Commentary (Stanford/Ostrander): Prostate Cancer Risk Assessment Program

Bruner et al describe a model for risk assessment and genetic counseling of individuals and families at increased risk for prostate cancer. This model includes the establishment of a prostate cancer risk registry and screening clinic for unaffected men at higher risk. The latter component assumes that early detection and treatment of prostate cancer are curative, although the effectiveness of screening in reducing prostate cancer mortality remains controversial. There also is ongoing debate about the most effective treatment options and associated quality-of-life issues.

Several large-scale, randomized trials are underway to evaluate the efficacy of prostate cancer screening, although indirect evidence supports a potential benefit. For example, since the introduction of prostate-specific antigen (PSA) testing in the middle to late 1980s, there has been a significant decline in the incidence of advanced-stage prostate cancer.[1] Furthermore, age-adjusted US mortality from prostate cancer declined by 7% in whites from 1991 to 1995 and by 5% in blacks from 1993 to 1995. Among men under age 65 years, the magnitude of the decline in mortality was even greater, with a 15% reduction observed in whites and a 11% decrease in blacks from the early to mid-1990s.[2]

A definitive answer regarding the efficacy of prostate cancer screening in reducing mortality must await the results of the ongoing trials. However, the American Cancer Society currently advocates annual screening with digital rectal examination (DRE) and PSA beginning before age 50 years for men at higher risk (defined as African-American men and men with two or more first-degree relatives with prostate cancer).

Multidisciplinary team efforts, such as those described in the article by Bruner et al, will be important in developing appropriate methods and protocols for risk assessment and genetic counseling, as well as educational materials, for the substantial number of men who may seek these services. A greater challenge will be the refinement of the definition of which individuals are at increased risk based on genetic predisposition. Family structure and cancer history, population-based data, and risk factor profiles will need to be carefully examined so that predictive genetic screening and intervention activities can be targeted toward men most likely to benefit.

Limited Knowledge About Causation

Prostate cancer is a major source of morbidity and mortality, accounting for an estimated 29% of all newly diagnosed cancers and 13% of all cancer deaths in US men in 1998.[3] Despite its high incidence, knowledge about the causes of prostate cancer is limited.

Age is the strongest risk factor identified for prostate cancer; incidence increases steeply after age 40 years. The average age at diagnosis is 71 years in whites and 69 years in blacks. With the introduction of the PSA blood test for early detection of the disease, more patients are being diagnosed at younger ages.

African-American and Caucasian-American men have the highest incidence rates of prostate cancer in the world.[2] Within the United States, the incidence of and mortality from prostate cancer are approximately 60% and 100% higher, respectively, in blacks compared to whites.[2]

Aside from age and race, a family history of prostate cancer is the only other established risk factor for the disease. Epidemiologic studies confirm that there is a strong familial component of prostate cancer etiology, particularly among men diagnosed at younger ages.

A family history of prostate cancer in a first-degree relative (father or brother) has consistently been associated with significant two- to threefold elevations in relative risks,[4-6] with similar findings observed in US whites, blacks, and Asians. Significantly increased relative risks (RR) have been reported for brothers of prostate cancer patients who were diagnosed before age 65 years (RR = 6.0)[7] and for men with two (RR = 5.0) or three (RR = 11.0) first-degree family members affected with prostate cancer.[4]

Several segregation analyses support an autosomal-dominant model of prostate cancer inheritance, with both early age at diagnosis and multiple affected family members being strong predictors of risk.[8-10] Carter et al[8] hypothesized that inheritance of rare allele(s) (q = 0.003)* with a high lifetime penetrance (88%) may explain only about 9% of all prostate cancers but perhaps as many as 43% of all cases diagnosed at an early age (£ 55 years).

*q = Prevalence of the high-risk allele in the general population

A more recent population-based segregation analysis estimated a higher frequency of the dominant risk allele(s) in the population (q = 0.0167) and a lower lifetime penetrance of 63%.[9] Data from two other studies, conducted in a hospital-based screening clinic population and a population-based cohort, showed a higher relative risk of prostate cancer in men with affected brothers than in those with affected fathers; these data led to the hypothesis that there is an X-linked, or recessive, model of inheritance of susceptibility genes for prostate cancer.[11,12] Based on these analyses, several groups initiated genome-wide searches for loci contributing to hereditary prostate cancer.

Four Susceptibility Loci Identified

To date, four inherited susceptibility loci for prostate cancer have been mapped by linkage analysis. A study of 91 high-risk prostate cancer families (defined as those families with three or more first-degree relatives with prostate cancer, three generations with prostate cancer, or two first-degree relatives with prostate cancer diagnosed at a relatively young age) led to the identification of the first prostate cancer susceptibility locus (HPC1) on the long arm of chromosome 1 (1q24-25).[13] Confirmation of this linkage result has been reported by some[14,15] but not all[16-18] studies of high-risk prostate cancer families.

A second prostate cancer susceptibility locus (PCAP) was localized to 1q42.2-43 in a set of 47 French and German families,[18] and a third locus (HPCX) was mapped on the X chromosome (Xq27-28) by an international collaboration of groups from the United States, Sweden, and Finland.[19]

Most recently, a fourth susceptibility locus was identified on the short arm of chromosome 1 (1p36).[20] This locus (CAPB) appears to be important in high-risk prostate cancer families in which there are also close relatives with primary brain cancer.

Evidence corroborating linkage results for the latter three loci has not yet been reported, although several groups are working on these analyses. Based on the characteristics and proportions of families assumed to be linked to the above loci, however, it is clear that additional loci for hereditary prostate cancer remain to be mapped. Ongoing linkage analyses of genome-wide scans will undoubtedly identify other important susceptibility loci over the next few years.

Assessing High-Risk Families and Individuals

Mapping of inherited susceptibility loci for prostate cancer in high-risk families is a major step toward understanding the molecular origins of the disease. Once linkages are confirmed and specific mutations in these genes are identified, we can assess both high-risk families as well as individuals deemed “at risk” from population-based studies to determine the likelihood of disease given a particular mutation and family history profile.

Collective experiences with the breast cancer susceptibility genes BRCA1 and BRCA2 have taught us that this is apt to be a difficult process. Studies of high-risk families suggest that mutations in BRCA1 and BRCA2 are highly penetrant, with over 80% of female carriers acquiring the disease at some point in their life.[21,22] However, in studies of Ashkenazi Jewish women culled from the general population, the penetrance appears to be much lower for both breast and ovarian cancer, even though such women carry mutations commonly observed in high-risk families.[23] This finding suggests that there may be particular genetic backgrounds that affect risk, or, alternatively, that extremely high-risk families really represent an aggregation of stochastic risk.

This is mirrored in the age-dependent penetrance observed with mutations of cancer genes. Although studies of high-risk families suggest that such mutations are highly penetrant, they are only about 50% penetrant, for instance, by age 50 years.[24] Since there is little correlation between type or location of mutation and penetrance, the question of which genetic backgrounds and environmental risk factors affect penetrance is now the focus of intense study by several groups. Incorporation of such data into risk assessment models will lead to greater accuracy in predicting disease incidence.

Based on the accelerated level of progress in the field of molecular genetics, susceptibility genes for this disease will likely be cloned within the next few years. Genetic screening for prostate cancer will then become a reality, and programs that offer genetic testing and counseling, early detection and screening for disease, prevention strategies and related educational materials will be in demand. Given the anticipated discovery of inherited genes that predispose to prostate cancer, the predictive risk assessment model of Bruner et al is both timely and comprehensive.

References:

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2. Stanford JL, Stephenson RA, Coyle LM, et al: Prostate cancer trends 1973-1995. SEER Program, National Cancer Institute. Bethesda, Maryland, 1998 (in press). Available at: http://www-seer.ims.nci.nih.gov.

3. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1998. CA Cancer J Clin 46:6-29, 1998.

4. Steinberg GD, Carter BS, Beaty TH, et al: Family history and the risk of prostate cancer. Prostate 17(4):337-347, 1990.

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6. Whittemore AS, Wu AH, Kolonel LN, et al: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141(8):732-740, 1995.

7. Cannon L, Bishop DT, Skolnick M, et al: Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv 1(1):47-69, 1982.

8. Carter BS, Beaty TH, Steinberg GD, et al: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci 89(8):3367-3371, 1992.

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13. Smith JR, Freije D, Carpten JD, et al: Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274:1371-1374, 1996.

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16. McIndoe RA, Stanford JL, Gibbs M, et al: Linkage analysis of 49 high-risk families does not support a common familial prostate cancer-susceptibility gene at 1q24-25. Am J Hum Genet 61:347-353, 1997.

17. Eeles R, Durocher F, Edwards S, et al: Linkage analysis of chromosome 1q markers in 136 prostate cancer families. Am J Hum Genet 62:653-658, 1998.

18. Berthon P, Valeri A, Cohen-Akenine A, et al: Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet 62:1416-1424, 1998.

19. Xu J, Meyers D, Freije D, et al: Evidence for a prostate cancer susceptibility locus on the X chromosome (letter). Nat Genet 20:175-179, 1998.

20. Gibbs M, Stanford JL, McIndoe RA, et al: Evidence for a rare prostate cancer susceptibility locus at chromosome 1p36. Am J Hum Genet, 1998 (in press).

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22. Easton DF, Ford D, Bishop DT and the Breast Cancer Linkage Consortium: Breast and ovarian cancer incidence in BRCA1 mutation carriers. Am J Hum Genet 56:265-271, 1995.

23. Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutation of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401-1408, 1997.

24. Ford D, Easton DF, Peto J: Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 57:1547-1562, 1995,