title: Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish patients with colorectal cancer: role in presurgical management.
abstract: OBJECTIVE
  This study summarizes our initial experience with prospective, single-amplicon (mutation-specific) A636P testing in Ashkenazi Jewish patients at risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC).
  
  
  BACKGROUND
  We previously described a founder mutation, MSH2*1906G >C (A636P) that causes HNPCC in 8/1345 (0.59%) of Ashkenazim with colorectal cancer. The mutation was more common in Ashkenazim diagnosed at <or=40 years (7%).
  
  
  METHODS
  Twenty-seven Ashkenazi probands at risk for HNPCC were ascertained. Single-amplicon A636P testing was performed on 21 by polymerase chain reaction of exon 12 of MSH2, followed by direct DNA sequencing. Mutational analysis of the entire open reading frame of MLH1 and MSH2 was performed on 7 by PCR of each exon, followed by heteroduplex analysis using denaturing high-performance liquid chromatography and direct sequencing of exons with variant chromatographs. One patient received both studies,
  
  
  RESULTS
  The A636P mutation was detected in 3/21 (14%) prospectively evaluated patients using single amplicon testing. In 6 patients, the entire open reading frame of MLH1 and MSH2 was analyzed, and 1 additional A636P carrier and 2 carriers of previously unrecognized mutations were identified. The A636P mutation was present in 2 patients who met Amsterdam criteria and in 2 patients who did not.
  
  
  CONCLUSIONS
  Although rare in the general population, A636P mutations are found at increased frequency in Ashkenazim with a personal or family history of colorectal or other HNPCC-associated cancers. This inexpensive and rapid approach may be useful preoperatively in helping determine the extent of colon resection for a subset of patients.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. guillemj@mskcc.org
authors.forename: Jose G
authors.initials: JG
authors.lastname: Guillem
authors.forename: Emily
authors.initials: E
authors.lastname: Glogowski
authors.forename: Harvey G
authors.initials: HG
authors.lastname: Moore
authors.forename: Khedoudja
authors.initials: K
authors.lastname: Nafa
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Markowitz
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Ellis
mesh_terms: D000328:Adult; D002851:Chromatography, High Pressure Liquid; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000208:ethnology* / Q000235:genetics* / Q000601:surgery; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D005061:Europe, Eastern; D005260:Female; D006801:Humans; D007585:Jews; D008297:Male; D053842:Microsatellite Instability; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D010375:Pedigree; D011446:Prospective Studies
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein