-untranslated region of the vitamin D receptor.This polymorphism is based on variation in thelength of a poly(A) tract. Ingles et al. [28] foundthat the presence of a long allele of this vitamin Dreceptor polymorphism (i.e. greater than 17 repeatunits) was associated with a four-fold increase inrisk of prostate cancer in non-Hispanic whites. How-ever, 95% of the control population carried at leastone copy of the susceptibility allele. Only 5% of thepopulation had two short alleles and could be con-sidered at low risk. Because the high risk allele iscommon, this polymorphism is not expected to ac-count for clustering of prostate cancer in families.Ingles et al. [27] then extended their study to includeAfrican-Americans. The poly(A) polymorphism was

BBACAN 87426 16-11-98


found not to be associated with prostate cancer inthis population. However, a third polymorphism,characterized by a BsmI restriction site, was associ-ated with advanced disease (odds ratio 0.39;P6 0.05). Surprisingly, the presence of the allelewas protective in African-Americans, in contrast toa previous study of Caucasians, which found that theallele was associated with increased risk. It is possiblethat these inconsistent results are due to small samplesizes. However, it is also possible that the BsmI poly-morphism is in linkage disequilibrium with the truesusceptibility allele, and that di¡erent alleles of theBsmI polymorphisms are associated with susceptibil-ity in the two di¡erent populations. Kibel et al. [32]found no di¡erence in the frequency of alleles ofeither of the two vitamin D receptor polymorphisms(TaqI and poly(A)) between a group of 41 men whodied of prostate cancer and 41 healthy controls.

In the largest study to date, Ma et al. [35] foundno overall association between prostate cancer riskand either of the two RFLPs in the vitamin D re-ceptor among men enrolled in the Physician's HealthStudy. However, among the subgroup of men withlow levels of plasma 25-hydroxyvitamin D, there wasa 57% reduction of risk observed for one genotype.Men with this genotype also had signi¢cantly highercirculating levels of 1,25-vitamin D. The reductionwas greatest among oldest men.

A third candidate gene is poly(ADP ribose) poly-merase (PADPRP). Doll et al. [11] reported an asso-ciation between a speci¢c allele of the (PADPRP)and prostate cancer in black Americans, but theirsample size was small and their observations havenot yet been replicated.

13. Prostate cancer progression

Theoretically, genetic factors might in£uence anyof the stages of prostate carcinogenesis, and a¡ectthe cancer incidence rate, or the rate of cancer pro-gression [41]. For example, the observation that anincreased incidence of prostate cancer is associatedwith a particular allele might be because the alleleincreases susceptibility to prostate cancer, or that,once established, the allele is associated with an in-creased rate of tumor growth, or a tendency to me-tastasize. For this reason, it is possible that di¡erent

genetic patterns may be observed, or di¡erent sus-ceptibility genes described, depending on how thecancer phenotype is de¢ned. For example, studiesbased on the occurrence of prostate cancer at autop-sy may give di¡erent results from studies of men whoare known to have died from prostate cancer. Sim-ilarly, a study of men with metastatic disease maygive results which di¡er from a study based on aseries of men who were detected with prostate cancerthrough an elevated PSA.

Data from the Physician's Health Study suggestthat the androgen receptor polymorphisms a¡ectthe rate of metastatic progression from localized dis-ease. Ingles et al. [28] suggest that the presence of thevitamin D receptor polymorphism was a particularrisk factor for advanced disease.

Rebbeck et al. [44] studied the e¡ect of a CYP3A4polymorphism on stage of prostate cancer at diagno-sis. This gene is a member of the cytochrome P450supergene family and is involved in androgen metab-olism. Individuals can be classi¢ed into di¡erentCYP3A4 genotypes based on the presence or absenceof a polymorphism in the nifedipine-speci¢c elementin the 5P-regulatory region of the gene. The authorsdivided prostate cancer patients by clinical subgroup,family history and age. The variant CYP3A4 allelewas present in 43% of stage T3/T4 tumors, but only15% of T1/T2 tumors (P6 0.001).

Studies to date have compared stage and grade atpresentation with the distribution of alleles of thecandidate gene. Direct evidence that a candidategene is involved in cancer progression will comewhen it is shown that among men diagnosed withlocalized disease, the presence of a particular alleleis associated with more rapid progression to meta-static disease.

14. Screening for familial prostate cancer

One of the main goals of identifying geneticmarkers for prostate cancer is that these markerswill allow clinicians to identify men at high risk ofcancer for preventive strategies. Because little isknown about environmental causes of prostate can-cer, current preventive strategies focus on early de-tection through screening. Family history is probablythe most important known factor which can be used

BBACAN 87426 16-11-98


to identify men at high risk. The serum test for pros-tate speci¢c antigen (PSA) is proposed to be a sensi-tive and speci¢c means of detecting asymptomaticprostate cancer prior to metastatic spread. It ishoped that population-based screening programs us-ing PSA will be successful in reducing mortality fromthe disease. The positive predictive value of a screen-ing test will increase with the prevalence of the con-dition in the screened population. Narod and col-leagues [40] found that the positive predictive valueof a PSA test above 3.0 was higher for men with apositive family history of prostate cancer. For exam-ple, among men with a normal rectal examinationand a PSA greater than 3.0 mg per liter, 12% werefound to have cancer if the family history was neg-ative, but 27% were found to have cancer if there wasan a¡ected ¢rst-degree relative. Genetic factors otherthan a positive family history have not been eval-uated in the context of prostate cancer screening. Itwill be of interest to determine if speci¢c alleles ofthe androgen receptor, or of other candidate genes,are useful in improving the positive predictive valueof the PSA test.

It is currently recommended in many centers thatPSA screening be o¡ered to men with a family his-tory of prostate cancer, but there is no consensus yetas to the appropriate age at which screening shouldbegin. It appears that hereditary prostate cancer oc-curs at a young age, but it is not clear if prostatecancer screening for men with only one a¡ected rel-ative should begin prior to age 50. McWhorter et al.[37] screened 34 healthy men from high risk prostatecancer families. Each family contained two brothersa¡ected with prostate cancer. Screening was per-formed using both PSA and random four quadrantneedle biopsies. Prostate cancer was found in eight(24%) of the men. The PSA level was elevated in onlythree of the men with cancer. This study suggeststhat enhanced surveillance is warranted in high riskmen based on family history and raised the possibil-ity that such surveillance should also include a ran-dom biopsy.

Acknowledgements

I thank William Foulkes and Robert Nam forhelpful discussion.

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BBACAN 87426 16-11-98


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Genetic epidemiology of prostate cancer