Analyses were performed at single variant, gene and pathway levels to maximise the power to detect putative associations with lower frequency variants or those with modest effect sizes. In this study, using data from the iCOGS project imputed to the 1000 Genomes Phase 3 reference panel, we have analysed a large panel of DNA-repair gene variants for 21 780 PrCa cases and 21 727 controls of European ancestry from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) Consortium ( Eeles et al, 2013). In spite of these discoveries, the majority of the excess familial risk of PrCa still remains to be explained ( Attard et al, 2015), with the contribution of DNA-repair gene variants identified to date making them attractive candidates for further investigation. Recently, increasing evidence has demonstrated that these germline DNA-repair gene mutation carriers are at increased likelihood of experiencing advanced disease, metastatic spread and poorer survival outcome yet these mutations also hold promise as potentially clinically actionable and responsive to targeted treatments ( Castro et al, 2013 Cybulski et al, 2013 Leongamornlert et al, 2014 Robinson et al, 2015). In addition, rare germline mutations in a small number of genes have been reported, with varying degrees of evidence, as potentially conferring greater risks of PrCa, including the DNA-repair genes ATM, BRCA1, BRCA2, BRIP1, CHEK2 and NBN ( Dong et al, 2003 Kote-Jarai et al, 2009, 2011 Leongamornlert et al, 2012, 2014 Robinson et al, 2015). This is consistent with observations from genome-wide association studies (GWAS), which have to date identified >100 low-penetrance susceptibility variants for PrCa, two of which implicate the DNA-repair genes RAD51B and RAD23B ( Xu et al, 2012 Al Olama et al, 2014 Eeles et al, 2014 Amin Al Olama et al, 2015). The heritability of PrCa is believed to be the highest of all the common forms of cancer ( Hjelmborg et al, 2014). In conjunction with the establishment of improved biomarkers for lethal PrCa, the identification of individuals at greater risk of developing prostate tumours that require clinical intervention would also help inform more targeted and appropriate application of treatment.
However, as the majority of prostate neoplasms develop extremely slowly, many do not require clinical intervention, which coupled with the low specificity of the prostate-specific antigen test for clinically relevant forms of the disease could potentially lead to considerable over-diagnosis and overtreatment of patients for relatively modest reductions in mortality ( Ilic et al, 2013). Prostate Cancer (PrCa) is the most frequently diagnosed cancer among men in developed countries and despite high survival rates also one of the highest for mortality ( Cancer Research UK, 2014 Quaresma et al, 2015). MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers. MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Single SNP analyses identified only the previously reported association with RAD51B.
We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. The PRACTICAL Consortium Australian Prostate Cancer BioResource,īritish Journal of Cancer volume 114, pages 945–952 ( 2016) Cite this article.The UK Genetic Prostate Cancer Study Collaborators,.Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array
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