Familial Prostate Cancer

Epidemiologic Reviews Copyright 2001 by the Johns Hopkins University Bloomberg School of Public Health All rights reserved Vol. 23, No. 1 Printed in U.S.A. Familial Prostate Cancer Janet L. Stanford 1 and Elaine A. Ostrander 2 INTRODUCTION This presentation reviews data on the familial component of prostate cancer and evidence to support a role of genetic susceptibility in this common and complex disease. Data from, cohort, cross-sectional, and twin studies provide consistent evidence for an inherited form of prostate cancer. Additional data from segregation analyses and family-based genetic linkage studies confirm the existence of an hereditary predisposition to prostate cancer. Although genetic polymorphisms in candidate genes (reviewed elsewhere in this issue of Epidemiologic Reviews) and shared environmental exposures may explain some familial clusters of prostate cancer, this review will focus on inherited susceptibility genes. To date, six loci for hereditary prostate cancer genes have been described. One putative gene has been cloned, which reportedly contributes to a small proportion of inherited disease. Once these genes are identified and associated mutations are characterized, genetic screening for prostate cancer susceptibility will become a reality. FAMILIAL AGGREGATION Familial aggregation describes the occurrence of multiple cases of prostate cancer within a family, although such clustering may be due to shared environment, shared genes, a combination of shared environmental and genetic effects, or chance given the high incidence of this disease. Clustering of prostate cancer within a family is evident when the frequency of prostate cancer among close relatives of prostate cancer patients is higher than the frequency of prostate cancer either in relatives of men without prostate cancer or in the general male population. Familial prostate cancer is commonly defined as a family in which there are two firstdegree (father, brother, son) relatives or one first-degree and at least two second-degree (grandfather, uncle, nephew, half brother) relatives with prostate cancer. This pattern of famil- Received for publication September 19, 2000, and accepted for publication March 13, 2001. Abbreviation: ICPCG, International Consortium for Prostate Cancer Genetics. 1 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. 2 Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA. Correspondence to Dr. Janet L. Stanford, Division of Public Health Sciences, Program in Epidemiology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., MVV-814, Seattle, WA 98109-1024 (e-mail: jstanfor@fhcrc.org). ial prostate cancer accounts for about 10-20 percent of all cases of the disease in the general population. A more strictly defined subset of familial prostate cancer, termed hereditary prostate cancer (1), describes families in which there is a pattern of Mendelian inheritance of rare susceptibility genes. Hereditary prostate cancer families are characterized by at least one of the following criteria: 1) three or more first-degree relatives with prostate cancer; 2) three successive generations with prostate cancer, either through paternal or maternal lineage; or 3) two siblings with prostate cancer diagnosed at a relatively young age (e.g., <55 years). It is estimated that hereditary prostate cancer may account for 5-10 percent of all cases of prostate cancer in the general population. However, as described below, the heritable form of prostate cancer may explain a larger proportion of the disease among younger men. The familial aggregation of prostate cancer has been recognized for over 40 years. As early as 1956, Morganti et al. (2) noted that a higher frequency of prostate cancer patients reported a close relative with the disease compared with hospitalized controls. Subsequently, Woolf (3) found that deaths due to prostate cancer were threefold higher among the fathers and brothers of men dying from prostate cancer compared with deceased relatives of men dying from other causes. In terms of heritability, two studies suggest that prostate cancer is more likely to be due to genetic factors than other major cancer sites with known susceptibility genes, such as breast and colon cancers (4, 5). A recent estimate indicates that as much as 42 percent (95 percent confidence interval: 29 percent, 50 percent) of the risk of prostate cancer may be accounted for by heritable factors (5). This summary estimate reflects the influence of rare, highly penetrant genes, more frequent weakly penetrant genes, and genes acting in concert with each other. Many epidemiologic studies employing different designs and populations have consistently found that a family history of prostate cancer in a first-degree relative is associated with at least a doubling of risk among relatives (6). Selected hospital-based (7, 8) and population-based (9-12) casecontrol and cohort studies (13-15) are summarized in table 1. As shown, the relative risk estimates associated with a history of prostate cancer in a first-degree relative range from 1.7 to 3.7, and all are statistically significantly elevated. Several of these studies found no significant increase in risk for men reporting second-degree affected relatives (7-9). However, younger ages at diagnosis and multiple relatives with prostate cancer were both associated with even higher relative risks. For example, men with three or more 19

20 Stanford and Ostrander TABLE 1. Summary of selected studies of prostate cancer risk according to family history Study (reference no.) and year Design No. of cases For first degree relative RR* 95% Cl* 2.0 1.2,3.2 RR in youngest age group 2.4 (<55 years) RRin multiple affecteds Steinberg et al. (7), 1990 Spitz et al. (8), 1991 Whittemore et al. (9), 1995 Hayes etal. (10), 1995 Leskoetal. (11), 1996 Ghadirian et al. (12), 1997 Goldgaretal. (13), 1994 Gronberg et al. (14), 1996 Cerhanetal. (15), 1999 Hospital-based, Hospital-based, 691 378 1,500 981 563 640 1,376 302 101 2.4 2.5 3.2 2.3 3.3 2.2 1.7 3.7 1.2,4.5 1.9,3.3 2.0, 5.0 1.7,3.3 2.2, 5.1 2.1,2.4 1.5, 1.9 1.9,7.2 2.6 (<60 years) 4.1 (<60 years) 5.3 (<60 years) 4.1 (<60 years) 3.4 (<50 years) 4.4 (<70 years) 4.9 (>2 relatives) 10.9 (>3 relatives) 4.2 (>2 relatives) 3.9 (>2 relatives) 2.8 (>2 relatives) * RR, relative risk; Cl, confidence interval. first-degree relatives with prostate cancer have almost an 11-fold increased risk of the disease compared with men with no family history (7). Although the majority of studies focused on whites, similar twofold or higher elevations in risk associated with a family history of prostate cancer have been reported for Asians (9) and blacks in the United States (9, 10) and Jamaica (16). Twin studies also support 'a role for inherited genes in the development of prostate cancer and suggest that this effect is independent of environmental factors. There is a higher concordance of prostate cancer among monozygotic twins (range: 16-20 percent) compared with dizygotic twins (range: 4 10 percent), and a substantial proportion of the variance of disease incidence (range: 36-57 percent) among twins can be attributed to genetic effects (17-20). Based on these data, segregation analyses were undertaken to characterize the genetic models that may explain the familial/ hereditary pattern of prostate cancer incidence. SEGREGATION ANALYSES The first segregation study, done by Carter et al. (21), analyzed data on 691 prostate cancer families ascertained though consecutive probands undergoing radical prostatectomy. The results showed that early age of onset and multiple affected family members were the strongest predictors of risk in relatives. Familial clustering of disease among early onset cases was best explained by the presence of rare autosomal dominant, highly penetrant allele(s) (q = 0.003), with carriers having an 88 percent cumulative risk of disease by the age of 85 years, compared with only 5 percent for noncarriers (21). Inherited alleles were predicted to account for about 43 percent of early onset disease (age <55 years) and 9 percent of total prostate cancers diagnosed through age 85 years. Two more recent studies provide similar data. Gronberg et al. (22) analyzed a population-based sample of 2,857 Swedish nuclear families. These data also support an autosomal dominant model of inheritance, but suggest a higher frequency of the susceptibility allele (1.67 percent) and a lower lifetime penetrance of 63 percent. Finally, Schaid et al. (23) analyzed 4,288 men undergoing radical prostatectomy during 1966-1995. Although no single genetic model of inheritance clearly explained familial clustering in these data, the best fitting model was also that of a rare autosomal dominant susceptibility gene with the best fit observed in men diagnosed before age 60 years. This analysis proposed a gene population frequency of 0.006, with a risk of 89 percent by age 85 years for carriers. In addition, the data suggest that 68 percent of all prostate cancers diagnosed before age 60 years may be accounted for by autosomal dominant genes (23). Following the initial segregation analysis in support of dominant susceptibility genes, several genome-wide scans were undertaken (24-26) to map the location of such genes. To date, six prostate cancer susceptibility loci have been identified and are briefly described below. HEREDITARY GENES Prostate cancer loci have now been mapped to chromosomes lq24-25, Iq42, Xq27-28, Ip36, and 20ql3 (24, 27-30). In addition, a putative susceptibility gene has recently been described on chromosome 17p. In each case, the findings resulted from complete or partial genome scans followed by extensive heterogeneity analysis to determine the subset of families most likely to be linked. Because HPC1 was the first linkage reported, it has been the most heavily scrutinized by the scientific community, and valuable insights have been gleaned regarding the contributions that genetic heterogeneity, phenocopy, and model mispecification make to the analysis of complex traits such as prostate cancer. Therefore, we have selected HPC1 for a detailed discussion and describe the other four loci only briefly.

Familial Prostate Cancer 21 HPC1 was mapped to chromosome lq24-25 by linkage analysis of 91 high-risk prostate cancer families from the United States and Sweden, each having at least three affected first-degree relatives (24). A maximum multipoint Lod score of 5.43 was obtained under the assumption of heterogeneity, with 34 percent of families hypothesized to be linked. These conclusions were strongly supported by significant nonparametric linkage results (31) (maximum multipoint z score = 4.71, p < 0.000001). While the initial report did not suggest any subgroup of families were more or less likely to be linked, a strong age of onset effect, with nearly all linked families having an average age of diagnosis <65 years, has since been noted (32). Although still a topic of debate (33), Gronberg et al. (32) also reported that high grade cancers and advanced stage disease were more common in potentially linked families. While the initial reports of linkage to HPC1 were clearly significant, efforts to replicate these results have been inconclusive. Based on nonparametric analyses, both Cooney et al. (34) and Hsieh et al. (35) weakly support the observations of Smith et al. (24), with nonparametric linkage scores of 1.72 (p = 0.045) and 1.83 (p = 0.036), respectively. The significance of these results, however, is debatable. Lander and Kruglyak (36) have suggested a p value of <0.01 for replication of significant linkage, which reflects a nominal p value of 0.05, but with correction for a modest amount of multiple testing. Therefore, while the above data support the original result, they do not formally confirm it. Other investigators testing independent but seemingly similar data sets, including as many as 150 families, also failed to replicate the initial HPC1 finding (27, 37, 38). There are, however, three recent papers providing weak confirmatory evidence for linkage which shed light on this seemingly contradictory result. First, in an analysis of 41 Utah families with a mean number of 10.7 affecteds per family, Neuhausen et al. (39) observed evidence for linkage with two and three point Lod scores of 1.73 (p 0.0005) and 2.06 (p = 0.002), respectively. These authors hypothesized that the extraordinarily large number of cases per family provided sufficient power to overcome the problem of phenocopies. The authors also observed that adjustments to the transmission model to better fit the true age at diagnosis observed in the Utah families provided stronger confirmation. This latter fact suggests that model mispecification may contribute to the contradictory findings and is consistent with emerging thinking that the model-free nonparametric linkage statistic may be more appropriate for analysis of complex traits than traditional parametric approaches (40). Based on these findings, the International Consortium for Prostate Cancer Genetics undertook a pooled analysis of HPC1 in 773 hereditary prostate cancer families. Overall, the parametric analysis provided weak evidence for linkage at Iq24, with an estimated proportion of 6 percent of families linked (41). No evidence for linkage was observed using a nonparametric analysis approach, perhaps due to extensive heterogeneity. Because the data set was so large, more refined analyses were then undertaken and revealed that a disproportionate contribution to linkage was derived from families with evidence of male-to-male inheritance. Stronger results were also seen in families with an early mean age at diagnosis (<65 years) or those with many (five or more) affected men. These conclusions are supported by Berry et al. (42), who showed modest evidence for linkage to HPC1 in a data set of 102 families with male-to-male transmission (nonparametric linkage = 1.99, p = 0.03). In aggregate, these studies demonstrate that any approach defined a priori to either increase power or reduce heterogeneity can be the key to unraveling the genetics of a complex trait. The mapping of four additional loci, HPCX, HPC20, CAPB, and PCAP also illustrate these principles. HPCX was mapped to Xq27-28 (maximum two-point Lod score of 4.60 at 0 = 0.26) by a consortium of four groups analyzing 360 families (28). Key to their success was the stratification of families by apparent mode of transmission, i.e., the presence or absence of a male-to-male transmission pattern, with the strongest evidence for linkage coming from the 129 families without evidence of paternal transmission. Although the estimates varied dramatically between the individual groups contributing to the analysis, overall HPCX is estimated to account for 16 percent of familial prostate cancer. Support for these findings has been reported by two other studies (43, 44). Interestingly, however, in the analysis of Lange et al. (43), the 11 African- American families had consistently negative nonparametric linkage z scores across the region, suggesting that HPCX may not be a major susceptibility gene for prostate cancer in this population. However, larger studies will be required to confirm or refute this observation among African-American families with prostate cancer. Stratification by male-to-male transmission was also instrumental in the mapping of HPC20, identified by Berry et al. (30) following a genome-wide scan of 162 North American families. The strongest evidence for linkage was in families with less than five affected men, a later age at diagnosis, and no evidence of male-to-male transmission, with the strongest results seen in the latter (multipoint nonparametric linkage = 3.94, p =. 0.00007). While the above mapping efforts highlight the power of stratification by presumed mode of inheritance, the mapping of the CAPB gene illustrates the power of subset identification in which detailed family cancer history data are available. Focusing only on prostate cancer families with a confirmed family history of primary brain cancer, a prostate cancer susceptibility locus at Ip36 with a maximum twopoint Lod score of 3.22 at 0 = 0.06 was identified (29). This region was of particular interest since an excess of brain and central nervous system cancers had been reported previously in prostate cancer families (13, 45), and because Ip36 is a region of frequent loss of heterozygosity (LOH) in brain tumors. Again, stratification by age of onset was useful as the majority of the evidence was derived from families with a mean age at diagnosis of prostate cancer of <66 years (maximum two-point Lod score of 3.65 at 9 = 0.0). The mapping of one other locus, PCAP, to Iq42.43 using a set of 47 French and German families also illustrates the value of increased homogeneity in locus identification (27). While there has been some weak confirma-

22 Stanford and Ostrander tory evidence for this locus (46), in general, lack of replication reports mimicking those initially described for HPCl have been published (42, 47). This is not surprising in that US families reflect much greater genetic diversity than the families used in the initial study, and no stratification has yet been reported which removes likely X- linked families. Recently, evidence for a prostate cancer susceptibility gene on chromosome 17p, termed HPC2IELAC2, has been reported. In 33 high-risk prostate cancer families from Utah, a maximum two-point Lod score of 4.5 was observed at marker D17S1289 (G = 0.07); however, expansion of the data set to 127 families failed to provide evidence for the linkage (48). Positional cloning efforts identified ELAC2 as the candidate gene, although only two of the families were found to segregate mutations in this gene. In addition, two missense changes (Ser217Leu, Ala541Thr) in the gene, which were reported to be in strong linkage disequilibrium, were observed more frequently in prostate cancer cases than among unaffected family members or among a group of unrelated controls. A subsequent clinic-based study found the "at risk" genotype, i.e., the combined Leu217/Thr541 variants, in 7.5 percent of prostate cancer patients and 3.5 percent of the controls (49). Although these results are intriguing, the assertion that HPC2/ELAC2 is a candidate prostate cancer susceptibility gene awaits confirmation from other high-risk family linkage and population-based casecontrol studies. INTERNATIONAL CONSORTIUM FOR PROSTATE CANCER GENETICS To accelerate progress in the field of gene discovery, the International Consortium for Prostate Cancer Genetics (ICPCG) was formed in 1995. This collaborative effort includes investigators from 11 groups worldwide who have ascertained families in which two or more close relatives have been diagnosed with prostate cancer. A major advantage of the consortium is the ability to pool data on large numbers of families, which provides more power to evaluate complex diseases such as prostate cancer and to analyze more homogeneous subgroups in which evidence for a given locus may become more apparent. One of the first projects completed by the ICPCG was an analysis of HPCl in 772 families (41). This analysis allowed for more precision in estimating what proportion of high-risk families may be linked to this locus (6 percent), and stratification of families by age and other characteristics, such as assumed mode of inheritance, in an effort to create more homogeneous subgroups. The consortium approach may help deal with problems such as genetic and locus heterogeneity and enhances statistical power for subset analyses. Several additional analyses of pooled data from the ICPCG are planned to further evaluate the evidence for other reported loci. Based on experience to date, the ICPCG is poised to make important contributions to understanding the underlying molecular biology and genetic epidemiology of familial and hereditary prostate cancer over the coming decade. FUTURE CLINICAL IMPLICATIONS Once the genes that predispose to hereditary prostate cancer are cloned and the specific genetic changes that trigger the development of prostate cancer are defined, there will be an opportunity to identify men at high risk. Knowledge of the characteristics of prostate cancer patients from high-risk families with particular genetic mutations will allow for more accurate genetic counseling and may be used to target early detection programs. At the present time, the approach for reducing morbidity and mortality for men at elevated risk of prostate cancer is through annual screening for the disease, i.e., testing of serum prostate-specific antigen level and digital rectal examination. This recommendation is based on the notion that early detection of cancer allows for treatment when the disease is most curable. The identification of men prone to develop prostate cancer based on their genetic background may also be used to target prevention programs. Predictive genetic testing will be vital if cancer prevention strategies, such as dietary changes, use of nutritional supplements, or use of chemopreventive agents, are shown to alter the natural history of prostate cancer in high-risk men. Among men with predisposing genetic mutations, such interventions may not eliminate prostate cancer risk, but may alter the pattern of disease incidence or severity. 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