Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array.
Al Olama, AA
MetadataShow full item record
Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.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. 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.Single SNP analyses identified only the previously reported association with RAD51B. 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. 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.MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
UK Genetic Prostate Cancer Study Collaborators
UK ProtecT Study Collaborators
Genetic Predisposition to Disease
DNA Repair Enzymes
Cell Cycle Proteins
Polymorphism, Single Nucleotide
Genome-Wide Association Study
License start date
British journal of cancer, 2016, 114 (8), pp. 945 - 952
Showing items related by title, author, creator and subject.
Open-label, multicentre, randomised, phase II study of the EpSSG and the ITCC evaluating the addition of bevacizumab to chemotherapy in childhood and adolescent patients with metastatic soft tissue sarcoma (the BERNIE study). Chisholm, JC; Merks, JHM; Casanova, M; Bisogno, G; Orbach, D; Gentet, J-C; Thomassin-Defachelles, A-S; Chastagner, P; Lowis, S; Ronghe, M; McHugh, K; van Rijn, RR; Hilton, M; Bachir, J; Fürst-Recktenwald, S; Geoerger, B; Oberlin, O; European paediatric Soft tissue sarcoma Study Group (EpSSG) and the European Innovative Therapies for Children with Cancer (ITCC) ConsortiumPURPOSE: We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). PATIENTS AND ...
Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Kieran, MW; Chisholm, J; Casanova, M; Brandes, AA; Aerts, I; Bouffet, E; Bailey, S; Leary, S; MacDonald, TJ; Mechinaud, F; Cohen, KJ; Riccardi, R; Mason, W; Hargrave, D; Kalambakas, S; Deshpande, P; Tai, F; Hurh, E; Geoerger, B (2017-10-19)Background: Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase ...
A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial. Battersby, NJ; Dattani, M; Rao, S; Cunningham, D; Tait, D; Adams, R; Moran, BJ; Khakoo, S; Tekkis, P; Rasheed, S; Mirnezami, A; Quirke, P; West, NP; Nagtegaal, I; Chong, I; Sadanandam, A; Valeri, N; Thomas, K; Frost, M; Brown, G (2017-08-29)BACKGROUND: Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative ...