Challenges to linkage studies of prostate cancer

Paralleling studies of other complex diseases, segregation analyses have suggested a heterogeneous genetic etiology of inherited prostate cancer that is characteristic of complex diseases. The suggestion of multiple modes of inheritance implicates the presence of multiple genes in hereditary prostate cancer susceptibility. In linkage studies, the presence of genetic heterogeneity dramatically decreases the power to detect the effect of any single major gene when the LOD scores of multiple families (presumably with a spectrum of inherited mutations) are tabulated.

As if genetic variability were not enough of a barrier to the detection of prostate cancer susceptibility genes, linkage analysis of prostate cancer has also proven difficult because the natural history and clinical characteristics of this disease beget many pedigrees that are only marginally informative for linkage analysis. Commonly samples from affected men in multiple generations of a family are not available because, relative to the proband, individuals in the parental generations are more likely to be deceased, and individuals in the offspring generations are usually too young to manifest the phenotype. This creates a narrow range of available affected individuals within a given family and may be further limited by the clinical misclassification intrinsic to prostate cancer within the context of a family history. Men from high-risk families who carry a high-risk susceptibility gene, and who truly have a high lifetime risk for prostate cancer, may avoid identification due to death from an unrelated disease or accident at a relatively young age. All of this may be further confounded by the presence of phenocopies (non-gene carriers with disease) within a family. Given the high prevalence of prostate cancer and the fact that twin studies have established a significant contribution of environmental factors to prostate cancer, the presence of phenocopies within hereditary prostate cancer families may pose a significant problem for linkage analyses. The late age of onset, incomplete penetrance, age-dependent penetrance and high prevalence of the disease may collectively result in misclassified inheritance patterns and loss of power in linkage studies. The complexity of prostate cancer genetics was suspected when the first genomewide screen for inherited prostate cancer susceptibility genes were initiated, although this complexity may not have been fully appreciated by many researchers in this field until relatively recently. Indeed, as of the writing of this capter, there appears to be no definitive prostate cancer gene of any clinical utility.

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