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A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Mark Clendenning
  • Leigha Senter
  • Heather Hampel
  • Kristina Lagerstedt Robinson
  • Shuying Sun
  • Daniel Buchanan
  • Michael D Walsh
  • Nilbert, Mef Christina
  • Jane S Green
  • John Potter
  • Annika Lindblom
  • Albert de la Chapelle
BACKGROUND: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. METHODS: Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis. RESULTS: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n=61). These individuals all display the rare allele (population frequency < 0.05) at a SNP in exon 11, and have been shown to possess a short common haplotype; allowing us to calculate that the mutation arose around 1625 years ago (65 generations; 95% CI: [22, 120]). DISCUSSION: Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are >10,000 carriers of this mutation in the United States alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families would suggest that this is a prevalent mutation with reduced penetrance.
OriginalsprogEngelsk
TidsskriftJournal of Medical Genetics
Vol/bind45
Sider (fra-til)340-45
ISSN0022-2593
DOI
StatusUdgivet - 2008

ID: 40183256