Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).
BACKGROUND
Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome.


METHODS
Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing.


RESULTS
Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not.


CONCLUSIONS
Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.
Hampel
Heather
H
Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, USA.
Frankel
Wendy L
WL
Martin
Edward
E
Arnold
Mark
M
Khanduja
Karamjit
K
Kuebler
Philip
P
Nakagawa
Hidewaki
H
Sotamaa
Kaisa
K
Prior
Thomas W
TW
Westman
Judith
J
Panescu
Jenny
J
Fix
Dan
D
Lockman
Janet
J
Comeras
Ilene
I
de la Chapelle
Albert
A
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis / Q000379:methods*; D004260:DNA Repair / Q000235:genetics; D004586:Electrophoresis; D005260:Female; D042822:Genomic Instability; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1