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Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3
  1. Anthony R Dallosso (paard{at}bristol.ac.uk)
  1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
    1. Sunil Dolwani (sunil.dolwani{at}cardiffandvale.wales.nhs.uk)
    1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
      1. Natalie Jones (jonesn2{at}cardiff.ac.uk)
      1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
        1. Sian Jones (joness88{at}jhmi.edu)
        1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
          1. James Colley (colleyjp{at}cardiff.ac.uk)
          1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
            1. Julie Maynard (maynardjh{at}cardiff.ac.uk)
            1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
              1. Shelley Idziaszczyk (idziaszczyksa1{at}cardiff.ac.uk)
              1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
                1. Vikki Humphreys (humphreysvl{at}cardiff.ac.uk)
                1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
                  1. Julie Arnold (juliea{at}adhb.govt.nz)
                  1. Department of Clinical Genetics, Auckland City Hospital, New Zealand
                    1. Alan Donaldson (alan.donaldson{at}ubht.nhs.uk)
                    1. Bristol Clinical Genetics Unit, Institute of Child Health, St Michael's Hospital, United Kingdom
                      1. Diana Eccles (d.m.eccles{at}soton.ac.uk)
                      1. Wessex Clinical Genetics Service, Princess Anne Hospital, United Kingdom
                        1. Anthony Ellis (a.ellis{at}liv.ac.uk)
                        1. Department of Gastroenterology, Royal Liverpool Hospital, United Kingdom
                          1. D. Gareth Evans (gareth.evans{at}cmmc.nhs.uk)
                          1. Academic Unit of Medical Genetics, St Mary's Hospital, Manchester, United Kingdom
                            1. Ian M. Frayling (ian.frayling{at}cardiffandvale.wales.nhs.uk)
                            1. All-Wales Laboratory Genetics Service, University Hospital of Wales, Cardiff, United Kingdom
                              1. Frederik J. Hes (f.j.hes{at}lumc.nl)
                              1. Centre of Human and Clinical Genetics, Leiden University Medical Centre, Leiden, Netherlands
                                1. Richard S. Houlston (r.houlston{at}icr.ac.uk)
                                1. Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom
                                  1. Eamonn R. Maher (e.r.maher{at}bham.ac.uk)
                                  1. Section of Medical and Molecular Genetics, University of Birmingham, Birmingham, United Kingdom
                                    1. Maartje Nielsen (m.nielsen{at}lumc.nl)
                                    1. Centre of Human and Clinical Genetics, Leiden University Medical Centre, Leiden, Netherlands
                                      1. Susan Parry (sparry{at}adhb.govt.nz)
                                      1. Department of Clinical Genetics, Auckland City Hospital, Auckland, New Zealand
                                        1. Emma Tyler (emma.tyler{at}suht.swest.nhs.uk)
                                        1. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
                                          1. Valentina Moskvina (mostkvinav1{at}cardiff.ac.uk)
                                          1. Biostatistics and Bioinformatics Unit, School of Medicine, Cardiff University, United Kingdom
                                            1. Jeremy P. Cheadle (cheadlejp{at}cardiff.ac.uk)
                                            1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
                                              1. Julian R. Sampson (sampson{at}cardiff.ac.uk)
                                              1. Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom

                                                Abstract

                                                Background: MUTYH associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage.

                                                Objectives: To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype.

                                                Methods: Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. We also characterised these variants in ~ 300 population controls.

                                                Results: Thirty three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (i.e. carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified of which 4 were novel. MAP cases had significantly more adenomas than non-MAP cases (P=0.0009; Exact test for trends in proportions) and presented earlier (P=0.013; ANOVA). Twenty four protein altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls and no variants were significantly over (or under-) represented in cases.

                                                Conclusion: Multiple rare alleles of MUTYH are associated with autosomal recessive MUTYH Associated Polyposis (MAP) whilst OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.

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