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Germline epimutations of APC are not associated with inherited colorectal polyposis
  1. M Hitchins1,
  2. C Suter2,
  3. J Wong3,
  4. K Cheong4,
  5. N Hawkins5,
  6. B Leggett6,
  7. R Scott7,
  8. A Spigelman7,
  9. I Tomlinson8,
  10. D Martin9,
  11. R Ward10
  1. 1Medical Oncology Department, Faculty of Medicine, University of New South Wales, Sydney, Australia
  2. 2Victor Chang Cardiac Research Institute, Sydney, Australia
  3. 3Medical Oncology Department, Faculty of Medicine, University of New South Wales, Sydney, Australia
  4. 4Medical Oncology Department, St Vincent’s Hospital, Sydney, Australia
  5. 5Pathology Department, School of Biomedical Sciences, University of New South Wales, Sydney, Australia
  6. 6University of Queensland, School of Medicine, Brisbane, Australia
  7. 7University of Newcastle and the Hunter Medical Research Institute, Newcastle, Australia
  8. 8Cancer Research UK, London Institute, UK
  9. 9Victor Chang Cardiac Research Institute, Sydney, Australia
  10. 10Medical Oncology Department, St Vincent’s Hospital, Sydney, Australia, and Medical Oncology Department, Faculty of Medicine, University of New South Wales, Sydney, Australia
  1. Correspondence to:
    Professor R Ward
    Medical Oncology Department, St Vincent’s Hospital Sydney, 384 Victoria Street, Darlinghurst, Sydney NSW 2010, Australia; r.ward{at}garvan.unsw.edu.au

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We have recently reported that germline epimutations of the mismatch repair gene, MLH1, produce a clinical phenotype consistent with hereditary non-polyposis colorectal cancer (HNPCC).1MLH1 germline epimutations have now been reported in eight individuals clinically classified as having HNPCC and in whom no sequence mutations of the mismatch repair genes were identified.1–4 These manifest as soma-wide monoallelic hypermethylation of the promoter (in the absence of a sequence mutation within the gene) and cause transcriptional silencing of the epimutant allele.1 These cases provide evidence that germline epimutations represent a novel mechanism for disease, which can mimic that of a genetic mutation by conferring a similar phenotype. We hypothesised that germline epimutations may occur in genes other than MLH1 to cause other cancer prone syndromes apart from HNPCC. The APC gene represented a likely candidate as heterozygous inactivating mutations of APC are strongly associated with colorectal polyposis and cancer, but not all individuals harbour germline sequence mutations. Autosomal dominant familial adenomatous polyposis (FAP) is caused by heterozygous sequence mutations of the APC gene,5 and a recessive form is associated with biallelic mutations of MYH.6 However, no mutations of either gene are identifiable in approximately 20% of cases. Furthermore, somatic methylation of the CpG island encompassing …

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