Gene polymorphisms

Over the last decade, the explosive advances in sequencing and genotyping technologies fueled by major financial investments in basic science, have evidenced that hundreds of genes harboring variations contribute to human cancers and that genetic variability may influence patients' responses to post-surgical treatments (Hamburg and Collins, N Engl J Med 363(4):301-304, 2010). Several studies have reported the association between one or multiple single nucleotide polymorphisms (SNPs) in multiple pathways linked to prostate cancer onset and progression (Sfanos and De Marzo, Histopathology (1):199-215, 2012). For instance, a SNP (GG genotype) in the promoter region of alpha-1-antichymotrypsin (ACT), an acute-phase protein up-regulated in inflammatory conditions, has been reported as linked to the increased risk of prostate cancer (Licastro et al., Anticancer Res 28:395-399, 2008). Moreover, a correlation between circulating levels of PSA and the ACT GG genotype was reported in younger prostate cancer patients too. ACT is of particular interest because is bound, in men, to most of circulating PSA. As well, the association between increased risk for prostate cancer or aggressive prostate cancer and the IL10-1082GG variant of IL-10 has been recently reported (Zabaleta et al., Carcinogenesis 29:573-578, 2008; Zabaleta et al., Carcinogenesis 30:1358-1362, 2009). In addition, SNPs between multiple different cytokines have been investigated as a potential source of increased risk of prostate cancer (Zabaleta et al., Carcinogenesis 29:573-578, 2008; Zabaleta et al., Carcinogenesis 30:1358-1362, 2009; Kwon et al., Cancer Epidemiol Biomarkers Prev 20:923-933, 2011). 143 SNPs in 16 inflammation-related genes [CXC ligand 12 (CXCL12), IL-4, IL-6, IL-6ST, prostaglandin-endoperoxide synthase 2 (PTGS2), signal transducer and activator of transcription 3 (STAT3), TNF, protein kinase B (AKT1), CXCR4, IL-6R, IL-8, IL-10, nuclear factor kappa B (NFκb), phosphatidylinositol 3-kinase (PIK3)R1, PTGS1 and vascular endothelial growth factor (VEGF)] have been examined in a case-control study of African American versus Caucasian men (Kwon et al., Cancer Epidemiol Biomarkers Prev 20:923-933, 2011). SNPs in IL-4, IL-6ST, PTGS2 and STAT3 resulted independently associated with prostate cancer susceptibility, while SNPs in AKT1, PIK3R1 and STAT3 were associated with aggressive prostate cancer. Overall, men carrying multiple 'high-risk' alleles have been found at an elevated risk for prostate cancer development. These studies strongly support the importance of inflammatory pathways in conferring prostate cancer risk. A multitude of emerging findings support the increasing efforts of the scientific community to look at the molecular background of prostate cancer as the key brick to develop new therapies targeted to the patient, for its molecularly unique tumor. Obviously, the ultimate goal of this exciting line of research will be to develop genetic tests readily and safely transferable to clinical use for the diagnosis and prediction of patients' responses to therapy. The way to reach this objective is sprinkled by many obstacles. We are still unaware of the real clinical significance of several genetic markers and the available data concerning the side-effects of the existing gene-based therapies are far away to be conclusive. Nevertheless, the endlessly mounting reports on this topic are very encouraging, for their promising relevance in prostate cancer patients therapeutic management. ©