title: Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes.
abstract: OBJECTIVE
  Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes.
  
  
  METHODS
  Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLH1, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel.
  
  
  RESULTS
  The National Cancer Institute five-marker panel system scored 31 (29%) as (NCI)MSI-High, 13 (12%) as (NCI)MSI-Low, and 63 (59%) as (NCI)MS-Stable. The 10-marker panel classified 18 (17%) as (10)MSI-High, 17 (16%) as (10)MSI-Low, and 72 (67%) as (10)MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all (10)MSI-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored (10)MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored (10)MSI-High).
  
  
  CONCLUSIONS
  In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Leeanne J
authors.initials: LJ
authors.lastname: Mead
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Simon G
authors.initials: SG
authors.lastname: Royce
authors.forename: Letitia
authors.initials: L
authors.lastname: Smith
authors.forename: D James B
authors.initials: DJ
authors.lastname: St John
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000293:Adolescent; D000328:Adult; D015179:Colorectal Neoplasms / Q000175:diagnosis*; D053843:DNA Mismatch Repair; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D042241:Early Diagnosis; D005260:Female; D005819:Genetic Markers; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats
chemical_list: D005819:Genetic Markers; D045643:DNA Repair Enzymes