title: Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability.
abstract: Hereditary non-polyposis colorectal cancer (HNPCC) is caused by mutations in one of the mismatch repair genes MLH1, MSH2, MSH6, or PMS2 and results in high-level microsatellite instability (MSI-high) in tumours of HNPCC patients. The MSI test is considered reliable for indicating mutations in MLH1 and MSH2, but is questioned for MSH6. Germline mutation analysis was performed in 19 patients with an MSI-high tumour and absence of MSH2 and/or MSH6 protein as determined by immunohistochemistry (IHC), without an MLH1 or MSH2 mutation, and in 76 out of 295 patients suspected of HNPCC, with a non-MSI-high colorectal cancer (CRC). All 295 non-MSI-high CRCs were analysed for presence of MSH6 protein by IHC. In 10 patients with an MSI-high tumour without MSH2 and/or MSH6 expression, a pathogenic MSH6 mutation was detected, whereas no pathogenic MSH6 mutation was detected in 76 patients with a non-MSI-high CRC and normal MSH6 protein expression. In none of the 295 CRCs loss of MSH6 protein expression was detected. The prevalence of a germline MSH6 mutation is very low in HNPCC suspected patients with non-MSI-high CRC. Microsatellite instability analysis in CRCs is highly sensitive to select patients for MSH6 germline mutation analysis.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 849 Human Genetics, PO Box 9101, 6500 HB Nijmegen, The Netherlands. m.kets@antrg.umcn.nl
authors.forename: C M
authors.initials: CM
authors.lastname: Kets
authors.forename: J H J M
authors.initials: JH
authors.lastname: van Krieken
authors.forename: K M
authors.initials: KM
authors.lastname: Hebeda
authors.forename: S J
authors.initials: SJ
authors.lastname: Wezenberg
authors.forename: M
authors.initials: M
authors.lastname: Goossens
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
authors.forename: M J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: N
authors.initials: N
authors.lastname: Hoogerbrugge
mesh_terms: D000328:Adult; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics; D015995:Prevalence
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein