Clinical findings with implications for genetic testing in families with clustering of colorectal cancer.
BACKGROUND
Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing.


METHODS
We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families.


RESULTS
Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1.


CONCLUSIONS
Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.
Department of Human Genetics, Leiden University Medical Center, The Netherlands.
J T
JT
Wijnen
H F
HF
Vasen
P M
PM
Khan
A H
AH
Zwinderman
H
H
van der Klift
A
A
Mulder
C
C
Tops
P
P
Møller
R
R
Fodde
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000367:Age Factors; D000368:Aged; D002352:Carrier Proteins; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D016521:Electrophoresis, Gel, Pulsed-Field; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009378:Neoplasms, Multiple Primary / Q000453:epidemiology / Q000235:genetics; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein