Candidate Prostate Cancer Susceptibility Genes Identified Through Linkage Studies

As described under Subheading 2, overwhelming evidence now exists to support a strong genetic influence in the etiology of at least some fraction of prostate cancer cases. However, the definition and characterization of this genetic influence is far more nebulous. Several major approaches have

Fig. 2. Regions of implicated to harbor prostate cancer susceptibility genes from linkage studies of prostate cancer families. (Adapted from Simard et al. 2003).

been taken to define the genes involved in inherited susceptibility for prostate cancer. Based on the foundation laid by segregation analyses, many groups worldwide have pursued linkage studies of families with multiple men affected with prostate cancer to map genes affecting prostate cancer susceptibility. Systematic searches using family-based linkage scans with genetic markers genotyped at approx 10-cM intervals along each chromosome can provide powerful statistical evidence of the existence and location of disease predisposing genes. Hereditary prostate cancer 1 (HPC1) on chromosome 1 was the first locus implicated in prostate cancer using this approach (30), and numerous other loci have now been suggested to contain prostate cancer susceptibility genes (Fig. 2). ELAC2 at 17q (31), RNASEL at 1q24-25 (HPC1) (32), and MSR1 at 8p22 (33) are genes located in regions implicated by linkage analysis, and which contain inactivating mutations in affected members of at least one or more prostate cancer families.

3.1. ELAC2/HPC2

A genome-wide scan of extended high-risk pedigrees from Utah provided evidence for linkage to a locus on chromosome arm 17p (31). Positional cloning and mutation screening within the defined region allowed identification of a gene, ELAC2, harboring mutations that segregate with prostate cancer in two pedigrees; one mutation is a frame shift and the other a nonconservative missense change. In addition, two common missense variants, Ala541Thr and Ser217Leu, in the gene were reported to be associated with the occurrence of prostate cancer (31,34). Follow-up studies have been carried out by multiple independent groups. Although some positive associations of these two mis-

sense variants have been found, several null findings have been reported as well (35-42). A metaanalysis of six independent studies estimated that risk genotypes in ELAC2 may cause 2% of prostate cancer in the general population (43).

3.2. RNASEL

The RNASEL gene encodes the 2'-5'-oligoadenylate-dependant RNase L, a mediator of the interferon-induced RNA degradation pathway mediating defense against viral infection. Its tumor suppressor potential has been postulated because the introduction of truncated RNase L protein in murine cells abolished the antiproliferative effect of interferon (44). The RNASEL gene locus was implicated in prostate cancer susceptibility as a result of the first genome-wide linkage scan, which observed evidence of linkage at 1q25 in 91 hereditary prostate cancer pedigrees from North America and Sweden (30), and the subsequent identification of a nonsense mutation E265X in four affected brothers in a European-American family, and a second deleterious variation, Mil, in affected brothers in a family of African descent (32). In a follow-up study by Finnish investigators (45) of 116index cases with hereditary prostate cancer, the truncating mutation,E262X, was found in five (4.3%) cases; four of these five index cases came from families with at least three men with prostate cancer. A study by Chen et al. (46) of 95 men with prostate cancer from 75 families found the E262X mutation in one family, with two of three affected brothers being heterozygous carriers. In a study of Ashkenazi Jews, a novel frameshift mutation (471delAAAG) in RNASEL was detected, which leads to premature truncation of the protein, and was estimated to be as frequent as 4% in this population (47). A subsequent study by Kotar et al. (48) confirmed the presence of this founder mutation in an Ashkenazi Jewish population in Montreal, but found no significant association with prostate cancer risk.

Using families from the United States, Casey et al. (49) evaluated a common missense variant of RNASEL, Arg462Gln, which codes for a protein with decreased enzymatic activity. From 423 cases and 454 sibling controls, it was estimated that heterozygous carriers of the Gln-containing allele had an OR of 1.46, and homozygous carriers had an OR of 2.12, giving a population attributable fraction for this variant of 13%. A study conducted at the Mayo Clinic found an opposite trend, however, with ORs of 0.83 for heterozygotes and 0.54 for homozygotes (50). Furthermore, a study from Japan based on 101 familial prostate cancers and 105 controls did not find the Arg462Gln variant among any cases, but found that 7.6% of the controls carried it (51). Nonetheless, this study did find an increased prostate cancer risk for a different RNASEL variant, Asp541Glu, with an OR of 3.07. Subsequent studies in both the German (52) and Swedish (53) family populations failed to find significant evidence for RNASEL as a prostate cancer susceptibility gene. Thus, although a number of studies provide support, both functional and epidemio-logical, that RNASEL plays a role in hereditary prostate cancer, evidence to the contrary has also been presented.

The MSR1 gene is located on 8p22 and encodes a homotrimeric class A scavenger receptor. This receptor is macrophage specific and is able to bind a wide range of polyanionic ligands, which includes gram-negative and gram-positive bacteria, oxidized low-density lipoprotein, and certain polynucleotides. As part of a systematic evaluation of genes in a region of linkage on 8p, Xu et al. (33) found multiple carriers of nonsense and missense mutations in MSR1 in a collection of prostate cancer families. To date, seven studies have been published regarding the role of MSR1 mutations and variants with prostate cancer risk (33,54-60). These studies investigated the R293X-null mutation and prostate cancer risk, as well the association of the rare mutations, S41T and D174Y, which were only detected in African-American men (33,55,60), and five common sequence variants: PRO3, 1NDEL1, IVS5-59, P275A, and INDEL7. As with ELAC2 and RNASEL, however, the results were inconsistent across different reports, and it has been difficult to draw definitive conclusions from the individual studies. To address this issue, Sun et al. performed a meta-analysis that included all of the published studies on MSR1 up to September 2005 (61). This analysis indicated that several variants were significantly associated with sporadic prostate cancer risk, including R293X in white men (fixed effect OR, 1.35; p = 0.04; and random effect OR, 1.34; p = 0.09) and D174Y in black men (fixed effect OR, 2.39; p = 0.01; and random effect OR, 2.41; p = 0.04). When the initial study was excluded from the meta-analysis, the associations with prostate cancer risk were not significant in the remaining replication studies. However, the frequency of the D174Y mutation was consistently higher among cases in all three studies that examined African-American men. Overall, this meta-analysis suggests the MSR1 gene does not independently confer a major risk to prostate cancer but may confer a moderate risk to prostate cancer, especially in African-American men.

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