Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish patients with colorectal cancer: role in presurgical management.
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.
Guillem
Jose G
JG
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. guillemj@mskcc.org
Glogowski
Emily
E
Moore
Harvey G
HG
Nafa
Khedoudja
K
Markowitz
Arnold J
AJ
Shia
Jinru
J
Offit
Kenneth
K
Ellis
Nathan A
NA
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
C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein