Disease summary:

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  Prostate cancer is the second most fatal cancer for American men. It is the most common male noncutaneous cancer in developing countries, and a leading cause of death for men 60 years or older.

  
  
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  Age, African ancestry, and a positive family history are risk factors for disease development (Table 48-1).

  
  
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  Recent evidence suggests that approximately 10% of prostate cancers are hereditary.

  
  
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  Adenocarcinoma, cancer of glandular epithelial cells, is the most commonly diagnosed form.

  
  
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  Early diagnosis significantly improves treatment response and overall survival and is based on both biochemical studies using prostate-specific antigen (PSA) levels in patients and subsequent biopsies with Gleason scoring.

  
  
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  Treatment modalities for prostate cancer include hormone-based approaches, radiation, cytotoxic chemotherapy, and radical prostatectomy. Despite proper treatment many prostate cancer patients experience recurrence and will eventually develop aggressive metastatic prostate cancer, even when presenting initially with localized or indolent disease. No consistent biomarkers yet exist to distinguish between indolent and aggressive forms. Prostate cancer’s genetic heterogeneity and complexity have hindered the elucidation and exploitation of the pathways driving pathogenesis and disease progression.

Hereditary basis:

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  While age, race, and family history are known risk factors for prostate cancer, our understanding of the genetic basis of disease remains unclear. Germline mutations, often inherited in an autosomal dominant manner, may account for 9% of all prostate cancers and 45% of cases in men younger than 55 years. Linkage-based studies, positional gene cloning, and genome-wide association studies (GWAS) have been attempted and for the most part have been relatively unsuccessful in identifying the molecular basis for inherited risk.

  
  
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  Complex segregation analyses have modeled the effects of genetics on familial prostate cancer. Carter et al. imply that familial aggregation can be best explained by autosomal dominant inheritance of a rare, high-risk allele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer in this study was 88% for carriers and 5% for noncarriers by age 85 years. This inherited form of prostate cancer was estimated to account for a significant fraction of early-onset disease, and in total account for about 9% of all cases of the disease.

  
  
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  Men with a familial risk of prostate cancer represent an enriched pool for the identification of mutations and polymorphisms in tumor suppressor genes that lead to both the development and progression of the disease. This is based on the standard established methodologies and paradigms established for other cancer predisposition gene discoveries, in which the use of linkage analysis and positional gene cloning families is used to identify causative genes of interest. Genes identified in this manner can then be further examined and studied for their potential role in the progression of sporadic cancer. This approach has localized a number of prostate cancer-susceptibility loci and identified genes including PTEN1, HPC1, and KLF6 (Table 48-2).

  
  
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  Race-associated differences in prostate cancer incidence and aggressiveness suggest an interaction between both hereditary and environmental factors. Epidemiologic studies have shown that the incidence of prostate cancer is highest in the Scandinavian countries while Asian countries have the lowest rates. African-American men have the highest risk for prostate cancer development, and in general are diagnosed with more advanced disease than Caucasians. African-American men also have higher mortality rates, even when diagnosed at the same clinical stage. The presence of significantly shorter CAG and GGC trinucleotide alleles of the androgen receptor gene in African Americans compared to non-African populations may represent a possible explanation for the increased risk, higher grade, and advanced stage of prostate cancer at diagnosis.