Prostate cancer susceptibility genes: lessons learned and challenges posed.

Abstract

In most developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that the role of candidate genetic markers to this multifactorial malignancy is more difficult to identify than the identification of other cancer susceptibility genes. Indeed, despite the localization of several susceptibility loci, there has been limited success in identifying high-risk susceptibility genes analogous to BRCA1 or BRCA2 for breast and ovarian cancer. Nonetheless, three strong candidate susceptibility genes have been described, namely ELAC2 (chromosome 17p11/HPC2 region), 2′-5′-oligoadenylate-dependent ribonuclease L (RNASEL), a gene in the HPC1 region, and Macrophage Scavenger Receptor 1 (MSR1), a gene within a region of linkage on chromosome 8p. Additional studies using larger cohorts are needed to fully evaluate the role of these susceptibility genes in prostate cancer risk. It is also of interest to mention that a significant percentage of men with early-onset prostate cancer harbor germline mutation in the BRCA2 gene thus confirming its role as a high-risk prostate cancer susceptibility gene. Although initial segregation analyses supported the hypothesis that a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, current experimental evidence better supports the hypothesis that some of the familial risks may be due to inheritance of multiple moderate-risk genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants in some of those genes.

Germline BRCA2 mutations and the risk of esophageal squamous cell carcinoma

“…Germline mutations of BRCA2 also contribute to the development of ovarian (Narod, 2002), prostate (Simard et al, 2003) and pancreatic cancers (Lowenfels and Maisonneuve, 2005). Moreover, biallelic BRCA2 mutations cause Fanconi anemia (FA) (Howlett et al, 2002;Offit et al, 2003).…”

ATM polymorphisms as risk factors for prostate cancer development

“…Linkage studies in multiple case families have suggested susceptibility loci on chromosomes 1q24, 1q42, 1p36, 8p22 -23, 17p, 20q13 and Xq (see recent reviews by DeMarzo et al, 2003;Gronberg, 2003) but none have been definitively replicated. As a consequence of these linkage studies, variants in prostate cancer families have been identified in several genes including Macrophage Scavenger Receptor 1(MSR1), 2 0 -5 0 -oligoadenylate-dependent ribonuclease L (RNASEL) and ELAC2 (chromosome 17p11/HPC2 region) (reviewed in Simard et al, 2003), but again none have been reliably associated with risk.Several independent studies have demonstrated that individuals with germline mutations in BRCA2 are at increased risk of prostate cancer (The Breast Cancer Linkage Consortium, 1999;Edwards et al, 2003;Giusti et al, 2003). There is also some evidence for an increased risk in carriers of BRCA1 mutations (Thompson et al, 2002).…”

“…Linkage studies in multiple case families have suggested susceptibility loci on chromosomes 1q24, 1q42, 1p36, 8p22 -23, 17p, 20q13 and Xq (see recent reviews by DeMarzo et al, 2003;Gronberg, 2003) but none have been definitively replicated. As a consequence of these linkage studies, variants in prostate cancer families have been identified in several genes including Macrophage Scavenger Receptor 1(MSR1), 2 0 -5 0 -oligoadenylate-dependent ribonuclease L (RNASEL) and ELAC2 (chromosome 17p11/HPC2 region) (reviewed in Simard et al, 2003), but again none have been reliably associated with risk.…”

Association between estrogen and androgen receptor genes and prostate cancer risk

“…This is in agreement with other studies including a multiethnic cohort study of 1014 cases (19) and another study of 460 cases (20), which did not observe any association between AR CAG repeats and PC risk. Indeed, results regarding the AR CAG repeat polymorphism and association with PC risk have been very contradictory as reviewed by Simard et al (21). Several studies have found an association between short CAG repeats (%20 or 22) and the risk of PC in Caucasian populations (22,23) whereas others have reported a reduced risk of PC associated with short alleles (%22) after an analysis of 1461 and 288 cases respectively (24,25).…”