Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish patients with colorectal cancer: Role in presurgical management Journal Article


Authors: Guillem, J. G.; Glogowski, E.; Moore, H. G.; Nafa, K.; Markowitz, A. J.; Shia, J.; Offit, K.; Ellis, N. A.
Article 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). SUMMARY BACKGROUND DATA: 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 ≤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. © 2007 Lippincott Williams & Wilkins, Inc.
Keywords: adult; aged; gene mutation; gene sequence; major clinical study; exon; anamnesis; cancer risk; preoperative evaluation; prospective studies; polymerase chain reaction; colorectal cancer; gene frequency; mutational analysis; heterozygote; risk assessment; pedigree; microsatellite instability; dna mismatch repair; family history; amplicon; colon resection; dna sequence; chromatography, high pressure liquid; dna mutational analysis; jews; protein mlh1; protein msh2; colorectal neoplasms, hereditary nonpolyposis; muts homolog 2 protein; open reading frame; denaturing high performance liquid chromatography; heteroduplex analysis; chromatography; europe, eastern
Journal Title: Annals of Surgery
Volume: 245
Issue: 4
ISSN: 0003-4932
Publisher: Lippincott Williams & Wilkins  
Date Published: 2007-04-01
Start Page: 560
End Page: 565
Language: English
DOI: 10.1097/01.sla.0000252589.26244.d4
PUBMED: 17414604
PROVIDER: scopus
PMCID: PMC1877028
DOI/URL:
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 17 November 2011" - "CODEN: ANSUA" - "Source: Scopus"
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MSK Authors
  1. Harvey Moore
    31 Moore
  2. Kenneth Offit
    790 Offit
  3. Arnold J Markowitz
    139 Markowitz
  4. Khedoudja Nafa
    243 Nafa
  5. Nathan A Ellis
    74 Ellis
  6. Jose Guillem
    414 Guillem
  7. Jinru Shia
    720 Shia