Cancer Health Center

Like most cancers, prostate cancer is a complex neoplastic disorder in which disease initiation is the result of an interaction between genetic and nongenetic factors. The identification of causative genes for prostate cancer, however, has been elusive in spite of segregation analyses of prostate cancer families that support the existence of one or more hereditary prostate cancer genes. [1,2,3,4,5,6,7,8] Several candidate loci have been identified by performing genome-wide linkage analysis studies in high-risk families, but confirmation of these proposed susceptibility loci from subsequent studies has occasionally been lacking. Further, some prostate cancer susceptibility genes have been characterized by positional cloning, but follow-up studies have not yet demonstrated that any of these loci contribute to a significant number of high-risk prostate cancer families. While the goal of linkage analysis is to identify the chromosomal location of prostate cancer susceptibility genes, none of the putative genes in these regions identified to date have been widely accepted as clinically useful. Examples of loci that have been identified in studies of high-risk families are discussed below and are summarized in Table 2.

Prostate Cancer Linkage Studies

The recognition that prostate cancer clusters within families has led many investigators to collect multiplex families with the goal of localizing prostate cancer susceptibility genes through linkage studies. Despite the extensive collection of prostate cancer families and the formation of a collaborative research group (the International Consortium for Prostate Cancer Genetics [ICPCG]), the identification of prostate cancer genes has been exceedingly difficult. A review of eight prostate cancer linkage studies that evaluated a total of 4,600 cases of prostate cancer from 1,293 kindreds found several methodological differences. The authors suggest that differences in populations, enrollment criteria, and underlying genetic models used for each analysis may account for the lack of consistency between linkage studies.[9] The following discussion highlights both the clinical and research issues leading to this complexity.

Linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals, and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. The statistical power of linkage analysis is affected by the following:

• Family size and having a sufficient number of family members who volunteer to contribute DNA.
• The number of disease cases in each family.
• Factors related to age at disease onset (e.g., utilization of screening).
• Gender differences in disease risk (not relevant in prostate cancer but remains relevant in linkage analysis for other conditions).
• Heterogeneity of disease in cases (e.g., aggressive vs. non-aggressive phenotype).